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Title:
METHOD FOR TREATING CROHN'S DISEASE
Document Type and Number:
WIPO Patent Application WO/2017/087735
Kind Code:
A1
Abstract:
The present invention provides methods for treating Crohn's Disease in an individual. The invention further provides methods for determining if an individual suffering from Crohn's Disease is likely to respond favorably or experience an enhanced treatment effect in response to treatment with vedolizumab. In some embodiments, the methods comprise determining the presence of polymorphisms in the in the TraB Domain Containing 2B (TRABD2B) gene and/or the Phosducin (PDC) gene and/or the Neuropeptide Y (NPY) gene and/or the One Cut Homeobox 1 (ONECUT1) gene and/or the Discs, Large Homolog 4 (DLG4) gene and/or the Claudin 7 (CLDN7) gene and/or the Elongator Acetyltranferase Complex Subunit 5 (ELP5) gene.

Inventors:
ZHU, Yonghong (Inc.One Takeda Parkwa, Deerfield Illinois, 60015, US)
LAI, Eric (Inc.One Takeda Parkwa, Deerfield Illinois, 60015, US)
Application Number:
US2016/062651
Publication Date:
May 26, 2017
Filing Date:
November 18, 2016
Export Citation:
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Assignee:
MILLENNIUM PHARMACEUTICALS, INC. (40 Landsdowne Street, Cambridge, Massachusetts, 02139, US)
International Classes:
A61K39/395; A61P1/04; C12Q1/68; G06F19/20
Domestic Patent References:
WO2015134585A12015-09-11
WO2015153629A12015-10-08
WO2011088306A12011-07-21
WO2003066897A22003-08-14
Foreign References:
US20120282249A12012-11-08
US20130136720A12013-05-30
US20130012602A12013-01-10
US20040241823A12004-12-02
Other References:
XU ET AL.: "Psychometric Precision In Phenotype Definition Is A Useful Step In Molecular Genetic Investigation Of Psychiatric Disorders.", TRANSLATIONAL PSYCHIATRY., vol. 5, 30 June 2015 (2015-06-30), pages 1 - 8, XP055383177
SRIVASTAVA ET AL.: "Genetics Of Human Age Related Disorders.", ADVANCES IN GERONTOLOGY., vol. 28, January 2015 (2015-01-01), pages 228 - 247
EL-SALHY ET AL.: "The Role Of The Neuropeptide Y (NPY) Family In The Pathophysiology Of Inflammatory Bowel Disease.", NEUROPEPTIDES., vol. 55, 25 September 2015 (2015-09-25), pages 137 - 144, XP029417822
SANDBORN ET AL.: "Vedolizumab As Induction And Maintenance Therapy For Crohn's Disease.", THE NEW ENGLAND JOURNAL OF MEDICINE., vol. 369, no. 8, 22 August 2013 (2013-08-22), pages 711 - 721, XP055245598
Attorney, Agent or Firm:
SCHORR, Kristel et al. (FOLEY & LARDNER LLP, 3000 K Street NW Suite 60, Washington District of Columbia, 20007-5109, US)
Download PDF:
Claims:
WHAT IS CLAIMED IS: 1. A method for treating Crohn’s Disease in an individual, comprising administering vedolizumab to an individual identified as (i) TRABD2B variant positive, (ii) PDC variant positive, (iii) NPY variant positive, (iv) ONECUT1 variant positive, (v) DLG4 variant positive, (vi) CLDN7 variant positive, (vii) ELP5 variant positive, or (viii) any combination of these. 2. The method of claim 1, wherein the treating comprises remission of Crohn’s Disease. 3. The method of claim 1, wherein the individual is heterozygous for the TRABD2B variant and/or the PDC variant and/or the NPY variant and/or the ONECUT1 variant and/or the DLG4 variant and/or the CLDN7 variant and/or the ELP5 variant. 4. The method of claim 1, wherein the individual is homozygous for the TRABD2B variant and/or the PDC variant and/or the NPY variant and/or the ONECUT1 variant and/or the DLG4 variant and/or the CLDN7 variant and/or the ELP5 variant. 5. The method of claim 1, wherein the TRABD2B variant is selected from the group consisting of rs7543124, rs6671927, rs12134443, rs11211624, rs2088361, rs1556981, rs11205430, rs1561573, rs11211613, rs12061891, rs11211632, rs17103939, rs6684538, and combinations thereof. 6. The method of claim 1, wherein the PDC variant is selected from the group consisting of rs1882926, rs11801527, rs12407957, rs10798041, and combinations thereof. 7. The method of claim 1, wherein the NPY variant is selected from the group consisting of rs16141, rs3779477, rs16129, and combinations thereof. 8. The method of claim 1, wherein the ONECUT1 variant is selected from the group consisting of rs2440335, rs2440332, rs1899750, rs7180600, rs2456507, rs2456525, and combinations thereof.

9. The method of claim 1, wherein the DLG4 variant is selected from the group consisting of rs17203281, rs3826408, rs1875673, rs739669, rs2017365, rs929229, and combinations thereof. 10. The method of claim 1, wherein the CLDN7 variant and/or ELP5 variant is rs2106842, exm1286317, rs2074217, rs222843, and combinations thereof. 11. The method of claim 1, wherein the individual is identified as TRABD2B variant positive. 12. The method of claim 11, wherein the individual has rs1556981, rs2088361, rs1561573, and rs6671927 variants. 13. The method of claim 11, wherein the individual has rs1556981, rs2088361, rs1561573, rs6671927, and rs11205430 variants. 14. The method of claim 11, wherein the individual has rs1561573, rs11211613, rs12061891, rs11211632, and rs11205430. 15. The method of claim 1, wherein the individual is identified as TRABD2B variant positive, PDC variant positive, NPY variant positive, ONECUT1 variant positive, CLDN7 variant positive, and ELP5 variant positive. 16. The method of claim 14, wherein the individual has rs7543124, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs1899750, and rs2106842 variants. 17. The method of claim 1, wherein the individual is identified as TRABD2B variant positive, PDC variant positive, NPY variant positive, ONECUT1 variant positive, DLG4 variant positive, CLDN7 variant positive, and ELP5 variant positive.

18. The method of claim 17, wherein the individual has rs7543124, rs6671927, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs2440335, rs1899750, rs1875673, and rs2106842 variants. 19. A method for determining the likelihood that an individual suffering from

Crohn’s Disease will experience an enhanced treatment effect when treated with vedolizumab comprising: (i) assaying a biological sample obtained from an individual for the presence or absence of a TRABD2B variant and/or a PDC variant and/or a NPY variant and/or a ONECUT1 variant and/or a DLG4 variant and/or a CLDN7 variant and/or a ELP5 variant and (ii) detecting the presence of the TRABD2B variant and/or the PDC variant and/or the NPY variant and/or the ONECUT1 variant and/or the DLG4 variant and/or the CLDN7 variant and/or the ELP5 variant, wherein the presence of the TRABD2B variant and/or the PDC variant and/or the NPY variant and/or the ONECUT1 variant and/or the DLG4 variant and/or the CLDN7 variant and/or the ELP5 variant indicates an increased likelihood that the individual will experience an enhanced treatment effect. 20. The method of claim 19, wherein the individual is heterozygous for the TRABD2B variant and/or the PDC variant and/or the NPY variant and/or the ONECUT1 variant and/or the DLG4 variant and/or the CLDN7 variant and/or the ELP5 variant. 21. The method of claim 19, wherein the individual is homozygous for the TRABD2B variant and/or the PDC variant and/or the NPY variant and/or the ONECUT1 variant and/or the DLG4 variant and/or the CLDN7 variant and/or the ELP5 variant. 22. The method of claim 19, wherein the TRABD2B variant is selected from the group consisting of rs7543124, rs6671927, rs12134443, rs11211624, rs2088361, rs1556981, rs11205430, rs1561573, rs11211613, rs12061891, rs11211632, rs17103939, rs6684538, and combinations thereof. 23. The method of claim 19, wherein the PDC variant is selected from the group consisting of rs1882926, rs11801527, rs12407957 rs10798041 and combinations thereof.

24. The method of claim 19, wherein the NPY variant is selected from the group consisting of rs16141, rs3779477, rs16129 and combinations thereof. 25. The method of claim 19, wherein the ONECUT1 variant is selected from the group consisting of rs2440335, rs2440332, rs1899750, rs7180600, rs2456507, rs2456525, and combinations thereof. 26. The method of claim 19, wherein the DLG4 variant is selected from the group consisting of rs17203281, rs3826408, rs1875673,rs739669, rs2017365, rs929229 and combinations thereof. 27. The method of claim 19, wherein the CLDN7 variant and/or ELP5 variant is rs2106842, exm1286317, rs2074217, rs222843, and combinations thereof. 28. The method of claim 19, comprising detecting the presence of the TRABD2B variant. 29. The method of claim 28, comprising detecting the presence of rs1556981, rs2088361, rs1561573, and rs6671927 variants. 30. The method of claim 28, comprising detecting the presence of rs1556981, rs2088361, rs1561573, rs6671927, and rs11205430 variants. 31. The method of claim 28, comprising detecting the presence of rs1561573, rs11211613, rs12061891, rs11211632, and rs11205430. 32. The method of claim 19, comprising detecting the presence of the TRABD2B variant, the PDC variant, the NPY variant, the ONECUT1 variant, CLDN7 variant, and the ELP5 variant. 33. The method of claim 31, comprising detecting the presence of rs7543124, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs1899750, and rs2106842 variants.

34. The method of claim 19, comprising detecting the presence of the TRABD2B variant, the PDC variant, the NPY variant the ONECUT1 variant, the DLG4 variant, the CLDN7 variant, and the ELP5 variant. 35. The method of claim 34, comprising detecting the presence of rs7543124, rs6671927, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs2440335, rs1899750, rs1875673, and rs2106842 variants. 36. A method for determining the likelihood that an individual suffering from

Crohn’s Disease will respond favorably to treatment with vedolizumab comprising: (i) assaying a biological sample obtained from an individual for the presence or absence of a TRABD2B variant and/or a PDC variant and/or a NPY variant and/or a ONECUT1 variant and/or a DLG4 variant and/or a CLDN7 variant and/or a ELP5 variant and (ii) detecting the presence of the TRABD2B variant and/or the PDC variant and/or the NPY variant and/or the ONECUT1 variant and/or the DLG4 variant and/or the CLDN7 variant and/or the ELP5 variant, wherein the presence of the TRABD2B variant and/or the PDC variant and/or the NPY variant and/or the ONECUT1 variant and/or the DLG4 variant and/or the CLDN7 variant and/or the ELP5 variant indicates an increased likelihood that the individual will respond favorably to vedolizumab. 37. The method of claim 36, wherein the individual is heterozygous for the TRABD2B variant and/or the PDC variant and/or the NPY variant and/or the ONECUT1 variant and/or the DLG4 variant and/or the CLDN7 variant and/or the ELP5 variant. 38. The method of claim 36, wherein the individual is homozygous for the TRABD2B variant and/or the PDC variant and/or the NPY variant and/or the ONECUT1 variant and/or the DLG4 variant and/or the CLDN7 variant and/or the ELP5 variant. 39. The method of claim 36, wherein the TRABD2B variant is selected from the group consisting of rs7543124, rs6671927, rs12134443, rs11211624, rs2088361, rs1556981, rs11205430, rs1561573, rs11211613, rs12061891, rs11211632, rs17103939, rs6684538, and combinations thereof.

40. The method of claim 36, wherein the PDC variant is selected from the group consisting of rs1882926, rs11801527, rs12407957, rs10798041, and combinations thereof. 41. The method of claim 36, wherein the NPY variant is selected from the group consisting of rs16141, rs3779477, rs16129, and combinations thereof. 42. The method of claim 36, wherein the ONECUT1 variant is selected from the group consisting of rs2440335, rs2440332, rs1899750, rs7180600, rs2456507, rs2456525, and combinations thereof. 43. The method of claim 36, wherein the DLG4 variant is selected from the group consisting of rs17203281, rs3826408, rs1875673, rs739669, rs2017365, rs929229, and combinations thereof. 44. The method of claim 36, wherein the CLDN7 variant or ELP5 variant is rs2106842, exm1286317, rs2074217, rs222843, and combinations thereof. 45. The method of claim 36, comprising detecting the presence of the TRABD2B variant. 46. The method of claim 45, comprising detecting the presence of rs1556981, rs2088361, rs1561573, and rs6671927 variants. 47. The method of claim 45, comprising detecting the presence of rs1556981, rs2088361, rs1561573, rs6671927, and rs11205430 variants. 48. The method of claim 45, comprising detecting the presence of rs1561573, rs11211613, rs12061891, rs11211632, and rs11205430. 49. The method of claim 36, comprising detecting the presence of the TRABD2B variant, the PDC variant, the NPY variant, the ONECUT1 variant, CLDN7 variant, and the ELP5 variant.

50. The method of claim 49, comprising detecting the presence of rs7543124, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs1899750, and rs2106842 variants. 51. The method of claim 36, comprising detecting the presence of the TRABD2B variant, the PDC variant, the NPY variant, the ONECUT1 variant, the DLG4 variant, the CLDN7 variant, and the ELP5 variant. 52. The method of claim 51, comprising detecting the presence of rs7543124, rs6671927, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs2440335, rs1899750, rs1875673, and rs2106842 variants. 53. A kit comprising: (i) at least one pair of primers that specifically hybridizes to a genetic variant independently selected from the group consisting of rs1556981, rs2088361, rs1561573, and rs6671927, and (ii) a detectably labeled probe that hybridizes to the genetic variant. 54. The kit of claim 53, wherein the kit comprises: a pair of primers that specifically hybridizes to rs1556981; a pair of primers that specifically hybridizes to rs2088361; a pair of primers that specifically hybridizes to rs1561573; and a pair of primers that specifically hybridizes to rs6671927. 55. The kit of claim 53, wherein the kit further comprises a pair of primers that specifically hybridizes to rs11205430. 56. A kit comprising: (i) at least one pair of primers that specifically hybridizes to a genetic variant independently selected from the group consisting of rs1561573, rs11211613, rs12061891, rs11211632, and rs11205430, and (ii) a detectably labeled probe that hybridizes to the genetic variant. 57. A kit comprising: (i) at least one pair of primers that specifically hybridizes to a genetic variant independently selected from the group consisting of rs7543124, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs1899750, and rs2106842, and (ii) a detectably labeled probe that hybridizes to the genetic variant. 58. A kit comprising: (i) at least one pair of primers that specifically hybridizes to a genetic variant independently selected from the group consisting of rs7543124, rs6671927, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs2440335, rs1899750, rs1875673, and rs2106842, and (ii) a detectably labeled probe that hybridizes to the genetic variant. 59. α4β7 integrin antagonist for use in the treatment of a subject with Crohn’s Disease, wherein the subject has been selected for treatment with said antagonist by having determined the presence or absence of at least one single nucleotide polymorphism in the TRABD2B genomic locus in a sample having been obtained from said subject, wherein said determined presence or absence of the at least one single nucleotide polymorphism in the TRABD2B genomic locus is predictive for the subject’s treatment response to said α4β7 integrin antagonist. 60. α4β7 integrin antagonist for the use according to claim 59, wherein the α4β7 integrin antagonist is vedolizumab. 61. α4β7 integrin antagonist for the use according to any one of claims 59 to 60, wherein the at least one single nucleotide polymorphism in the TRABD2B genomic locus is selected from the group consisting of rs7543124, rs6671927, rs12134443, rs11211624, rs2088361, rs1556981, rs11205430, rs1561573, rs11211613, rs12061891, rs11211632, rs17103939 and rs6684538. 62. α4β7 integrin antagonist for the use according to any one of claims 59 to 61, wherein the presence or absence of the single nucleotide polymorphisms rs2088361 and rs1556981 has been determined.

63. α4β7 integrin antagonist for the use according to claim 62, wherein the absence of the single nucleotide polymorphisms rs2088361 and rs1556981 is predictive for the subject’s treatment response to said α4β7 integrin antagonist. 64. α4β7 integrin antagonist for the use according to any one of claims 59 to 63, wherein the presence or absence of the single nucleotide polymorphisms rs6671927, rs2088361, rs1556981 and rs1561573 has been determined. 65. α4β7 integrin antagonist for the use according to claim 64, wherein the absence of the single nucleotide polymorphisms rs6671927, rs2088361 and rs1556981 and the presence of the single nucleotide polymorphism rs1561573 is predictive for the subject’s treatment response to said α4β7 integrin antagonist. 66. α4β7 integrin antagonist for the use according to claim 65, wherein the subject has been selected for treatment with the α4β7 integrin antagonist with the following formula: Scorei = (0.32 * rs1561573)– (0.4502 * rs6671927)– (0.6524 * rs2088361)– (0.8948 * rs1556981),

wherein the value for rs1561573, rs6671927, rs2088361 and rs1556981, respectively, is 2 if the single nucleotide polymorphism is present in both alleles, 1 if the single nucleotide polymorphism is present in one alleles, and 0 if the single nucleotide polymorphism is not present and wherein a subject having a score of more than

-1.4350 has been selected for treatment with said α4β7 integrin antagonist. 67. α4β7 integrin antagonist for the use according to any one of claims 59 to 63, wherein the presence or absence of the single nucleotide polymorphisms rs6671927, rs2088361, rs1556981, rs11205430 and rs1561573 has been determined. 68. α4β7 integrin antagonist for the use according to claim 67, wherein the absence of the single nucleotide polymorphisms rs6671927, rs2088361, rs1556981 and rs11205430 and the presence of the single nucleotide polymorphism rs1561573 is predictive for the subject’s treatment response to said α4β7 integrin antagonist

69. α4β7 integrin antagonist for the use according to claim 68, wherein the subject has been selected for treatment with the α4β7 integrin antagonist with the following formula: Scorei = (0.2738 * rs1561573)– (0.3913 * rs6671927)– (0.5404 * rs2088361)– (0.7396 * rs1556981)– (0.1912 * rs11205430),

wherein the value for rs1561573, rs6671927, rs2088361, rs1556981 and rs11205430, respectively, is 2 if the single nucleotide polymorphism is present in both alleles, 1 if the single nucleotide polymorphism is present in one allele, and 0 if the single nucleotide polymorphism is not present and wherein a subject having a score of more than -1.3896 has been selected for treatment with said α4β7 integrin antagonist. 70. α4β7 integrin antagonist for the use according to any one of claims 59 to 61, wherein the presence or absence of the single nucleotide polymorphisms rs11205430, rs1561573, rs11211613, rs12061891, rs11211632 has been determined. 71. α4β7 integrin antagonist for the use according to claim 70, wherein the absence of the single nucleotide polymorphisms rs11211613, rs12061891, rs11211632 and rs11205430 and the presence of the single nucleotide polymorphism rs1561573 is predictive for the subject’s treatment response to said α4β7 integrin antagonist. 72. α4β7 integrin antagonist for the use according to claim 71, wherein the subject has been selected for treatment with the α4β7 integrin antagonist with the following formula: Scorei = (0.2865 * rs1561573)– (0.3678 * rs11211613)– (1.0079 * rs12061891)– (0.5831 * rs11211632)– (0.2351 * rs11205430),

wherein the value for rs1561573, rs11211613, rs12061891, rs11211632 and rs11205430, respectively, is 2 if the single nucleotide polymorphism is present in both alleles, 1 if the single nucleotide polymorphism is present in one allele, and 0 if the single nucleotide polymorphism is not present and wherein a subject having a score of more than -1.5910 has been selected for treatment with said α4β7 integrin antagonist.

73. α4β7 integrin antagonist for the use according to any one of claims 59 to 61, wherein additionally the presence or absence of at least one single nucleotide polymorphism in at least one genomic locus selected from the group consisting of PDC, NPY, ONECUT1, DLG4 and ELP5 has been determined. 74. α4β7 integrin antagonist for the use according claim 73, wherein the presence or absence of at least one single nucleotide polymorphism in each of the genomic loci of PDC, NPY, ONECUT1, DLG4 and ELP5 has been determined. 75. α4β7 integrin antagonist for the use according to claim 73 or 74, wherein the single nucleotide polymorphism in the PDC genomic locus is selected from the group consisting of rs1882926, rs11801527, rs12407957, and rs10798041. 76. α4β7 integrin antagonist for the use according to claim 73 or 74, wherein the single nucleotide polymorphism in the NPY genomic locus is selected from the group consisting of rs16141, rs3779477, and rs16129. 77. α4β7 integrin antagonist for the use according to claim 73 or 74, wherein the single nucleotide polymorphism in the ONECUT1 genomic locus is selected from the group consisting of rs2440335, rs2440332, rs1899750, rs7180600, rs2456507, and rs2456525. 78. α4β7 integrin antagonist for the use according to claim 73 or 74, wherein the single nucleotide polymorphism in the DLG4 genomic locus is selected from the group consisting of rs17203281, rs3826408, rs1875673, rs739669, rs2017365, and rs929229. 79. α4β7 integrin antagonist for the use according to claim 73 or 74, wherein the single nucleotide polymorphism in the ELP5 genomic locus is selected from the group consisting of rs2106842, exm1286317, rs2074217, and rs222843. 80. α4β7 integrin antagonist for the use according to any one of claims 73 to 79, wherein the presence or absence of the single nucleotide polymorphisms rs7543124, rs6671927, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs2440335, rs1899750, rs1875673 and rs2106842 has been determined. 81. α4β7 integrin antagonist for the use according to claim 80, wherein the absence of the single nucleotide polymorphisms rs7543124, rs6671927, rs2088361, rs1556981, rs11801527 and rs3779477and the presence of the single nucleotide polymorphisms rs1882926, rs2440335, rs1899750, rs1875673 and rs2106842 is predictive for the subject’s treatment response to said α4β7 integrin antagonist. 82. α4β7 integrin antagonist for the use according to claim 81, wherein the subject has been selected for treatment with the α4β7 integrin antagonist with the following formula: Scorei = (-0.1797 * rs7543124)– (0.3707 * rs6671927)– (0.5741 * rs2088361)– (0.5848 * rs1556981) + (0.7127 * rs1882926)– (0.7024 * rs11801527)– (0.6841 * rs3779477) + (0.2158 * rs2440335) + (0.6147 * rs1899750) + (0.3475 * rs1875673) + (0.397 * rs2106842),

wherein the value for rs7543124, rs6671927, rs2088361, rs1556981, rs11801527, rs3779477, rs1882926, rs2440335, rs1899750, rs1875673 and rs2106842, respectively, is 2 if the single nucleotide polymorphism is present in both alleles, 1 if the single nucleotide polymorphism is present in one allele, and 0 if the single nucleotide polymorphism is not present and wherein a subject having a score of more than 0.2123 has been selected for treatment with said α4β7 integrin antagonist. 83. α4β7 integrin antagonist for the use according to any one of claims 73 to 79, wherein the presence or absence of the single nucleotide polymorphisms rs7543124, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs1899750 and rs2106842 has been determined. 84. α4β7 integrin antagonist for the use according to claim 83, wherein the absence of the single nucleotide polymorphisms rs7543124, rs2088361, rs1556981, rs11801527 and rs3779477 and the presence of the single nucleotide polymorphisms rs1882926, rs1899750 and rs2106842 is predictive for the subject’s treatment response to said α4β7 integrin antagonist.

85. α4β7 integrin antagonist for the use according to claim 84, wherein the subject has been selected for treatment with the α4β7 integrin antagonist with the following formula: Scorei = (-0.2213 * rs7543124)– (0.8735 * rs2088361)– (0.659 * rs1556981) + (0.8567 * rs1882926)– (0.858 * rs11801527)– (0.6935 * rs3779477) + (0.9288 * rs1899750) + (0.7159 * rs2106842)

wherein the value for rs7543124, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs1899750 and rs2106842, respectively, is 2 if the single nucleotide polymorphism is present in both alleles, 1 if the single nucleotide polymorphism is present in one allele, and 0 if the single nucleotide polymorphism is not present and wherein a subject having a score of more than 0.6803 has been selected for treatment with said α4β7 integrin antagonist. 86. Method for predicting a treatment response to an α4β7 integrin antagonist in a subject with Crohn’s Disease, said method comprising the step of determining the presence or absence of at least one single nucleotide polymorphism in the TRABD2B genomic locus in a nucleic acid sample obtained from said subject, wherein the presence or absence of the at least one single nucleotide polymorphism in the TRABD2B genomic locus is predictive for the treatment response to said α4β7 integrin antagonist. 87. Method according to claim 86, wherein the α4β7 integrin antagonist is

vedolizumab. 88. Method according to any one of claims 86 to 87, wherein the at least one single nucleotide polymorphism in the TRABD2B genomic locus is selected from the group consisting of rs7543124, rs6671927, rs12134443, rs11211624, rs2088361, rs1556981, rs11205430, rs1561573, rs11211613, rs12061891, rs11211632, rs17103939 and rs6684538. 89. Method according to any one of claims 86 to 88, wherein the presence or absence of the single nucleotide polymorphisms rs2088361 and rs1556981 is determined.

90. Method according to claim 89, wherein the absence of the single nucleotide polymorphisms rs2088361 and rs1556981 is predictive for the subject’s treatment response to said α4β7 integrin antagonist 91. Method according to any one of claims 86 to 90, wherein the presence or absence of the single nucleotide polymorphisms rs6671927, rs2088361, rs1556981 and rs1561573 is determined. 92. Method according to claim 91, wherein the absence of the single nucleotide polymorphisms rs6671927, rs2088361 and rs1556981 and the presence of the single nucleotide polymorphism rs1561573 is predictive for the treatment response to said α4β7 integrin antagonist. 93. Method according to claim 92, wherein a subject that is likely to respond to α4β7 integrin antagonist therapy is identified with the following formula:

Scorei = (0.32 * rs1561573)– (0.4502 * rs6671927)– (0.6524 * rs2088361)– (0.8948 * rs1556981),

wherein the value for rs1561573, rs6671927, rs2088361 and rs1556981, respectively, is 2 if the single nucleotide polymorphism is present in both alleles, 1 if the single nucleotide polymorphism is present in one allele, and 0 if the single nucleotide polymorphism is not present and wherein a subject having a score of more than

-1.4350 is likely to respond to α4β7 integrin antagonist therapy. 94. Method according to any one of claims 86 to 90, wherein the presence or absence of the single nucleotide polymorphisms rs6671927, rs2088361, rs1556981, rs11205430 and rs1561573 is determined. 95. Method according to claim 94, wherein the absence of the single nucleotide polymorphisms rs6671927, rs2088361, rs1556981 and rs11205430 and the presence of the single nucleotide polymorphism rs1561573 is predictive for the treatment response to said α4β7 integrin antagonist.

96. Method according to claim 95, wherein a subject that is likely to respond to α4β7 integrin antagonist therapy is identified with the following formula:

Scorei = (0.2738 * rs1561573)– (0.3913 * rs6671927)– (0.5404 * rs2088361)– (0.7396 * rs1556981)– (0.1912 * rs11205430),

wherein the value for rs1561573, rs6671927, rs2088361, rs1556981 and rs11205430, respectively, is 2 if the single nucleotide polymorphism is present in both alleles, 1 if the single nucleotide polymorphism is present in one allele, and 0 if the single nucleotide polymorphism is not present and wherein a subject having a score of more than -1.3896 is likely to respond to α4β7 integrin antagonist therapy. 97. Method according to any one of claims 86 to 88, wherein the presence or absence of the single nucleotide polymorphisms rs11205430, rs1561573, rs11211613, rs12061891, rs11211632 is determined. 98. Method according to claim 97, wherein the absence of the single nucleotide polymorphisms rs11211613, rs12061891, rs11211632 and rs11205430 and the presence of the single nucleotide polymorphism rs1561573 is predictive for the treatment response to said α4β7 integrin antagonist. 99. Method according to claim 98, wherein a subject that is likely to respond to α4β7 integrin antagonist therapy is identified with the following formula:

Scorei = (0.2865 * rs1561573)– (0.3678 * rs11211613)– (1.0079 * rs12061891)– (0.5831 * rs11211632)– (0.2351 * rs11205430),

wherein the value for rs1561573, rs11211613, rs12061891, rs11211632 and rs11205430, respectively, is 2 if the single nucleotide polymorphism is present in both alleles, 1 if the single nucleotide polymorphism is present in one allele, and 0 if the single nucleotide polymorphism is not present and wherein a subject having a score of more than -1.5910 is likely to respond to α4β7 integrin antagonist therapy.

100. Method according to any one of claims 86 to 88, wherein additionally the presence or absence of at least one single nucleotide polymorphism in at least one genomic locus selected from the group consisting of PDC, NPY, ONECUT1, DLG4 and ELP5 is determined. 101. Method according claim 100, wherein the presence or absence of at least one single nucleotide polymorphism in each of the genomic loci of PDC, NPY, ONECUT1, DLG4 and ELP5 is determined. 102. Method according to claim 100 or 101, wherein the single nucleotide

polymorphism in the PDC genomic locus is selected from the group consisting of rs1882926, rs11801527, rs12407957, and rs10798041. 103. Method according to claim 100 or 101, wherein the single nucleotide

polymorphism in the NPY genomic locus is selected from the group consisting of rs16141, rs3779477, and rs16129. 104. Method according to claim 100 or 101, wherein the single nucleotide

polymorphism in the ONECUT1 genomic locus is selected from the group consisting of rs2440335, rs2440332, rs1899750, rs7180600, rs2456507, and rs2456525. 105. Method according to claim 100 or 101, wherein the single nucleotide

polymorphism in the DLG4 genomic locus is selected from the group consisting of rs17203281, rs3826408, rs1875673, rs739669, rs2017365, and rs929229. 106. Method according to claim 100 or 101, wherein the single nucleotide

polymorphism in the ELP5 genomic locus is selected from the group consisting of rs2106842, exm1286317, rs2074217, and rs222843. 107. Method according to any one of claims 100 to 106, wherein the presence or absence of the single nucleotide polymorphisms rs7543124, rs6671927, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs2440335, rs1899750, rs1875673 and rs2106842 is determined. 108. Method according to claim 107, wherein the absence of the single nucleotide polymorphisms rs7543124, rs6671927, rs2088361, rs1556981, rs11801527 and rs3779477and the presence of the single nucleotide polymorphisms rs1882926, rs2440335, rs1899750, rs1875673 and rs2106842 is predictive for the treatment response to said α4β7 integrin antagonist. 109. Method according to claim 108, wherein a subject that is likely to respond to α4β7 integrin antagonist therapy is identified with the following formula:

Scorei = (-0.1797 * rs7543124)– (0.3707 * rs6671927)– (0.5741 * rs2088361)– (0.5848 * rs1556981) + (0.7127 * rs1882926)– (0.7024 * rs11801527)– (0.6841 * rs3779477) + (0.2158 * rs2440335) + (0.6147 * rs1899750) + (0.3475 * rs1875673) + (0.397 * rs2106842),

wherein the value for rs7543124, rs6671927, rs2088361, rs1556981, rs11801527, rs3779477, rs1882926, rs2440335, rs1899750, rs1875673 and rs2106842, respectively, is 2 if the single nucleotide polymorphism is present in both alleles, 1 if the single nucleotide polymorphism is present in one allele, and 0 if the single nucleotide polymorphism is not present and wherein a subject having a score of more than 0.2123 is likely to respond to α4β7 integrin antagonist therapy. 110. Method according to any one of claims 100 to 106, wherein the presence or absence of the single nucleotide polymorphisms rs7543124, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs1899750 and rs2106842 is determined. 111. Method according to claim 110, wherein the absence of the single nucleotide polymorphisms rs7543124, rs2088361, rs1556981, rs11801527 and rs3779477 and the presence of the single nucleotide polymorphisms rs1882926, rs1899750 and rs2106842 is predictive for the treatment response to said α4β7 integrin antagonist.

112. Method according to claim 111 wherein a subject that is likely to respond to α4β7 integrin antagonist therapy is identified with the following formula:

Scorei = (-0.2213 * rs7543124)– (0.8735 * rs2088361)– (0.659 * rs1556981) + (0.8567 * rs1882926)– (0.858 * rs11801527)– (0.6935 * rs3779477) + (0.9288 * rs1899750) + (0.7159 * rs2106842)

wherein the value for rs7543124, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs1899750 and rs2106842, respectively, is 2 if the single nucleotide polymorphism is present in both alleles, 1 if the single nucleotide polymorphism is present in one allele, and 0 if the single nucleotide polymorphism is not present and wherein a subject having a score of more than 0.6803 is likely to respond to α4β7 integrin antagonist therapy. 113. A group of biomarkers comprising SNP rs2088361 and SNP rs1556981. 114. Group of biomarkers according to claim 113, further comprising at least two SNPs selected from the group consisting of rs7543124, rs6671927, rs1561573 and rs11205430. 115. Group of biomarkers according to claim 113 or 114, consisting of SNPs rs6671927, rs2088361, rs1556981 and rs1561573. 116. Group of biomarkers according to claim 113 or 114, consisting of SNPs rs6671927, rs2088361, rs1556981, rs11205430 and rs1561573. 117. Group of biomarkers according to claim 113 or 114, further comprising SNPs rs11801527, rs3779477, rs1882926, rs2440335, rs1899750, rs1875673 and rs2106842. 118. Group of biomarkers according to claim 117, consisting of SNPs rs7543124, rs6671927, rs2088361, rs1556981, rs11801527, rs3779477, rs1882926, rs2440335, rs1899750, rs1875673 and rs2106842. 119. Group of biomarkers according to claim 113, further comprising SNPs rs7543124, rs11801527, rs3779477, rs1882926, rs1899750, and rs2106842.

120. Group of biomarkers according to claim 119, consisting of SNPs rs2088361, rs1556981, rs7543124, rs11801527, rs3779477, rs1882926, rs1899750, and rs2106842. 121. A group of biomarkers, comprising SNPs rs11205430, rs1561573, rs11211613, rs12061891 and rs11211632. 122. Kit, diagnostic composition or device comprising a probe selective for at least one single nucleotide polymorphism in the TRABD2B genomic locus. 123. Kit, diagnostic composition or device according to claim 122, wherein the at least one single nucleotide polymorphism in the TRABD2B genomic locus is selected from the group consisting of rs7543124, rs6671927, rs12134443, rs11211624, rs2088361, rs1556981, rs11205430, rs1561573, rs11211613, rs12061891, rs11211632, rs17103939 and rs6684538. 124. Kit, diagnostic composition or device according to claim 122 or 123, comprising probes selective for the single nucleotide polymorphisms rs6671927, rs2088361, rs1556981 and rs1561573. 125. Kit, diagnostic composition or device according to claim 122 or 123, comprising probes selective for the single nucleotide polymorphisms rs6671927, rs2088361, rs1556981, rs11205430 and rs1561573. 126. Kit, diagnostic composition or device according to claim 122 or 123, comprising probes selective for the single nucleotide polymorphisms rs11205430, rs1561573, rs11211613, rs12061891, rs11211632. 127. Kit, diagnostic composition or device according to claim 122 or 123, further comprising a probe selective for at least one single nucleotide polymorphism in at least one genomic locus selected from the group consisting of PDC, NPY, ONECUT1, DLG4 and ELP5.

128. Kit, diagnostic composition or device according to claim 127, further comprising probes selective for at least one single nucleotide polymorphism in each of the genomic loci of PDC, NPY, ONECUT1, DLG4 and ELP5. 129. Kit, diagnostic composition or device according to claim 127 or 128, wherein the single nucleotide polymorphism in the PDC genomic locus is selected from the group consisting of rs1882926, rs11801527, rs12407957, and rs10798041. 130. Kit, diagnostic composition or device according to claim 127 or 128, wherein the single nucleotide polymorphism in the NPY genomic locus is selected from the group consisting of rs16141, rs3779477, and rs16129. 131. Kit, diagnostic composition or device according to claim 127 or 128, wherein the single nucleotide polymorphism in the ONECUT1 genomic locus is selected from the group consisting of rs2440335, rs2440332, rs1899750, rs7180600, rs2456507, and rs2456525. 132. Kit, diagnostic composition or device according to claim 127 or 128, wherein the single nucleotide polymorphism in the DLG4 genomic locus is selected from the group consisting of rs17203281, rs3826408, rs1875673, rs739669, rs2017365, and rs929229. 133. Kit, diagnostic composition or device according to claim 127 or 128, wherein the single nucleotide polymorphism in the ELP5 genomic locus is selected from the group consisting of rs2106842, exm1286317, rs2074217, and rs222843. 134. Kit, diagnostic composition or device according to any one of claims 127 to 133, comprising probes selective for the single nucleotide polymorphisms rs7543124, rs6671927, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs2440335, rs1899750, rs1875673 and rs2106842.

135. Kit, diagnostic composition or device according to any one of claims 127 to 133, comprising probes selective for the single nucleotide polymorphisms rs7543124, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs1899750 and rs2106842. 136. Kit, diagnostic composition or device according to any one of claims 122 to 135, further comprising an enzyme for primer elongation, nucleotides and/or labeling agents. 137. Microarray comprising a probe selective for at least one single nucleotide polymorphism in the TRABD2B genomic locus. 138. Microarray according to claim 137, wherein the at least one single nucleotide polymorphism in the TRABD2B genomic locus is selected from the group consisting of rs7543124, rs6671927, rs12134443, rs11211624, rs2088361, rs1556981, rs11205430, rs1561573, rs11211613, rs12061891, rs11211632, rs17103939 and rs6684538. 139. Microarray according to claim 137 or 138, comprising probes selective for the single nucleotide polymorphisms rs6671927, rs2088361, rs1556981 and rs1561573. 140. Microarray according to claim 137 or 138, comprising probes selective for the single nucleotide polymorphisms rs6671927, rs2088361, rs1556981, rs11205430 and rs1561573. 141. Microarray according to claim 137 or 138, comprising probes selective for the single nucleotide polymorphisms rs11205430, rs1561573, rs11211613, rs12061891, rs11211632. 142. Microarray according to claim 137 or 138, further comprising a probe selective for at least one single nucleotide polymorphism in at least one genomic locus selected from the group consisting of PDC, NPY, ONECUT1, DLG4 and ELP5. 143. Microarray according to claim 142, further comprising probes selective for the single nucleotide polymorphisms in each of the genomic loci of PDC, NPY, ONECUT1, DLG4 and ELP5.

144. Microarray according to claim 142 or 143, wherein the single nucleotide polymorphism in the PDC genomic locus is selected from the group consisting of rs1882926, rs11801527, rs12407957, and rs10798041. 145. Microarray according to claim 142 or 143, wherein the single nucleotide polymorphism in the NPY genomic locus is selected from the group consisting of rs16141, rs3779477, and rs16129. 146. Microarray according to claim 142 or 143, wherein the single nucleotide polymorphism in the ONECUT1 genomic locus is selected from the group consisting of, rs2440335, rs2440332, rs1899750, rs7180600, rs2456507, and rs2456525. 147. Microarray according to claim 142 or 143, wherein the single nucleotide polymorphism in the DLG4 genomic locus is selected from the group consisting of rs17203281, rs3826408, rs1875673, rs739669, rs2017365, and rs929229. 148. Microarray according to claim 142 or 143, wherein the single nucleotide polymorphism in the ELP5 genomic locus is selected from the group consisting of rs2106842, exm1286317, rs2074217, and rs222843. 149. Microarray according to any one of claims 142 to 148, comprising probes selective for the single nucleotide polymorphisms rs7543124, rs6671927, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs2440335, rs1899750, rs1875673 and rs2106842. 150. Microarray according to any one of claims 142 to 148, comprising probes selective for the single nucleotide polymorphisms rs7543124, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs1899750 and rs2106842 is determined. 151. Use of the group of biomarkers according to any one of claims 113 to 121, the kit, diagnostic composition or device according to any one of claims 122 to 136 or of the microarray according to any one of claims 137 to 150 for predicting a patient’s response to treatment with a α4β7 integrin antagonist. 152. Use of the group of biomarkers according to any one of claims 113 to 121, the kit, diagnostic composition or device according to any one of claims 122 to 136 or of the microarray according to any one of claims 137 to 150 for identifying a patient with Crohn’s Disease as being eligible for treatment with a α4β7 integrin antagonist. 153. Use according to claim 151 or 152, wherein the α4β7 integrin antagonist is vedolizumab.

Description:
Method for Treating Crohn’s Disease CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefits under 35 U.S.C. § 119(e) to U.S. provisional application 62/257,173 filed November 18, 2015, the contents of which are incorporated herein by reference in their entirety. BACKGROUND Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the gastrointestinal tract, and it is characterized by any of the following symptoms: abdominal pain, vomiting, diarrhea, rectal bleeding, severe internal cramps/muscle spasms, tenesmus, fistulae formation, weight loss, and fever. Crohn’s Disease is classified as one of the two main IBDs.

Crohn’s Disease is an IBD in which inflammation extends beyond the inner gut lining and penetrates deeper layers of the intestinal wall of any part of the digestive system. Symptoms of Crohn’s Disease can include any of persistent diarrhea, rectal bleeding, urgent need to move bowels, abdominal cramps and pain, sensation of incomplete evacuation, constipation, fever, loss of appetite, weight loss, fatigue, night sweats, and loss of menstrual cycle.

Treatment Crohn’s Disease typically includes the use of medication such as aminosalicylates, corticosteroids, immunomodulators, anti-TNFα, or antibiotics; alterations in diet and nutrition; and, sometimes, surgical procedures. However, it is believed that genetics may play a role in how a treatment regimen affects an individual, although non-genetic variables may also play a role. As a result, it is difficult to predict the best treatment option for a given patient with Crohn’s Disease. Accordingly, it would be beneficial to devise a method for identifying subpopulations of patients suffering from Crohn’s Disease that are likely to respond most favorably to a treatment comprising an antagonist of the α4β7 integrin, such as vedolizumab. SUMMARY The present invention relates to methods and kits for treating Crohn’s Disease in an individual, and for identifying the likelihood that an individual suffering from Crohn’s Disease will experience an enhanced treatment effect (e.g.,experience an enhanced clinical response or clinical remission) to treatment with an antagonist of the α4β7 integrin, such as an anti-α4β7 antibody (e.g., vedolizumab) and/or experience an enhanced treatment effect when treated with the antagonist. These methods and kits are based on detecting the presence of polymorphisms in, for example, TRABD2B, PDC, NPY, ONECUT1, DLG4, CLDN7, and/or ELP5 genes.

One aspect of the present invention provides methods for treating Crohn’s Disease in an individual, comprising administering an antagonist of the α4β7 integrin, such as an anti-α4β7 antibody (e.g., vedolizumab) to an individual identified as (i) TRABD2B variant positive, (ii) PDC variant positive, (iii) NPY variant positive, (iv) ONECUT1 variant positive, (v) DLG4 variant positive, (vi) CLDN7 variant positive, (vii) ELP5 variant positive, or (viii) any combination of these.

In some embodiments, the treating comprises remission of Crohn’s Disease.

In some embodiments, the individual is heterozygous for the TRABD2B variant and/or the PDC variant and/or the NPY variant and/or the ONECUT1 variant and/or the DLG4 variant and/or the CLDN7 variant and/or the ELP5 variant. In some embodiments, the individual is homozygous for the TRABD2B variant and/or the PDC variant and/or the NPY variant and/or the ONECUT1 variant and/or the DLG4 variant and/or the CLDN7 variant and/or the ELP5 variant.

One aspect of the invention comprises methods for determining the likelihood that an individual suffering from Crohn’s Disease will experience an enhanced treatment effect when treated with an anti-α4β7 antibody, e.g., vedolizumab, comprising: (i) assaying a biological sample obtained from an individual for the presence or absence of a TRABD2B variant and/or a PDC variant and/or a NPY variant and/or a ONECUT1 variant and/or a DLG4 variant and/or a CLDN7 variant and/or a ELP5 variant and (ii) detecting the presence of the TRABD2B variant and/or the PDC variant and/or the NPY variant and/or the ONECUT1 variant and/or the DLG4 variant and/or the CLDN7 variant and/or the ELP5 variant, wherein the presence of the TRABD2B variant and/or the PDC variant and/or the NPY variant and/or the ONECUT1 variant and/or the DLG4 variant and/or the CLDN7 variant and/or the ELP5 variant indicates an increased likelihood that the individual will experience an enhanced treatment effect.

Some embodiments comprise methods for determining the likelihood that an individual suffering from Crohn’s Disease will respond favorably to treatment with vedolizumab comprising: (i) assaying a biological sample obtained from an individual for the presence or absence of a TRABD2B variant and/or a PDC variant and/or a NPY variant and/or a ONECUT1 variant and/or a DLG4 variant and/or a CLDN7 variant and/or a ELP5 variant and (ii) detecting the presence of the TRABD2B variant and/or the PDC variant and/or the NPY variant and/or the ONECUT1 variant and/or the DLG4 variant and/or the CLDN7 variant and/or the ELP5 variant, wherein the presence of the TRABD2B variant and/or the PDC variant and/or the NPY variant and/or the ONECUT1 variant and/or the DLG4 variant and/or the CLDN7 variant and/or the ELP5 variant indicates an increased likelihood that the individual will respond favorably to vedolizumab.

In some embodiments, the TRABD2B variant is selected from the group consisting of rs7543124, rs6671927, rs12134443, rs11211624, rs2088361, rs1556981, rs11205430, rs1561573, rs11211613, rs12061891, rs11211632, rs6684538, rs17103939, and combinations thereof.

In some embodiments a variant is selected from the group consisting of rs7543124, rs6671927, rs12134443, rs11211624, rs2088361, rs1556981, rs11205430, rs1561573, rs11211613, rs12061891, rs11211632, rs6684538, rs17103939, SNPs in linkage disequilibrium with any of the foregoing, and combinations thereof.

In some embodiments, the PDC variant is selected from the group consisting of rs1882926, rs11801527, rs12407957, rs10798041, and combinations thereof.

In some embodiments a variant is selected from the group consisting of rs1882926, rs11801527, rs12407957, rs10798041, SNPs in linkage disequilibrium with any of the foregoing, and combinations thereof. In some embodiments, the NPY variant is selected from the group consisting of rs16141, rs3779477, rs16129, and combinations thereof.

In some embodiments a variant is selected from the group consisting of rs16141, rs3779477, rs16129, SNPs in linkage disequilibrium with any of the foregoing, and combinations thereof

In some embodiments, the ONECUT1 variant is selected from the group consisting of rs2440335, rs2440332, rs1899750, rs7180600, rs2456507, rs2456525, and combinations thereof.

In some embodiments a variant is selected from the group consisting of rs2440335, rs2440332, rs1899750, rs7180600, rs2456507, rs2456525, SNPs in linkage disequilibrium with any of the foregoing, and combinations thereof.

In some embodiments, the DLG4 variant is selected from the group consisting of rs17203281, rs3826408, rs1875673, rs739669, rs2017365, rs929229, and combinations thereof.

In some embodiments a variant is seleted from the group consisting of rs17203281, rs3826408, rs1875673, rs739669, rs2017365, rs929229, SNPs in linkage disequilibrium with any of the foregoing, and combinations thereof.

In some embodiments, the CLDN7 variant or ELP5 variant is rs2106842, exm1286317, rs2074217, rs222843, and combinations thereof.

In some embodiments a variant is selected from the group consisting of rs2106842, exm1286317, rs2074217, rs222843, SNPs in linkage disequilibrium with any of the foregoing, and combinations thereof.

One aspect of the invention comprises an α4β7 integrin antagonist for use in the treatment of a subject with Crohn’s Disease, wherein the subject has been selected for treatment with said antagonist by having determined the presence or absence of at least one single nucleotide polymorphism in the TRABD2B genomic locus in a sample having been obtained from said subject, wherein said determined presence or absence of the at least one single nucleotide polymorphism in the TRABD2B genomic locus is predictive for the subject’s treatment response to said α4β7 integrin antagonist. In some embodiments, the α4β7 integrin antagonist is vedolizumab. Some embodiments comprise an α4β7 integrin antagonist for use in the treatment of a subject with Crohn’s Disease, wherein the subject is selected for treatment with said α4β7 integrin antagonist by determining or having determined the presence or absence of at least one single nucleotide polymorphism in the TRABD2B genomic locus in a sample having been obtained from said subject, wherein the hereby determined presence or absence of the at least one single nucleotide polymorphism in the TRABD2B genomic locus is associated with a response to said treatment.

Some embodiments comprise an α4β7 integrin antagonist for use in the treatment of a subject with Crohn’s Disease, wherein the subject has been selected for treatment with said α4β7 integrin antagonist by determining or having determined the presence or absence of at least one single nucleotide polymorphism in the TRABD2B genomic locus in a sample having been obtained from said subject, wherein the hereby determined presence or absence of the at least one single nucleotide polymorphism in the TRABD2B genomic locus is associated with a response to said treatment.

Some embodiments comprise an α4β7 integrin antagonist for use in the treatment of a subject with Crohn’s Disease, wherein the subject has been identified as being eligible for treatment with said α4β7 integrin antagonist by determining the presence or absence of at least one single nucleotide polymorphism in the TRABD2B genomic locus, wherein the hereby determined presence or absence of the at least one single nucleotide polymorphism in the TRABD2B genomic locus is predictive for the subject’s treatment response to said α4β7 integrin antagonist.

Some embodiments comprise an α4β7 integrin antagonist for use in the treatment of a subject with Crohn’s Disease, wherein the subject is selected for said treatment by determining or having determined the presence or absence of at least one single nucleotide polymorphism in the TRABD2B genomic locus, wherein the hereby determined presence or absence of the at least one single nucleotide polymorphism in the TRABD2B genomic locus is associated with a response to said treatment. Some embodiments comprise an α4β7 integrin antagonist for use in the treatment of a subject with inflammatory bowel disease, wherein the subject has been selected by determining the presence or absence of at least one single nucleotide polymorphism in the TRABD2B genomic locus, wherein the hereby determined presence or absence of the at least one single nucleotide polymorphism in the TRABD2B genomic locus is associated with a response to said treatment.

Some embodiments comprise an α4β7 integrin antagonist for use in the treatment of a subject with inflammatory bowel disease, wherein the subject is characterized by the presence or absence of at least one single nucleotide polymorphism in the TRABD2B genomic locus and the treatment comprises a step of determining whether the single nucleotide polymorphism in the TRABD2B genomic locus is present or absent, wherein the hereby determined presence or absence of the at least one single nucleotide polymorphism in the TRABD2B genomic locus is associated with a response to said treatment.

The following aspects of the invention apply to all embodiments of the medical use of the α4β7 integrin antagonist displayed above.

One aspect of the invention comprises a method for predicting a treatment response to an α4β7 integrin antagonist in a subject with Crohn’s Disease, said method comprising the step of determining the presence or absence of at least one single nucleotide polymorphism in the TRABD2B genomic locus in a nucleic acid sample obtained from said subject, wherein the presence or absence of the at least one single nucleotide polymorphism in the TRABD2B genomic locus is predictive for the treatment response to said α4β7 integrin antagonist.

In some embodiments, the at least one single nucleotide polymorphism in the TRABD2B genomic locus is selected from the group consisting of rs7543124, rs6671927, rs12134443, rs11211624, rs2088361, rs1556981, rs11205430, rs1561573, rs11211613, rs12061891, rs11211632, rs17103939 and rs6684538.

In some embodiments, at least one single nucleotide polymorphism is selected from the group consisting of rs7543124, rs6671927, rs12134443, rs11211624, rs2088361, rs1556981, rs11205430, rs1561573, rs11211613, rs12061891, rs11211632, rs17103939, rs6684538, SNPs in linkage disequilibrium with any of the foregoing, and combinations thereof.

In some embodiments, the presence or absence of the single nucleotide polymorphisms rs2088361 and rs1556981 has been determined.

In some embodiments, the absence of the single nucleotide polymorphisms rs2088361 and rs1556981 is predictive for the subject’s treatment response to said α4β7 integrin antagonist.

In some embodiments, the presence or absence of the single nucleotide polymorphisms rs6671927, rs2088361, rs1556981 and rs1561573 has been determined.

In some embodiments, the absence of the single nucleotide polymorphisms rs6671927, rs2088361 and rs1556981 and the presence of the single nucleotide polymorphism rs1561573 is predictive for the subject’s treatment response to said α4β7 integrin antagonist.

In some embodiments, the subject has been selected for treatment with the α4β7 integrin antagonist, or has been identified as likely to respond to α4β7 integrin antagonist therapy, with the following formula: Score i = (0.32 * rs1561573)– (0.4502 * rs6671927)– (0.6524 * rs2088361)– (0.8948 * rs1556981), wherein the value for rs1561573, rs6671927, rs2088361 and rs1556981, respectively, is 2 if the single nucleotide polymorphism is present in both alleles, 1 if the single nucleotide polymorphism is present in one allele, and 0 if the single nucleotide polymorphism is not present and wherein a subject having a score of more than -1.4350 has been selected for treatment with said α4β7 integrin antagonist.

In some embodiments, the presence or absence of the single nucleotide polymorphisms rs6671927, rs2088361, rs1556981, rs11205430 and rs1561573 has been determined.

In some embodiments, the single nucleotide polymorphisms rs6671927, rs2088361, rs1556981 and rs11205430 and the presence of the single nucleotide polymorphism rs1561573 is predictive for the subject’s treatment response to said α4β7 integrin antagonist.

In some embodiments, the subject has been selected for treatment with the α4β7 integrin antagonist, or has been identified as likely to respond to α4β7 integrin antagonist therapy, with the following formula: Score i = (0.2738 * rs1561573)– (0.3913 * rs6671927)– (0.5404 * rs2088361)– (0.7396 * rs1556981)– (0.1912 * rs11205430), wherein the value for rs1561573, rs6671927, rs2088361, rs1556981 and rs11205430, respectively, is 2 if the single nucleotide polymorphism is present in both alleles, 1 if the single nucleotide polymorphism is present in one allele, and 0 if the single nucleotide polymorphism is not present and wherein a subject having a score of more than -1.3896 has been selected for treatment with said α4β7 integrin antagonist.

In some embodiments, the presence or absence of the single nucleotide polymorphisms rs11205430, rs1561573, rs11211613, rs12061891, and rs11211632 has been determined.

In some embodiments, the absence of the single nucleotide polymorphisms rs11211613, rs12061891, rs11211632 and rs11205430 and the presence of the single nucleotide

polymorphism rs1561573 is predictive for the subject’s treatment response to said α4β7 integrin antagonist.

In some embodiments, the subject has been selected for treatment with the α4β7 integrin antagonist, or has been identified as likely to respond to α4β7 integrin antagonist therapy, with the following formula: Score i = (0.2865 * rs1561573)– (0.3678 * rs11211613)– (1.0079 * rs12061891)– (0.5831 * rs11211632)– (0.2351 * rs11205430), wherein the value for rs1561573, rs11211613, rs12061891, rs11211632 and rs11205430, respectively, is 2 if the single nucleotide polymorphism is present in both alleles, 1 if the single nucleotide polymorphism is present in one allele, and 0 if the single nucleotide polymorphism is not present and wherein a subject having a score of more than -1.5910 has been selected for treatment with said α4β7 integrin antagonist.

In some embodients, the presence or absence of at least one single nucleotide polymorphism in at least one genomic locus selected from the group consisting of PDC, NPY, ONECUT1, DLG4 and ELP5 has additionally been determined.

In some embodiments, the presence or absence of at least one single nucleotide polymorphism in each of the genomic loci of TRABD2B, PDC, NPY, ONECUT1, DLG4 and ELP5 has been determined.

In some embodiments, the single nucleotide polymorphism in the PDC genomic locus is selected from the group consisting of rs1882926, rs11801527, rs12407957, and rs10798041. In some embodiments, the single nucleotide polymorphism is selected from the group consisting of rs1882926, rs11801527, rs12407957, rs10798041, SNPs in linkage disequilibrium with any of the foregoing, and combinations thereof.

In some embodiments, the single nucleotide polymorphism in the NPY genomic locus is selected from the group consisting of rs16141, rs3779477, and rs16129.

In some embodiments, the single nucleotide polymorphism is selected from the group consisting of rs16141, rs3779477, rs16129, SNPs in linkage disequilibrium with any of the foregoing, and combinations thereof.

In some embodiments, the single nucleotide polymorphism in the ONECUT1 genomic locus is selected from the group consisting of rs2440335, rs2440332, rs1899750, rs7180600, rs2456507, and rs2456525.

In some embodiments, the single nucleotide polymorphism is selected from the group consisting of rs2440335, rs2440332, rs1899750, rs7180600, rs2456507, rs2456525, SNPs in linkage disequilibrium with any of the foregoing, and combinations thereof.

In some embodiments, the single nucleotide polymorphism in the DLG4 genomic locus is selected from the group consisting of rs17203281, rs3826408, rs1875673, rs739669, rs2017365, and rs929229.

In some embodiments, the single nucleotide polymorphism is selected from the group consisting of rs17203281, rs3826408, rs1875673, rs739669, rs2017365, rs929229, SNPs in linkage disequilibrium with any of the foregoing, and combinations thereof.

In some embodiments, the single nucleotide polymorphism in the ELP5 genomic locus is rs2106842, exm1286317, rs2074217, and rs222843.

In some embodiments, the single nucleotide polymorphism is rs2106842, exm1286317, rs2074217, rs222843, SNPs in linkage disequilibrium with any of the foregoing, and combinations thereof.

In some embodiments, the presence or absence of the single nucleotide polymorphisms rs7543124, rs6671927, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs2440335, rs1899750, rs1875673 and rs2106842 has been determined. In some embodiments, the absence of the single nucleotide polymorphisms rs7543124, rs6671927, rs2088361, rs1556981, rs11801527 and rs3779477and the presence of the single nucleotide polymorphisms rs1882926, rs2440335, rs1899750, rs1875673 and rs2106842 is predictive for the subject’s treatment response to said α4β7 integrin antagonist.

In some embodiments, the subject has been selected for treatment with the α4β7 integrin antagonist, or has been identified as likely to respond to α4β7 integrin antagonist therapy, with the following formula: Score i = (-0.1797 * rs7543124)– (0.3707 * rs6671927)– (0.5741 * rs2088361)– (0.5848 * rs1556981) + (0.7127 * rs1882926)– (0.7024 * rs11801527)– (0.6841 * rs3779477) + (0.2158 * rs2440335) + (0.6147 * rs1899750) + (0.3475 * rs1875673) + (0.397 * rs2106842), wherein the value for rs7543124, rs6671927, rs2088361, rs1556981, rs11801527, rs3779477, rs1882926, rs2440335, rs1899750, rs1875673 and rs2106842, respectively, is 2 if the single nucleotide polymorphism is present in both alleles, 1 if the single nucleotide polymorphism is present in one allele, and 0 if the single nucleotide polymorphism is not present and wherein a subject having a score of more than 0.2123 has been selected for treatment with said α4β7 integrin antagonist.

In some embodiments, the presence or absence of the single nucleotide polymorphisms rs7543124, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs1899750 and rs2106842 has been determined.

In some embodiments, the absence of the single nucleotide polymorphisms rs7543124, rs2088361, rs1556981, rs11801527 and rs3779477 and the presence of the single nucleotide polymorphisms rs1882926, rs1899750 and rs2106842 is predictive for the subject’s treatment response to said α4β7 integrin antagonist.

In some embodiments, the subject has been selected for treatment with the α4β7 integrin antagonist, or has been identified as likely to respond to α4β7 integrin antagonist therapy, with the following formula: Score i = (-0.2213 * rs7543124)– (0.8735 * rs2088361)– (0.659 * rs1556981) + (0.8567 * rs1882926)– (0.858 * rs11801527)– (0.6935 * rs3779477) + (0.9288 * rs1899750) + (0.7159 * rs2106842), wherein the value for rs7543124, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs1899750 and rs2106842, respectively, is 2 if the single nucleotide polymorphism is present in both alleles, 1 if the single nucleotide polymorphism is present in one allele, and 0 if the single nucleotide polymorphism is not present and wherein a subject having a score of more than 0.6803 has been selected for treatment with said α4β7 integrin antagonist.

Some embodiments comprise detecting the presence of the TRABD2B variant. Some embodiments comprise detecting the presence of rs1556981, rs2088361, rs1561573, and rs6671927 variants. Some embodiments comprise detecting the presence of rs1556981, rs2088361, rs1561573, rs6671927, and rs11205430 variants. Some embodiments comprise detecting the presence of rs1561573, rs11211613, rs12061891, rs11211632, and rs11205430.

Some embodiments comprise detecting the presence of the TRABD2B variant, the PDC variant, the NPY variant, the ONECUT1 variant, CLDN7 variant, and the ELP5 variant. Some embodiments comprise detecting the presence of rs7543124, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs1899750, and rs2106842 variants.

Some embodiments comprise detecting the presence of the TRABD2B variant, the PDC variant, the NPY variant the ONECUT1 variant, the DLG4 variant, the CLDN7 variant, and the ELP5 variant. Some embodiments comprise detecting the presence of rs7543124, rs6671927, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs2440335, rs1899750, rs1875673, and rs2106842 variants.

One aspect of the invention comprises a group of biomarkers comprising SNP rs2088361 and SNP rs1556981.

In some embodiments, a group of biomarkers comprises SNP rs2088361, SNP rs1556981, and at least two SNPs selected from the group consisting of rs7543124, rs6671927, rs1561573 and rs11205430.

In some embodiments, a group of biomarkers consists of SNPs rs6671927, rs2088361, rs1556981 and rs1561573.

In some embodiments, a group of biomarkers consists of SNPs rs6671927, rs2088361, rs1556981, rs11205430 and rs1561573. In some embodiments, a group of biomarkers comprises SNP rs2088361, SNP rs1556981, and SNPs rs11801527, rs3779477, rs1882926, rs2440335, rs1899750, rs1875673 and rs2106842.

In some embodiments, a group of biomarkers consists of SNPs rs7543124, rs6671927, rs2088361, rs1556981, rs11801527, rs3779477, rs1882926, rs2440335, rs1899750, rs1875673 and rs2106842.

In some embodiments, a group of biomarkers comprises SNP rs2088361, SNP rs1556981, and SNPs rs7543124, rs11801527, rs3779477, rs1882926, rs1899750, and rs2106842.

In some embodiments, the group of biomarkers consists of SNPs rs2088361, rs1556981, rs7543124, rs11801527, rs3779477, rs1882926, rs1899750, and rs2106842.

In some embodiments, a group of biomarkers comprises SNPs rs11205430, rs1561573, rs11211613, rs12061891 and rs11211632.

One aspect of the invention comprises kits, such as kits comprising: (i) at least one pair of primers that specifically hybridizes to a genetic variant independently selected from the group consisting of rs1556981, rs2088361, rs1561573, and rs6671927, and (ii) a detectably labeled probe that hybridizes to the genetic variant.

In some embodiments, the kits comprise: a pair of primers that specifically hybridizes to rs1556981; a pair of primers that specifically hybridizes to rs2088361; a pair of primers that specifically hybridizes to rs1561573; and a pair of primers that specifically hybridizes to rs6671927.

In some embodiments, the kits comprise: a pair of primers that specifically hybridizes to rs1556981; a pair of primers that specifically hybridizes to rs2088361; a pair of primers that specifically hybridizes to rs1561573; a pair of primers that specifically hybridizes to rs6671927; and a pair of primers that specifically hybridizes to rs11205430.

In some embodiments, the kits comprise: (i) at least one pair of primers that specifically hybridizes to a genetic variant independently selected from the group consisting of rs1561573, rs11211613, rs12061891, rs11211632, and rs11205430, and (ii) a detectably labeled probe that hybridizes to the genetic variant.

In some embodiments, the kits comprise: (i) at least one pair of primers that specifically hybridizes to a genetic variant independently selected from the group consisting of rs7543124, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs1899750, and rs2106842, and (ii) a detectably labeled probe that hybridizes to the genetic variant.

In some embodiments, the kits comprise: (i) at least one pair of primers that specifically hybridizes to a genetic variant independently selected from the group consisting of rs7543124, rs6671927, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs2440335, rs1899750, rs1875673, and rs2106842, and (ii) a detectably labeled probe that hybridizes to the genetic variant.

One aspect of the invention comprises a kit, diagnostic composition or device comprising a probe selective for at least one single nucleotide polymorphism in the TRABD2B genomic locus. In some embodiments, the at least one single nucleotide polymorphism in the TRABD2B genomic locus is selected from the group consisting of rs7543124, rs6671927, rs12134443, rs11211624, rs2088361, rs1556981, rs11205430, rs1561573, rs11211613, rs12061891, rs11211632, rs17103939 and rs6684538.

Some embodiments of the kit, diagnostic composition or device comprise a probe selected for at least one single nucleotide polymorphism selected from the group consisting of rs7543124, rs6671927, rs12134443, rs11211624, rs2088361, rs1556981, rs11205430, rs1561573, rs11211613, rs12061891, rs11211632, rs17103939, rs6684538, SNPs in linkage disequilibrium with any of the foregoing, and combinations thereof.

In some embodiments, the kit, diagnostic composition or device comprises probes selective for the single nucleotide polymorphisms rs6671927, rs2088361, rs1556981 and rs1561573.

In some embodiments, the kit, diagnostic composition or device comprises probes selective for the single nucleotide polymorphisms rs6671927, rs2088361, rs1556981, rs11205430 and rs1561573. In some embodiments, the kit, diagnostic composition or device comprises probes selective for the single nucleotide polymorphisms rs11205430, rs1561573, rs11211613, rs12061891, rs11211632.

In some embodiments, the kit, diagnostic composition or device further comprises a probe selective for at least one single nucleotide polymorphism in at least one genomic locus selected from the group consisting of PDC, NPY, ONECUT1, DLG4 and ELP5.

In some embodiments, the kit, diagnostic composition or device further comprises probes selective for at least one single nucleotide polymorphism in each of the genomic loci of PDC, NPY, ONECUT1, DLG4 and ELP5.

In some embodiments of the kit, diagnostic composition, or device, the single nucleotide polymorphism in the PDC genomic locus is selected from the group consisting of rs1882926, rs11801527, rs12407957, and rs10798041. For example, the single nucleotide polymorphism in the PDC genomic locus is selected from the group consisting of rs1882926 and rs11801527.

Some embodiments of the kit, diagnostic composition, or device comprise probes selected for at least one single nucleotide polymorphism selected from the group consisting of rs1882926, rs11801527, rs12407957, rs10798041, SNPs in linkage disequilibrium with any of the foregoing, and combinations thereof.

In some embodiments of the kit, diagnostic composition, or device, the single nucleotide polymorphism in the NPY genomic locus is selected from the group consisting of rs16141, rs3779477, and rs16129. For example, the single nucleotide polymorphism in the NPY genomic locus is selected from the group consisting of rs16141 and rs3779477.

Some embodiments of the kit, diagnostic composition, or device comprise probes selected for at least one single nucleotide polymorphism selected from the group consisting of rs16141, rs3779477, rs16129, SNPs in linkage disequilibrium with any of the foregoing, and combinations thereof.

In some embodiments of the kit, diagnostic composition, or device, the single nucleotide polymorphism in the ONECUT1 genomic locus is selected from the group consisting of rs2440335, rs2440332, rs1899750, rs7180600, rs2456507, and rs2456525. For example, the single nucleotide polymorphism in the ONECUT1 genomic locus is selected from the group consisting of rs2440335, rs2440332, rs1899750 and rs7180600.

Some embodiments of the kit, diagnostic composition, or device comprise probes selected for at least one single nucleotide polymorphism selected from the group consisting of rs16141, rs3779477, rs16129, SNPs in linkage disequilibrium with any of the foregoing, and combinations thereof.

In some embodiments of the kit, diagnostic composition, or device, the single nucleotide polymorphism in the DLG4 genomic locus is selected from the group consisting of rs17203281, rs3826408, rs1875673, rs739669, rs2017365, and rs929229. For example, the single nucleotide polymorphism in the DLG4 genomic locus is selected from the group consisting of rs17203281, rs3826408 and rs1875673.

Some embodiments of the kit, diagnostic composition, or device comprise probes selected for at least one single nucleotide polymorphism selected from the group consisting of rs17203281, rs3826408, rs1875673, rs739669, rs2017365, rs929229, SNPs in linkage disequilibrium with any of the foregoing, and combinations thereof.

In some embodiments of the kit, diagnostic composition, or device, the single nucleotide polymorphism in the ELP5 genomic locus is rs2106842, exm1286317, rs2074217, and rs222843. For example, the single nucleotide polymorphism in the ELP5 genomic locus is rs2106842.

Some embodiments of the kit, diagnostic composition, or device comprise probes selected for at least one single nucleotide polymorphism selected from the group consisting of rs2106842, exm1286317, rs2074217, rs222843, SNPs in linkage disequilibrium with any of the foregoing, and combinations thereof.

In some embodiments, the kit, diagnostic composition comprises probes selective for the single nucleotide polymorphisms rs7543124, rs6671927, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs2440335, rs1899750, rs1875673 and rs2106842.

In some embodiments, the kit, diagnostic composition or device comprises probes selective for the single nucleotide polymorphisms rs7543124, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs1899750 and rs2106842. In some embodiments, the kit, diagnostic composition or device further comprises an enzyme for primer elongation, nucleotides and/or labeling agents.

On aspect of the invention comprises a microarray comprising a probe selective for at least one single nucleotide polymorphism in the TRABD2B genomic locus. In some embodiments, the at least one single nucleotide polymorphism in the TRABD2B genomic locus is selected from the group consisting of rs7543124, rs6671927, rs12134443, rs11211624, rs2088361, rs1556981, rs11205430, rs1561573, rs11211613, rs12061891, rs11211632, rs17103939 and rs6684538.

In some embodiments, the microarray comprises probes selective for the single nucleotide polymorphisms rs6671927, rs2088361, rs1556981 and rs1561573.

In some embodiments, the microarray comprises probes selective for the single nucleotide polymorphisms rs6671927, rs2088361, rs1556981, rs11205430 and rs1561573.

In some embodiments, the microarray comprises probes selective for the single nucleotide polymorphisms rs11205430, rs1561573, rs11211613, rs12061891, rs11211632.

In some embodiments, the microarray further comprises a probe selective for at least one single nucleotide polymorphism in at least one genomic locus selected from the group consisting of PDC, NPY, ONECUT1, DLG4 and ELP5.

In some embodiments, the microarray further comprises probes selective for the single nucleotide polymorphisms in each of the genomic loci of PDC, NPY, ONECUT1, DLG4 and ELP5.

In some embodiments of the microarray, the single nucleotide polymorphism in the PDC genomic locus is selected from the group consisting of rs1882926, rs11801527, rs12407957, and rs10798041. For example, the single nucleotide polymorphism in the PDC genomic locus is selected from the group consisting of rs1882926 and rs11801527.

In some embodiments of the microarray, the single nucleotide polymorphism is selected from the group consisting of rs1882926, rs11801527, rs12407957, rs10798041, SNPs in linkage disequilibrium with any of the foregoing, and combinations thereof. In some embodiments of the microarray, the single nucleotide polymorphism in the NPY genomic locus is selected from the group consisting of rs16141, rs3779477, and rs16129. For example, the single nucleotide polymorphism in the NPY genomic locus is selected from the group consisting of rs16141 and rs3779477.

In some embodiments of the microarray, the single nucleotide polymorphism is selected from the group consisting of rs16141, rs3779477, rs16129, SNPs in linkage disequilibrium with any of the foregoing, and combinations thereof.

In some embodiments of the microarray, the single nucleotide polymorphism in the ONECUT1 genomic locus is selected from the group consisting of rs2440335, rs2440332, rs1899750, rs7180600, rs2456507, and rs2456525. For example, the single nucleotide polymorphism in the ONECUT1 genomic locus is selected from the group consisting of rs2440335, rs2440332, rs1899750 and rs7180600.

In some embodiments of the microarray, the single nucleotide polymorphism is selected from the group consisting of rs2440335, rs2440332, rs1899750, rs7180600, rs2456507, rs2456525, SNPs in linkage disequilibrium with any of the foregoing, and combinations thereof.

In some embodiments of the microarray, the single nucleotide polymorphism in the DLG4 genomic locus is selected from the group consisting of rs17203281, rs3826408, rs1875673, rs739669, rs2017365, and rs929229. For example, the single nucleotide polymorphism in the DLG4 genomic locus is selected from the group consisting of rs17203281, rs3826408 and rs1875673.

In some embodiments of the microarray, the single nucleotide polymorphism is selected from the group consisting of rs17203281, rs3826408, rs1875673, rs739669, rs2017365, rs929229, SNPs in linkage disequilibrium with any of the foregoing, and combinations thereof.

In some embodiments of the microarray, the single nucleotide polymorphism in the ELP5 genomic locus is selected from the group consisting of rs2106842, exm1286317, rs2074217, and rs222843. For example, the single nucleotide polymorphism in the ELP5 genomic locus is rs2106842. In some embodiments of the microarray, the single nucleotide polymorphism is selected from the group consisting of rs2106842, exm1286317, rs2074217, rs222843, SNPs in linkage disequilibrium with any of the foregoing, and combinations thereof.

In some embodiments, the microarray comprises probes selective for the single nucleotide polymorphisms rs7543124, rs6671927, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs2440335, rs1899750, rs1875673 and rs2106842.

In some embodiments, the microarray comprises probes selective for the single nucleotide polymorphisms rs7543124, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs1899750 and rs2106842 is determined.

One aspect of the invention comprises the use of the group of biomarkers, the kit, diagnostic composition or device, or the microarray as described herein for predicting a patient’s response to treatment with a α4β7 integrin antagonist. In some embodiments, the α4β7 integrin antagonist is vedolizumab.

In some embodiments, the use of the group of biomarkers, the kit, diagnostic composition or device, or the microarray as described herein for identifying a patient with Crohn’s Disease as being eligible for treatment with a α4β7 integrin antagonist. In some embodiments, the α4β7 integrin antagonist is vedolizumab. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows a summary of the genotype of individuals in clinical trials discussed in the Examples, after applying Quality Control (QC) procedures (1A), and baseline characteristics of individuals in the clinical trials discussed in the Examples (1B).

Figure 2 shows the top 10 genes whose SNPs are associated with clinical remission of Crohn’s Disease, as determined via a gene-level scan, in all individuals across multiple clinical trials (2A), in clinical trial C13007 (2B), and in clinical trial C13011 (2C); and in Caucasians across multiple clinical trials (2D).

Figure 3 shows the top 10 genes whose SNPs are associated with enhanced clinical response of vedolizumab in Crohn’s Disease patients, as determined via a gene-level scan, in all individuals across multiple clinical trials (3A), in clinical trial C13007 (3B), and in clinical trial C13011 (3C); and in Caucasians across multiple clinical trials (3D).

Figure 4 depicts a least square (LS) means plot for predicted clinical remission of Crohn’s disease using a 19-SNP model.

Figure 5 provides graphic data showing clinical remission or enhanced clinical response in individuals with Crohn’s Disease following administration of vedolizumab using an 11-SNP model. Figure 5A depicts a LS means plot showing clinical remission of Crohn’s Disease in individuals treated with vedolizumab vs. placebo; Figure 5B shows clinical remission over time in clinical trial C13007; Figure 5C shows clinical remission over time in clinical trial C13011; Figure 5D depicts a LS means plot showing enhanced clinical response to vedolizumab vs. placebo in individuals with Crohn’s Disease; Figure 5E shows enhanced clinical response over time in clinical trial C13007; Figure 5F shows enhanced clinical response over time in clinical trial C13011; Figure 5G depicts plots of Crohn’s Disease Activity Index (CDAI) score vs. genetic biomarker scores in patients treated with vedolizumab and placebo; and Figure 5H depicts a plot of the observed CDAIs vs. the predicted CDAI based on the 11-SNP genetic score.

Figure 6 depicts a LS means plot for predicted clinical remission of Crohn’s disease using an 8-SNP model.

Figure 7 provides graphic data showing clinical remission or enhanced clinical response in individuals with Crohn’s Disease following administration of vedolizumab using a 4-SNP model. Figure 7A depicts a LS means plot showing clinical remission of Crohn’s Disease in individuals treated with vedolizumab vs. placebo; Figure 7B shows clinical remission over time in clinical trial C13007; Figure 7C shows clinical remission over time in clinical trial C13011; Figure 7D depicts a LS means plot showing enhanced clinical response to vedolizumab vs. placebo in individuals with Crohn’s Disease; Figure 7E shows enhanced clinical response over time in clinical trial C13007; Figure 7F shows enhanced clinical response over time in clinical trial C13011; Figure 7G depicts plots of CDAI score vs. genetic biomarker scores in patients treated with vedolizumab and placebo; and Figure 7H depicts a plot of the observed CDAIs vs. the predicted CDAI based on the 4-SNP genetic score. Figure 8 depicts a LS means plot for predicted clinical remission of Crohn’s disease using a first 5-SNP model (8A) and a second 5-SNP model (8B).

Figure 9 shows a summary of demographic differences between cohorts 1 and 2 in the C13007 clinical trial (9A-B) and a summary of clinical characteristics in cohorts 1 and 2 of the C13007 clinical trial (9C).

Figure 10 depicts a LS means plot showing replication data with the 11-SNP model for predicted clinical remission of Crohn’s disease. DETAILED DESCRIPTION Provided herein are methods for treating Crohn’s Disease. In some embodiments, the individual is suffering from or has been diagnosed with Crohn’s Disease. Also described herein are methods for identifying an individual suffering from Crohn’s Disease that will likely respond favorably to treatment, e.g., by blocking α4β7 integrin signaling with α4β7 integrin direct binding agents. In some embodiments, the methods comprise identifying an individual that will respond favorably to treatment with an anti-integrin antibody, selected from the group consisting of vedolizumab, natalizumab, etrolizumab, and AMG181, or an anti-α4β7 ligand antibody (such as an antibody that binds MAdCAM-1) including binding agents such as PF-547659. Methods for identifying an individual who will likely experience an enhanced treatment response to, e.g., vedolizumab, natalizumab, etrolizumab, AMG181, and/or α4β7 ligand (MAdCAM-1) binding agents such as PF-547659 as compared to another individual are also described herein. Target Population The present inventors surprisingly discovered that individuals suffering from Crohn’s Disease who possess a TRABD2B variant, a CLDN7 variant, a GABARAP variant, an ELP5 variant, a CTDNEP1 variant, a PDC variant, a DLG4 variant, a MIR324 variant, a ONECUT1 variant, and/or a NPY variant are more likely to experience clinical remission and/or an enhanced treatment response, e.g., to vedolizumab, than individuals without the variants. The present inventors also surprisingly discovered that individuals suffering from Crohn’s Disease who possess a C5orf20 variant, a CLN5 variant, a COL24A1 variant, a TIFAB variant, a PLAGL1 variant, a CEP72 variant, a FBXL3 variant, a PAPOLG variant, a SLC47A1 variant, and/or a WRAP53 variant are more likely to experience clinical remission and/or an enhanced treatment response, e.g., to vedolizumab, than individuals without the variants. In some embodiments, the variants described herein are germline mutations and/or mutations in non-translated gene regions. In some embodiments, the mutations are located at the UTR region of a gene.

In some embodiments, an individual suffering from Crohn’s Disease who possesses a TRABD2B variant, a PDC variant, a NPY variant, a ONECUT1 variant, a DLG4 variant, a CLDN7 variant, and/or a ELP5 variant is more likely to experience an enhanced treatment response, e.g., to an anti-α4β7 antibody, e.g., to vedolizumab, than individuals without any of the variants. Individuals with variants as disclosed herein are likely to respond favorably to a treatment regimen administered to mitigate or cause remission of Crohn’s Disease. In some embodiments, the treatment comprises administration of vedolizumab. Unless otherwise noted, SNP positions disclosed herein are based on Genome Reference Consortium Human Genome Build GRCh37.

As used herein,“TRABD2B” refers to TraB Domain Containing 2B gene, which is located on chromosome 1. The start and end positions are located at 48,221,199 and 48,467,562. Hence, the TRABD2B genomic locus extends from position 48,221,199 to position 48,467,562 on chromosome 1. An exemplary gene sequence is Gene ID: 388630.

As used herein,“TRABD2B variant” is a TRABD2B gene with a sequence identity that is less than 100% identical to that of Gene ID: 388630. In some embodiments, the variant has a sequence identity that is from about 75% to about 99% identical to that of Gene ID: 388630, such as about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% identical to that of Gene ID: 388630. In some embodiments, a TRABD2B variant is a TRABD2B polynucleotide that exhibits at least one polymorphism in the TRABD2B coding region as compared to the coding region of Gene ID: 388630. In some embodiments, a TRABD2B variant is associated with a favorable response to α4β7 antagonist treatment, such as an anti-α4β7 antibody, such as vedolizumab. In some embodiments, a TRABD2B variant that is associated with a favorable response to treatment, such as vedolizumab, is selected from the group consisting of rs7543124 (position 48227135, alleles A/G), rs6671927 (position 48285768, alleles C/T), rs12134443 (position 48286563, alleles T/C), rs11211624 (position 48359634, alleles G/T), rs2088361 (position 48362713, alleles G/A), rs1556981 (position 48370525, alleles T/C), rs11205430 (position 48442182, alleles A/G), rs1561573 (position 48227943, alleles T/C), rs11211613 (position 48290860, alleles A/C), rs12061891 (position 48392033, alleles T/C), rs11211632 (position 48406460, alleles A/G), rs17103939 (position 48409812, alleles T/C), rs6684538 (position 48380390, alleles A/G), variants in linkage disequlibrium with any of these, and combinations thereof. Variants in linkage disequilibrium with one or more TRABD2B variants disclosed herein include any variant with a r 2 value > 0.8, > 0.9, or > 0.95.

An individual who is heterozygous or homozygous for a TRABD2B variant is“TRABD2B variant positive.”

The single nucleotide polymorphism in the TRABD2B genomic locus is, for example, selected from the group consisting of:

● SNP rs7543124 which is represented by a single polymorphic change at position 26 of SEQ ID NO: 1, wherein in one or two alleles of the wild-type nucleotide A is replaced by indicator nucleotide G,

● SNP rs6671927 which is represented by a single polymorphic change at position 26 of SEQ ID NO: 2, wherein in one or two alleles of the wild-type nucleotide C is replaced by indicator nucleotide T,

● SNP rs12134443 which is represented by a single polymorphic change at position 26 of SEQ ID NO: 3, wherein in one or two alleles of the wild-type nucleotide C is replaced by indicator nucleotide T,

● SNP rs11211624 which is represented by a single polymorphic change at position 26 of SEQ ID NO: 4, wherein in one or two alleles of the wild-type nucleotide G is replaced by indicator nucleotide T, ● SNP rs2088361 which is represented by a single polymorphic change at position 26 of SEQ ID NO: 5, wherein in one or two alleles of the wild-type nucleotide A is replaced by indicator nucleotide G,

● SNP rs1556981 which is represented by a single polymorphic change at position 26 of SEQ ID NO: 6, wherein in one or two alleles of the wild-type nucleotide C is replaced by indicator nucleotide T,

● SNP rs11205430 which is represented by a single polymorphic change at position 26 of SEQ ID NO: 7, wherein in one or two alleles of the wild-type nucleotide A is replaced by indicator nucleotide G,

● SNP rs1561573 which is represented by a single polymorphic change at position 26 of SEQ ID NO: 8, wherein in one or two alleles of the wild-type nucleotide C is replaced by indicator nucleotide T,

● SNP rs11211613 which is represented by a single polymorphic change at position 26 of SEQ ID NO: 9, wherein in one or two alleles of the wild-type nucleotide A is replaced by indicator nucleotide C,

● SNP rs12061891 which is represented by a single polymorphic change at position 26 of SEQ ID NO: 10, wherein in one or two alleles of the wild-type nucleotide C is replaced by indicator nucleotide T,

● SNP rs11211632 which is represented by a single polymorphic change at position 26 of SEQ ID NO: 11, wherein in one or two alleles of the wild-type nucleotide A is replaced by indicator nucleotide G,

● SNP rs17103939 which is represented by a single polymorphic change at position 26 of SEQ ID NO: 12, wherein in one or two alleles of the wild-type nucleotide C is replaced by indicator nucleotide T, and

● SNP rs6684538 which is represented by a single polymorphic change at position 26 of SEQ ID NO: 13, wherein in one or two alleles of the wild-type nucleotide A is replaced by indicator nucleotide G. As used herein,“PDC” refers to the Phosducin gene, which is located on chromosome 1. The start and end positions are located at 186,407,697 and 186,435,240. Hence, the PDC genomic locus extends from position 186,407,697 to position 186,435,240 on chromosome 1. An exemplary gene sequence is Gene ID: 5132.

As used herein,“PDC variant” is a PDC gene with a sequence identity that is less than 100% identical to that of Gene ID: 5132. In some embodiments, the variant has a sequence identity that is from about 75% to about 99% identical to that of Gene ID: 5132, such as about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% identical to that of Gene ID: 5132. In some embodiments, a PDC variant is a PDC polynucleotide that exhibits at least one polymorphism in the PDC coding region as compared to the coding region of Gene ID: 5132. In some embodiments, a PDC variant is associated with a favorable response to treatment, such as vedolizumab. In some embodiments, a PDC variant that is associated with a favorable response to treatment, such as vedolizumab, is selected from the group consisting of rs1882926 (position 186411579, alleles A/C), rs11801527 (position 186418798, alleles A/G), variants in linkage disequlibrium with any of these, and combinations thereof. Variants in linkage disequilibrium with one or more PDC variants disclosed herein include any variant with a r 2 value > 0.8, > 0.9, or > 0.95, such as rs12407957 and rs10798041.

An individual who is heterozygous or homozygous for a PDC variant is“PDC variant positive.”

The single nucleotide polymorphism in the PDC genomic locus is, for example, selected from the group consisting of:

● SNP rs1882926 which is represented by a single polymorphic change at position 26 of SEQ ID NO: 14, wherein in one or two alleles of the wild-type nucleotide A is replaced by indicator nucleotide C, and

● SNP rs11801527 which is represented by a single polymorphic change at position 26 of SEQ ID NO: 15, wherein in one or two alleles of the wild-type nucleotide A is replaced by indicator nucleotide G. As used herein,“NPY” refers to the Neuropeptide Y gene, which is located on chromosome 7. The start and end positions are located at 24,318,806 and 24,336,484. Hence, the NPY genomic locus extends from position 24,318,806 to position 24,336,484 on chromosome 7. An exemplary gene sequence is Gene ID: 4852.

As used herein,“NPY variant” is a NPY gene with a sequence identity that is less than 100% identical to that of Gene ID: 4852. In some embodiments, the variant has a sequence identity that is from about 75% to about 99% identical to that of Gene ID: 4852, such as about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% identical to that of Gene ID: 4852. In some embodiments, a NPY variant is a NPY polynucleotide that exhibits at least one polymorphism in the NPY coding region as compared to the coding region of Gene ID: 4852. In some embodiments, a NPY variant is associated with a favorable response to treatment, such as vedolizumab. In some embodiments, a NPY variant that is associated with a favorable response to treatment, such as vedolizumab, is selected from the group consisting of rs16141 (position 24324759, alleles A/C), rs3779477 (position 24327526, alleles T/C), variants in linkage disequlibrium with any of these, and combinations thereof. Variants in linkage disequilibrium with one or more NPY variants disclosed herein include any variant with a r 2 value > 0.8, > 0.9, or > 0.95, such as rs16129.

An individual who is heterozygous or homozygous for a NPY variant is“NPY variant positive.”

The single nucleotide polymorphism in the NPY genomic locus is, for example, selected from the group consisting of:

● SNP rs16141 which is represented by a single polymorphic change at position 26 of SEQ ID NO: 16, wherein in one or two alleles of the wild-type nucleotide A is replaced by indicator nucleotide C, and

● SNP rs3779477 which is represented by a single polymorphic change at position 26 of SEQ ID NO: 17, wherein in one or two alleles of the wild-type nucleotide C is replaced by indicator nucleotide T. As used herein,“ONECUT1” refers to the One Cut Homeobox 1 gene, which is located on chromosome 15. The start and end positions are located at 53,044,159 and 53,087,209. Hence, the ONECUT1 genomic locus extends from position 53,044,159 to position 53,087,209 on chromosome 15. An exemplary gene sequence is Gene ID: 3175.

As used herein,“ONECUT1 variant” is a ONECUT1 gene with a sequence identity that is less than 100% identical to that of Gene ID: 3175. In some embodiments, the variant has a sequence identity that is from about 75% to about 99% identical to that of Gene ID: 3175, such as about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% identical to that of Gene ID: 3175. In some embodiments, a ONECUT1 variant is a ONECUT1 polynucleotide that exhibits at least one polymorphism in the ONECUT1 coding region as compared to the coding region of Gene ID: 3175. In some embodiments, a ONECUT1 variant is associated with a favorable response to treatment, such as vedolizumab. In some embodiments, a ONECUT1 variant that is associated with a favorable response to treatment, such as vedolizumab, is selected from the group consisting of rs2440335 (position 53046210, alleles G/A), rs2440332 (position 53050252, alleles T/C), rs1899750 (position 53068506, alleles C/T), rs7180600 (position 53070141, alleles A/G), variants in linkage disequlibrium with any of these, and combinations thereof. Variants in linkage disequilibrium with one or more ONECUT1 variants disclosed herein include any variant with a r 2 value > 0.8, > 0.9, or > 0.95, such as rs2456507 and rs2456525.

An individual who is heterozygous or homozygous for a ONECUT1 variant is “ONECUT1 variant positive.”

The single nucleotide polymorphism in the ONECUT1 genomic locus is, for example, selected from the group consisting of:

● SNP rs2440335 which is represented by a single polymorphic change at position 26 of SEQ ID NO: 18, wherein in one or two alleles of the wild-type nucleotide A is replaced by indicator nucleotide G, ● SNP rs2440332 which is represented by a single polymorphic change at position 26 of SEQ ID NO: 19, wherein in one or two alleles of the wild-type nucleotide C is replaced by indicator nucleotide T,

● SNP rs1899750 which is represented by a single polymorphic change at position 26 of SEQ ID NO: 20, wherein in one or two alleles of the wild-type nucleotide C is replaced by indicator nucleotide T, and

● SNP rs7180600which is represented by a single polymorphic change at position 26 of SEQ ID NO: 21, wherein in one or two alleles of the wild-type nucleotide A is replaced by indicator nucleotide G.

As used herein,“DLG4” refers to the Discs, Large Homolog 4 gene, which is located on chromosome 15. The start and end positions are located at 7,088,209 and 7,128,369. Hence, the DLG4 genomic locus extends from position 7,088,209 to position 7,128,369 on chromosome 15. An exemplary gene sequence is Gene ID: 1742.

As used herein,“DLG4 variant” is a DLG4 gene with a sequence identity that is less than 100% identical to that of Gene ID: 1742. In some embodiments, the variant has a sequence identity that is from about 75% to about 99% identical to that of Gene ID: 1742, such as about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% identical to that of Gene ID: 1742. In some embodiments, a DLG4 variant is a DLG4 polynucleotide that exhibits at least one polymorphism in the DLG4 coding region as compared to the coding region of Gene ID: 1742. In some embodiments, a DLG4 variant is associated with a favorable response to treatment, such as vedolizumab. In some embodiments, a DLG4 variant that is associated with a favorable response to treatment, such as vedolizumab, is selected from the group consisting of rs17203281 (position 7099811, alleles A/G), rs3826408 (position 7101292, alleles T/C), rs1875673 (position 7108506, alleles T/G), variants in linkage disequlibrium with any of these, and combinations thereof. Variants in linkage disequilibrium with one or more DLG4 variants disclosed herein include any variant with a r 2 value > 0.8, > 0.9, or > 0.95, such as rs739669, rs2017365, and rs929229. An individual who is heterozygous or homozygous for a DLG4 variant is“DLG4 variant positive.”

The single nucleotide polymorphism in the DLG4 genomic locus is, for example, selected from the group consisting of:

● SNP rs17203281 which is represented by a single polymorphic change at position 26 of SEQ ID NO: 22, wherein in one or two alleles of the wild-type nucleotide A is replaced by indicator nucleotide G,

● SNP rs3826408 which is represented by a single polymorphic change at position 26 of SEQ ID NO: 23, wherein in one or two alleles of the wild-type nucleotide C is replaced by indicator nucleotide T, and

^ SNP rs1875673 which is represented by a single polymorphic change at position 26 of SEQ ID NO: 24, wherein in one or two alleles of the wild-type nucleotide A is replaced by indicator nucleotide T or G.

As used herein,“CLDN7” refers to the Claudin 7 gene, which is located on chromosome 17. The start and end positions are located at 7,158,221 and 7,171,512. Hence, the CLDN7 genomic locus extends from position 7,158,221 to position 7,171,512 on chromosome 17. An exemplary gene sequence is Gene ID: 1366.

As used herein,“CLDN7 variant” is a CLDN7 gene with a sequence identity that is less than 100% identical to that of Gene ID: 1366. In some embodiments, the variant has a sequence identity that is from about 75% to about 99% identical to that of Gene ID: 1366, such as about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% identical to that of Gene ID: 1366. In some embodiments, a CLDN7 variant is a CLDN7 polynucleotide that exhibits at least one polymorphism in the CLDN7 coding region as compared to the coding region of Gene ID: 1366. In some embodiments, a CLDN7 variant is associated with a favorable response to treatment, such as vedolizumab. In some embodiments, a CLDN7 variant that is associated with a favorable response to treatment, such as vedolizumab, is rs2106842 (position 7162451, alleles G/A), variants in linkage disequlibrium with any of these, and combinations thereof. Variants in linkage disequilibrium with one or more CLDN7 variants disclosed herein include any variant with a r 2 value > 0.8, > 0.9, or > 0.95, such as exm1286317, rs2074217, and rs222843.

An individual who is heterozygous or homozygous for a CLDN7 variant is“CLDN7 variant positive.”

As used herein,“ELP5” refers to the Elongator Acetyltransferase Complex Subunit 5 gene, which is located on chromosome 17. The start and end positions are located at 7,150,371 and 7,168,259. Hence, the ELP5 genomic locus extends from position 7,150,371 to position 7,168,259 on chromosome 17. An exemplary gene sequence is Gene ID: 23587.

As used herein,“ELP5 variant” is a ELP5 gene with a sequence identity that is less than 100% identical to that of Gene ID: 23587. In some embodiments, the variant has a sequence identity that is from about 75% to about 99% identical to that of Gene ID: 23587, such as about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% identical to that of Gene ID: 23587. ELP5 overlaps with CLDN7 and, therefore, in some embodiments an ELP5 variant is also a CLDN7 variant. Thus, in some embodiments, a single variant can be both an ELP5 variant and a CLDN7 variant. In some embodiments, a ELP5 variant is a ELP5 polynucleotide that exhibits at least one polymorphism in the ELP5 coding region as compared to the coding region of Gene ID: 23587. In some embodiments, a ELP5 variant is associated with a favorable response to treatment, such as vedolizumab. In some embodiments, a ELP5 variant that is associated with a favorable response to treatment, such as vedolizumab, is rs2106842 (position 7162451, alleles G/A), variants in linkage disequlibrium with any of these, and combinations thereof. Variants in linkage disequilibrium with one or more ELP5 variants disclosed herein include any variant with a r 2 value > 0.8, > 0.9, or > 0.95, such as rs2074217, rs222843, and exm1286317.

An individual who is heterozygous or homozygous for a ELP5 variant is“ELP5 variant positive.”

The single nucleotide polymorphism in the ELP5 genomic locus is, for example, SNP rs2106842 which is represented by a single polymorphic change at position 26 of SEQ ID NO: 25, wherein in one or two alleles of the wild-type nucleotide A is replaced by indicator nucleotide G.

As used herein,“GABARAP” refers to the GABA(A) Receptor-Associated Protein gene, which is located on chromosome 17. The start and end positions are located at 7,138,737 and 7,150,753. An exemplary gene sequence is Gene ID: 11337.

As used herein,“GABARAP variant” is a GABARAP gene with a sequence identity that is less than 100% identical to that of Gene ID: 11337. In some embodiments, the variant has a sequence identity that is from about 75% to about 99% identical to that of Gene ID: 11337, such as about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% identical to that of Gene ID: 11337. In some embodiments, a GABARAP variant is a GABARAP polynucleotide that exhibits at least one polymorphism in the GABARAP coding region as compared to the coding region of Gene ID: 11337. In some embodiments, a GABARAP variant is associated with a favorable response to treatment, such as vedolizumab.

An individual who is heterozygous or homozygous for a GABARAP variant is “GABARAP variant positive.”

As used herein,“CTDNEP1” refers to the CTD Nuclear Envelope Phosphatase 1 gene, which is located on chromosome 17. The start and end positions are located at 7,141,905 and 7,160,259. An exemplary gene sequence is Gene ID: 23399.

As used herein,“CTDNEP1 variant” is a CTDNEP1 gene with a sequence identity that is less than 100% identical to that of Gene ID: 23399. In some embodiments, the variant has a sequence identity that is from about 75% to about 99% identical to that of Gene ID: 23399, such as about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% identical to that of Gene ID: 23399. In some embodiments, a CTDNEP1 variant is a CTDNEP1 polynucleotide that exhibits at least one polymorphism in the CTDNEP1 coding region as compared to the coding region of Gene ID: 23399. In some embodiments, a CTDNEP1 variant is associated with a favorable response to treatment, such as vedolizumab.

An individual who is heterozygous or homozygous for a CTDNEP1 variant is “CTDNEP1 variant positive.” As used herein,“MIR324” refers to the MicroRNA 324 gene, which is located on chromosome 17. The start and end positions are located at 7,121,615 and 7,131,698. An exemplary gene sequence is Gene ID: 442898.

As used herein,“MIR324 variant” is a MIR324 gene with a sequence identity that is less than 100% identical to that of Gene ID: 442898. In some embodiments, the variant has a sequence identity that is from about 75% to about 99% identical to that of Gene ID: 442898, such as about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% identical to that of Gene ID: 442898. In some embodiments, a MIR324 variant is a MIR324 polynucleotide that exhibits at least one polymorphism in the MIR324 coding region as compared to Gene ID: 442898. In some embodiments, a MIR324 variant is associated with a favorable response to treatment, such as vedolizumab.

An individual who is heterozygous or homozygous for a MIR324 variant is“MIR324 variant positive.”

As used herein,“C5orf20” refers to the Chromosome 5 Open Reading Frame 20 gene (dendritic cell-associated nuclear protein, DCANP1), which is located on chromosome 5. The start and end positions are located at 134,774,903 and 134,788,038. An exemplary gene sequence is Gene ID: 140947.

As used herein,“C5orf20 variant” is a C5orf20 gene with a sequence identity that is less than 100% identical to that of Gene ID: 140947. In some embodiments, the variant has a sequence identity that is from about 75% to about 99% identical to that of Gene ID: 140947, such as about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% identical to that of Gene ID: 140947. In some embodiments, a C5orf20 variant is a C5orf20 polynucleotide that exhibits at least one polymorphism in the C5orf20 coding region as compared to the coding region of Gene ID: 140947. In some embodiments, a C5orf20 variant is associated with a favorable response to treatment, such as vedolizumab.

An individual who is heterozygous or homozygous for a C5orf20 variant is“C5orf20 variant positive.” As used herein,“CLN5” refers to the Ceroid-Lipofuscinosis, Neuronal 5 gene, which is located on chromosome 13. The start and end positions are located at 77,561,058 and 77,581,652. An exemplary gene sequence is Gene ID: 1203.

As used herein,“CLN5 variant” is a CLN5 gene with a sequence identity that is less than 100% identical to that of Gene ID: 1203. In some embodiments, the variant has a sequence identity that is from about 75% to about 99% identical to that of Gene ID: 1203, such as about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% identical to that of Gene ID: 1203. In some embodiments, a CLN5 variant is a CLN5 polynucleotide that exhibits at least one polymorphism in the CLN5 coding region as compared to the coding region of Gene ID: 1203. In some embodiments, a CLN5 variant is associated with a favorable response to treatment, such as vedolizumab.

An individual who is heterozygous or homozygous for a CLN5 variant is“CLN5 variant positive.”

As used herein,“COL24A1” refers to the Collagen, Type XXIV, Alpha 1 gene, which is located on chromosome 1. The start and end positions are located at 86,189,915 and 86,627,121. An exemplary gene sequence is Gene ID: 255631.

As used herein,“COL24A1 variant” is a COL24A1 gene with a sequence identity that is less than 100% identical to that of Gene ID: 255631. In some embodiments, the variant has a sequence identity that is from about 75% to about 99% identical to that of Gene ID: 255631, such as about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% identical to that of Gene ID: 255631. In some embodiments, a COL24A1 variant is a COL24A1 polynucleotide that exhibits at least one polymorphism in the COL24A1 coding region as compared to the coding region of Gene ID: 255631. In some embodiments, a COL24A1 variant is associated with a favorable response to treatment, such as vedolizumab.

An individual who is heterozygous or homozygous for a COL24A1 variant is“COL24A1 variant positive.”

As used herein,“TIFAB” refers to the TRAF-Interacting Protein With Forkhead- Associated Domain, Family Member B gene, which is located on chromosome 5. The start and end positions are located at 134,779,557 and 134,793,089. An exemplary gene sequence is Gene ID: 497189.

As used herein,“TIFAB variant” is a TIFAB gene with a sequence identity that is less than 100% identical to that of Gene ID: 497189. In some embodiments, the variant has a sequence identity that is from about 75% to about 99% identical to that of Gene ID: 497189, such as about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% identical to that of Gene ID: 497189. In some embodiments, a TIFAB variant is a TIFAB polynucleotide that exhibits at least one polymorphism in the TIFAB coding region as compared to the coding region of Gene ID: 497189. In some embodiments, a TIFAB variant is associated with a favorable response to treatment, such as vedolizumab.

An individual who is heterozygous or homozygous for a TIFAB variant is“TIFAB variant positive.”

As used herein,“PLAGL1” refers to the Pleiomorphic Adenoma Gene-Like 1 gene, which is located on chromosome 6. The start and end positions are located at 144,256,436 and 144,390,735. An exemplary gene sequence is Gene ID: 5325.

As used herein,“PLAGL1 variant” is a PLAGL1 gene with a sequence identity that is less than 100% identical to that of Gene ID: 5325. In some embodiments, the variant has a sequence identity that is from about 75% to about 99% identical to that of Gene ID: 5325, such as about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% identical to that of Gene ID: 5325. In some embodiments, a PLAGL1 variant is a PLAGL1 polynucleotide that exhibits at least one polymorphism in the PLAGL1 coding region as compared to the coding region of Gene ID: 5325. In some embodiments, a PLAGL1 variant is associated with a favorable response to treatment, such as vedolizumab.

An individual who is heterozygous or homozygous for a PLAGL1 variant is“PLAGL1 variant positive.”

As used herein,“CEP72” refers to the Centrosomal Protein 72kDa gene, which is located on chromosome 5. The start and end positions are located at 607,404 and 658,666. An exemplary gene sequence is Gene ID: 55722. As used herein,“CEP72 variant” is a CEP72 gene with a sequence identity that is less than 100% identical to that of Gene ID: 55722. In some embodiments, the variant has a sequence identity that is from about 75% to about 99% identical to that of Gene ID: 55722, such as about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% identical to that of Gene ID: 55722. In some embodiments, a CEP72 variant is a CEP72 polynucleotide that exhibits at least one polymorphism in the CEP72 coding region as compared to the coding region of Gene ID: 55722. In some embodiments, a CEP72 variant is associated with a favorable response to treatment, such as vedolizumab.

An individual who is heterozygous or homozygous for a CEP72 variant is“CEP72 variant positive.”

As used herein,“FBXL3” refers to the F-Box And Leucine-Rich Repeat Protein 3 gene, which is located on chromosome 13. The start and end positions are located at 77,574,388 and 77,606,331. An exemplary gene sequence is Gene ID: 26224.

As used herein,“FBXL3 variant” is a FBXL3 gene with a sequence identity that is less than 100% identical to that of Gene ID: 26224. In some embodiments, the variant has a sequence identity that is from about 75% to about 99% identical to that of Gene ID: 26224, such as about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% identical to that of Gene ID: 26224. In some embodiments, a FBXL3 variant is a FBXL3 polynucleotide that exhibits at least one polymorphism in the FBXL3 coding region as compared to the coding region of Gene ID: 26224. In some embodiments, a FBXL3 variant is associated with a favorable response to treatment, such as vedolizumab.

An individual who is heterozygous or homozygous for a FBXL3 variant is“FBXL3 variant positive.”

As used herein,“PAPOLG” refers to the Poly(A) Polymerase Gamma gene, which is located on chromosome 2. The start and end positions are located at 60,978,364 and 61,034,221. An exemplary gene sequence is Gene ID: 64895.

As used herein,“PAPOLG variant” is a PAPOLG gene with a sequence identity that is less than 100% identical to that of Gene ID: 64895. In some embodiments, the variant has a sequence identity that is from about 75% to about 99% identical to that of Gene ID: 64895, such as about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% identical to that of Gene ID: 64895. In some embodiments, a PAPOLG variant is a PAPOLG polynucleotide that exhibits at least one polymorphism in the PAPOLG coding region as compared to the coding region of Gene ID: 64895. In some embodiments, a PAPOLG variant is associated with a favorable response to treatment, such as vedolizumab.

An individual who is heterozygous or homozygous for a PAPOLG variant is“PAPOLG variant positive.”

As used herein,“SLC47A1” refers to the Solute Carrier Family 47 (Multidrug And Toxin Extrusion), Member 1 gene, which is located on chromosome 17. The start and end positions are located at 19,432,166 and 19,487,346. An exemplary gene sequence is Gene ID: 55244.

As used herein,“SLC47A1 variant” is a SLC47A1 gene with a sequence identity that is less than 100% identical to that of Gene ID: 55244. In some embodiments, the variant has a sequence identity that is from about 75% to about 99% identical to that of Gene ID: 55244, such as about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% identical to that of Gene ID: 55244. In some embodiments, a SLC47A1 variant is a SLC47A1 polynucleotide that exhibits at least one polymorphism in the SLC47A1 coding region as compared to the coding region of Gene ID: 55244. In some embodiments, a SLC47A1 variant is associated with a favorable response to treatment, such as vedolizumab.

An individual who is heterozygous or homozygous for a SLC47A1 variant is“SLC47A1 variant positive.”

As used herein,“WRAP53” refers to the WD Repeat Containing, Antisense to TP53 gene, which is located on chromosome 17. The start and end positions are located at 7,584,388 and 7,611,820. An exemplary gene sequence is Gene ID: 55135.

As used herein,“WRAP53 variant” is a WRAP53 gene with a sequence identity that is less than 100% identical to that of Gene ID: 55135. In some embodiments, the variant has a sequence identity that is from about 75% to about 99% identical to that of Gene ID: 55135, such as about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% identical to that of Gene ID: 55135. In some embodiments, a WRAP53 variant is a WRAP53 polynucleotide that exhibits at least one polymorphism in the WRAP53 coding region as compared to the coding region of Gene ID: 55135. In some embodiments, a WRAP53 variant is associated with a favorable response to treatment, such as vedolizumab.

An individual who is heterozygous or homozygous for a WRAP53 variant is“WRAP53 variant positive.”

As used herein, the term“variant” may refer to a“single nucleotide polymorphism” or “SNP”. In particular, the term“variant” may refer to the SNPs specifically disclosed herein.

As used herein, a single nucleotide polymorphism is a variation at a single position in a DNA sequence among individuals. For example, if more than 1% of a population does not carry the same nucleotide at a specific position in the DNA sequence, then this variation can be classified as a SNP. If a SNP occurs within a gene, then the gene is described as having more than one allele. In these cases, SNPs may lead to variations in the amino acid sequence. SNPs, however, are not just associated with genes; they can also occur in noncoding regions of DNA.

Although a particular SNP may not cause a disorder, some SNPs can be associated with certain diseases. These associations may allow the determination of one or more SNPs in order to evaluate an individual's genetic predisposition to develop a disease. In addition, if certain SNPs are known to be associated with a trait, stretches of DNA near these SNPs may be examined in an attempt to identify the gene or genes responsible for the trait.

Known SNPs can be taken from databases such as the SNP database at the NCBI

(National Center for Biotechnology Information, Bethesda, MD; available at

ncbi.nlm.nih.gov/SNP).

The SNPs as described herein may be present on the Watson or the Crick strand, with presence of the corresponding base. If, for example, a polymorphism is present on the Watson strand as A, it is present on the Crick strand as T, if the polymorphism is present on the Watson strand as T, it is present on the Crick strand as A, if the polymorphism is present on the Watson strand as G, it is present on the Crick strand as C, and if the polymorphism is present on the Watson strand as C, it is present on the Crick strand as G, and vice versa. Also, the insertion or deletion of bases may be detected on the Watson and/or the Crick strand, with correspondence as defined above. For analytic purposes the strand identity may be defined, or fixed, or may be chosen at will, e.g. in dependence on factors such the availability of binding elements, GC- content etc. Furthermore, for the sake of accuracy, the SNP may be defined on both strands (Crick and Watson) at the same time, and accordingly be analyzed.

The term "allele" or "allelic sequence" as used herein refers to a particular form of a gene or a particular nucleotide, e.g. a DNA sequence at a specific chromosomal location or locus. In certain embodiments a SNP as defined herein may be found at or on one of two alleles in the human genome of a single subject. In further specific embodiments, a SNP as defined herein may also be found at or on both alleles in the human genome of a single subject. The presence of an indicator nucleotide or an indicator triplet as defined herein on both alleles may have a higher predictive value than the presence of an indicator nucleotide or an indicator triplet on one allele only, the other allele comprising a wild-type genotype.

The nucleotide that is present in the majority of the population is also referred to as wild- type allele or major allele. In one embodiment, the term "wild-type sequence" as used herein refers to the sequence of an allele, which is not predictive for the subject’s treatment response to a α4β7 integrin antagonist. In another embodiment, the term "wild-type sequence" as used herein refers to the sequence of an allele, which is predictive for the subject’s treatment response to a α4β7 integrin antagonist. The term may further refer to the sequence of the non phenotype- associated allele with the highest prevalence within a population, e.g. within a Caucasian population. As used herein, this state is defined as“absence of a SNP”.

The specific nucleotide that is present in the minority of the population is also referred as the point mutation, mutated nucleotide or minor allele. As used herein, this state is defined as “presence of a SNP”, "the presence of a polymorphic variant" or "the presence of a biomarker".

In theory, the wild-type allele could be mutated to three different nucleotides. However, the event of a mutation to a first nucleotide in the reproductive cells of an individual that gets established in a population occurs very rarely. The event that the same position is mutated to a second nucleotide and established in the population virtually never occurs and can be therefore neglected. Therefore, as used herein, a certain nucleotide position in the genome of an individual can have two states, the wild-type state (absence of a SNP) and the mutated state (presence of a SNP).

As described above, the presence or absence of at least one single nucleotide

polymorphism in the TRABD2B gene in a sample of a patient can be indicative for a treatment response to a α4β7 integrin antagonist. The at least one polymorphic variant in the TRABD2B gene may be selected from a group of biomarkers. The term "biomarker", as used herein, relates to any nucleic acid sequence of any length, or a derivative thereof, which comprises a

polymorphic variant such as the polymorphic variant in the genes described herein. In particular, the term "biomarker" may relate to SNPs.

The term "indicator nucleotide" may refer to a non-wild-type nucleotide at positions of the sequences as described in Tables 1B and 7 and SEQ ID NOs.1-25.

Both the presence and the absence of an indicator nucleotide, i.e. a single nucleotide polymorphism, can be predictive for a patient’s response to treatment. This is also reflected in the embodiments described herein.

Polymorphisms in linkage disequilibrium with a SNP as disclosed herein can be identified by methods known in the art. For example, Develin and Risch (1995) Genomics:

29(2): 311-322 provide guidance for determining the parameter delta (also referred to as the“r”) as a standard measure of the disequilibrium. Gabriel et al. (2002) Science 296(5576):2225-2229 provides instructions for finding the maximal r 2 value in populations for disease gene mapping. Further, Carlson et al. (2004) Am. J. Hum. Genet.74(1): 106-120 disclose methods for selecting and analyzing polymorphisms based on linkage disequilibrium for disease gene association mapping. Stoyanovich and Pe’er (2008) Bioinformatics 24(3): 440-442 show that

polymorphisms in linkage disequilibrium with identified SNPs have virtually identical response profiles. Currently, several databases provide datasets that can be searched for polymorphisms in strong linkage disequilibrium, which can be accessed at the websites maintained by the following entities : 1000 Genomes project website maintained by the European Bioinformatics Institute, Hinxton, Cambridge, UK the International HapMap Project (website maintained by NCBI), the SNAP (SNP Annotation and Proxy Search website maintained by the Broad Institute, Cambridge MA. An example workflow for determining SNPs linkage disequilibrium to a specific SNP is outlined in Uhr et al. (2008) Neuron 57(2): 203-209.

As used herein, a SNP in strong linkage disequilibrium with a SNP as specified herein may refer to a SNP that is in linkage disequilibrium with an r 2 equal to or higher than 0.8, preferably equal to or higher than 0.9 and most preferably equal to or higher than 0.95 in the tested population or an ethnically close reference population with the specified SNP. Methods of Treatment “Treatment” as used herein refers to any measure that imparts a benefit to a subject afflicted with or diagnosed with Crohn’s Disease (i.e., an enhanced treatment effect), including improvement in the condition of the subject, e.g., human, or in one or more symptoms of Crohn’s Disease. In some embodiments, the improvement comprises clinical remission (e.g., as determined by a Crohn’s Disease Activity Index (CDAI) score of≤ 150 points at week 2, 4, 6, and/or 10 of treatment), and/or an enhanced clinical response (e.g., as determined by a≥ 100 point decrease in CDAI score from baseline). In some embodiments, treatment includes remission of the underlying condition and/or symptoms thereof. “Treatment” does not necessarily imply that the subject will be treated until total recovery. As used herein, a “favorable” response or that a patient will“respond favorably” to treatment with an α4β7 antagonist for the treatment of Crohn’s disease is that the patient will have clinical response and/or clinical remission of the disease, by typical clinical measures. For example, clinical response is a 70 point or greater decrease in the Crohn’s Disease Activity Index (CDAI) score from the baseline at entering treatment.

The term“treatment response” is intended to mean that a subject which is characterized by the presence or absence of at least one SNP as discussed herein shows an improvement in the condition of the subject or in one or more symptoms of Crohn’s disease as described above.

The term "subject eligible for treatment with a α4β7 antagonist" as used herein may refer to a patient with inflammatory bowel disease, for example Crohn’s disease, who shows, or is predicted to show, a positive treatment response during and/or after the treatment with said α4β7 antagonist compared to the state before the treatment. In one embodiment, a subject eligible for treatment with a α4β7 antagonist is identified by the methods for predicting a treatment response to an α4β7 antagonist as described herein.

As used herein, an“α4β7 antagonist” is a molecule which antagonizes, reduces or inhibits the function of α4β7 integrin. Such antagonist may antagonize the interaction of α4 β7 integrin with one or more of its ligands. Human α4β7 integrin is a heterodimer of an α 4 chain (CD49D, ITGA4) and a β 7 chain (ITGB7). Each chain can form a heterodimer with an alternative integrin chain, to form α 4 β 1 or α E β 7 . Human α 4 and β 7 genes (GenBank (National Center for Biotechnology Information, Bethesda, MD) RefSeq Accession numbers NM_000885 and NM_000889, respectively) are expressed by B and T lymphocytes, particularly memory CD4+ lymphocytes. Ligands for α4 β7 integrin include vascular cell adhesion molecule (VCAM), fibronectin and mucosal addressin (MAdCAM (e.g., MAdCAM-1)).

An α4β7 antagonist may bind either chain of the heterodimer or a complex requiring both chains of the α4β7 integrin, or it may bind a ligand, such as MAdCAM. An α4β7 antagonist may be an antibody which performs such binding function, such as an anti- α4β7-integrin antibody (e.g., MLN0002, described in PCT publications nos. WO98/06248 and WO07/61679, vedolizumab Chemical Abstract Service (CAS, American Chemical Society) Registry number 943609-66-3, or AMG-181 or other antibodies described in US 2010/0254975); an anti-α4- integrin antibody (e.g., humanized MAb 21.6 (Bendig et al., U.S. Pat. No. 5,840,299) and derivatives thereof), an anti-β7-integrin antibody (e.g., FIB504 or a humanized derivative (e.g., Fong et al., U.S. Pat. No. 7,528,236), an anti-MAdCAM antibody (see e.g., US Patent No. 8,277,808, PF-00547659 or antibodies described in WO2005/067620), or an engineered form of a ligand, such as a MAdCAM-Fc chimera such as described in US Patent No. 7,803,904. In some embodiments, an α4β7 antagonist has“binding specificity for the α4β7 complex” and binds to α4β7, but not to α4β1 or αE β7. Treatment methods using anti-α4β7 integrin antibodies are described in publication nos. U.S. 2005/0095238, U.S. 2005/0095238, WO2012151248 and WO 2012/151247. In some embodiments, the methods comprise treating Crohn’s Disease in an individual identified as TRABD2B variant positive, CLDN7 variant positive, GABARAP variant positive, ELP5 variant positive, CTDNEP1 variant positive, PDC variant positive, DLG4 variant positive, MIR324 variant positive, ONECUT1 variant positive, and/or NPY variant positive. In some embodiments, the methods comprise treating Crohn’s Disease in an individual identified as C5orf20 variant positive, CLN5 variant positive, COL24A1 variant positive, TIFAB variant positive, PLAGL1 variant positive, CEP72 variant positive, FBXL3 variant positive, PAPOLG variant positive, SLC47A1 variant positive, and/or WRAP53 variant positive.

In some embodiments, the methods comprise treating Crohn’s Disease in an individual identified as (i) TRABD2B variant positive, (ii) PDC variant positive, (iii) NPY variant positive, (iv) ONECUT1 variant positive, (v) DLG4 variant positive, (vi) CLDN7 variant positive, (vii) ELP5 variant positive, or (viii) any combination of these as provided herein by administering an anti-α4β7 antibody to the individual. In some embodiments, the individual is TRABD2B variant positive, PDC variant positive, NPY variant positive, ONECUT1 variant positive, DLG4 variant positive, CLDN7 variant positive, and ELP5 variant positive. In some embodiments, the anti- α4β7 antibody is vedolizumab.

In some embodiments, methods for treating Crohn’s Disease in an individual comprises determining that the individual is TRABD2B variant positive, CLDN7 variant positive, GABARAP variant positive, ELP5 variant positive, CTDNEP1 variant positive, PDC variant positive, DLG4 variant positive, MIR324 variant positive, ONECUT1 variant positive, NPY variant positive, or any combination of these, and administering to the individual an α4β7 integrin antagonist, such as a treatment selected from the group consisting of vedolizumab, natalizumab, etrolizumab, AMG181and α4β7 ligand (MAdCAM-1) binding agents such as PF- 547659 or other monoclonal antibodies or small molecules that target the same mechanism of action.

In some embodiments, methods for treating Crohn’s Disease in an individual comprises determining that the individual is C5orf20 variant positive, CLN5 variant positive, COL24A1 variant positive, TIFAB variant positive, PLAGL1 variant positive, CEP72 variant positive, FBXL3 variant positive, PAPOLG variant positive, SLC47A1 variant positive, WRAP53 variant positive, or any combination of these, and administering to the inidividual vedolizumab, natalizumab, etrolizumab, AMG181and/or α4β7 ligand (MAdCAM-1) binding agents such as PF-547659 or other monoclonal antibodies or small molecules that target the same mechanism of action.

In some embodiments, methods for treating Crohn’s Disease in an individual comprises determining that the individual is (i) TRABD2B variant positive, (ii) PDC variant positive, (iii) NPY variant positive, (iv) ONECUT1 variant positive, (v) DLG4 variant positive, (vi) CLDN7 variant positive, (vii) ELP5 variant positive, or (viii) any combination of these, such as TRABD2B, PDC, NPY, ONECUT1, DLG4, CLDN7, and ELP5 variant positive and administering to the inidividual vedolizumab, natalizumab, etrolizumab, AMG181 and/or α4β7 ligand (MAdCAM-1) binding agents such as PF-547659 or other monoclonal antibodies or small molecules that target the same mechanism of action.

Vedolizumab may be administered by any suitable method, such as by one or more of intravenous injection, subcutaneous injection, or infusion. In some embodiments, vedolizumab is administered at a dose of 50 mg, 100 mg, 300 mg, or 500 mg. In some embodiments, the vedolizumab is administered, for example subcutaneously, at a dose of 0.05 mg/kg, 0.10 mg/kg, 0.15 mg/kg, 0.2 mg/kg, 0.25 mg/kg, 0.3 mg/kg. 0.4 mg/kg, or 0.5 mg/kg, at a dose of 108 mg, 216 mg, 160 mg or 165 mg. The vedolizumab may be administered once per day, per week, per month, or per year. In some embodiments, the vedolizumab is administered at zero, two and six weeks, and then every four weeks or every eight weeks thereafter. In some embodiments, vedolizumab is administered one or more times, and then at least one month, at least six months, or at least one year later, vedolizumab is again administered one or more times. In some embodiments, 300 mg vedolizumab may be administered by intravenous infusion at zero, two, and six weeks, and then at four weeks intervals or eight week intervals thereafter. In some embodiments, 300 mg vedolizumab may be administered by intravenous infusion at zero, two, and six weeks, and then at two, three or four weeks intervals, 108 mg of vedolizumab may be administered subcutaneously. In some embodiments, methods comprise determining the likelihood that an individual suffering from Crohn’s disease is likely to experience an enhanced treatment effect when treated with vedolizumab. In some embodiments, the methods comprise assaying a biological sample obtained from an individual for the presence or absence of a TRABD2B variant, a CLDN7 variant, a GABARAP variant, an ELP5 variant, a CTDNEP1 variant, a PDC variant, a DLG4 variant, a MIR324 variant, a ONECUT1 variant, and/or a NPY variant. In some embodiments, the methods comprise assaying a biological sample obtained from an individual for the presence or absence of a C5orf20 variant, a CLN5 variant, a COL24A1 variant, a TIFAB variant, a PLAGL1 variant, a CEP72 variant, a FBXL3 variant, a PAPOLG variant, a SLC47A1 variant, and/or a WRAP53 variant. In some embodiments, the methods comprise assaying a biological sample obtained from an individual for the presence or absence of a TRABD2B variant and/or a PDC variant and/or a NPY variant and/or a ONECUT1 variant and/or a DLG4 variant and/or a CLDN7 variant and/or a ELP5 variant and (ii) detecting the presence of the TRABD2B variant and/or the PDC variant and/or the NPY variant and/or the ONECUT1 variant and/or the DLG4 variant and/or the CLDN7 variant and/or the ELP5 variant.

In some embodiments, the individual is determined to experience an enhanced treatment effect when treated with vedolizumab if the TRABD2B variant and/or the PDC variant and/or the NPY variant and/or the ONECUT1 variant and/or the DLG4 variant and/or the CLDN7 variant and/or the ELP5 variant are present in nucleic acids from the individual.

In some embodiments, the methods comprise administering vedolizumab to the individual that is TRABD2B variant positive, PDC variant positive, NPY variant positive, ONECUT1 variant positive, DLG4 variant positive, CLDN7 variant positive, and/or ELP5 variant positive.

Some embodiments comprise the use of an active agent in the treatment of Crohn’s Disease in an individual. Some embodiments comprise an active agent for use as a medicament in the treatment of Crohn’s Disease in an individual. Some embodiments comprise use of an active agent in the preparation of a medicament for the treatment of Crohn’s Disease in an individual. In some embodiments, the individual is identified as or characterized as being (i) TRABD2B variant positive, (ii) PDC variant positive, (iii) NPY variant positive, (iv) ONECUT1 variant positive, (v) DLG4 variant positive, (vi) CLDN7 variant positive, (vii) ELP5 variant positive, or (viii) any combination of these as provided herein by administering an anti-α4β7 antibody to the individual. In some embodiments, the individual is TRABD2B variant positive, PDC variant positive, NPY variant positive, ONECUT1 variant positive, DLG4 variant positive, CLDN7 variant positive, and ELP5 variant positive. In some embodiments, the active agent is an anti-integrin antibody selected from the group consisting of vedolizumab, natalizumab, etrolizumab, and AMG181, or an anti-α4β7 ligand antibody (such as an antibody that binds MAdCAM-1) including binding agents such as PF-547659.

One aspect of the invention comprises an α4β7 integrin antagonist for use in the treatment of a subject with Crohn’s Disease, wherein the subject has been selected for treatment with said antagonist by having determined the presence or absence of at least one single nucleotide polymorphism in the TRABD2B genomic locus in a sample obtained from said subject, wherein the presence or absence of the at least one single nucleotide polymorphism in the TRABD2B genomic locus is predictive for the subject’s treatment response to said α4β7 integrin antagonist.

Some embodiments comprise an α4β7 integrin antagonist for use in the treatment of a subject with Crohn’s Disease, wherein the subject is selected for treatment with said α4β7 integrin antagonist by determining or having determined the presence or absence of at least one single nucleotide polymorphism in the TRABD2B genomic locus in a sample obtained from said subject, wherein the presence or absence of the at least one single nucleotide polymorphism in the TRABD2B genomic locus is associated with a response to said treatment.

Some embodiments comprise an α4β7 integrin antagonist for use in the treatment of a subject with Crohn’s Disease, wherein the subject has been selected for treatment with said α4β7 integrin antagonist by determining or having determined the presence or absence of at least one single nucleotide polymorphism in the TRABD2B genomic locus in a sample obtained from said subject, wherein the presence or absence of the at least one single nucleotide polymorphism in the TRABD2B genomic locus is associated with a response to said treatment. Some embodiments comprise an α4β7 integrin antagonist for use in the treatment of a subject with Crohn’s Disease, wherein the subject has been identified as being eligible for treatment with said α4β7 integrin antagonist by determining or having determined the presence or absence of at least one single nucleotide polymorphism in the TRABD2B genomic locus, wherein the presence or absence of the at least one single nucleotide polymorphism in the TRABD2B genomic locus is predictive for the subject’s treatment response to said α4β7 integrin antagonist.

Some embodiments comprise an α4β7 integrin antagonist for use in the treatment of a subject with Crohn’s Disease, wherein the subject is selected for said treatment by determining or having determined the presence or absence of at least one single nucleotide polymorphism in the TRABD2B genomic locus, wherein the presence or absence of the at least one single nucleotide polymorphism in the TRABD2B genomic locus is associated with a response to said treatment.

Some embodiments comprise an α4β7 integrin antagonist for use in the treatment of a subject with inflammatory bowel disease, wherein the subject has been selected by determining or having determined the presence or absence of at least one single nucleotide polymorphism in the TRABD2B genomic locus, wherein the presence or absence of the at least one single nucleotide polymorphism in the TRABD2B genomic locus is associated with a response to said treatment.

Some embodiments comprise an α4β7 integrin antagonist for use in the treatment of a subject with inflammatory bowel disease, wherein the subject is characterized by the presence or absence of at least one single nucleotide polymorphism in the TRABD2B genomic locus and the treatment comprises a step of determining whether the single nucleotide polymorphism in the TRABD2B genomic locus is present or absent, wherein the presence or absence of the at least one single nucleotide polymorphism in the TRABD2B genomic locus is associated with a response to said treatment.

In some embodiments, the α4β7 integrin antagonist is vedolizumab. In the above embodiments, the at least one single nucleotide polymorphism in the TRABD2B genomic locus can be selected from the group consisting of rs7543124, rs6671927, rs12134443, rs11211624, rs2088361, rs1556981, rs11205430, rs1561573, rs11211613, rs12061891, rs11211632, rs17103939 and rs6684538.

In one embodiment, the presence or absence of the single nucleotide polymorphisms rs2088361 and rs1556981 is or has been determined, wherein for example the absence of the single nucleotide polymorphisms rs2088361 and rs1556981 is predictive for the subject’s treatment response to said α4β7 integrin antagonist.

In another embodiment, the presence or absence of the single nucleotide polymorphisms rs6671927, rs2088361, rs1556981 and rs1561573 is or has been determined wherein for example the absence of the single nucleotide polymorphisms rs6671927, rs2088361 and rs1556981 and the presence of the single nucleotide polymorphism rs1561573 is predictive for the subject’s treatment response to said α4β7 integrin antagonist. Preferably, the subject is or has been selected for treatment with the α4β7 integrin antagonist by using the following formula:

Score i = (0.32 * rs1561573)– (0.4502 * rs6671927)– (0.6524 * rs2088361)– (0.8948 * rs1556981),

wherein the value for rs1561573, rs6671927, rs2088361 and rs1556981, respectively, is 2 if the single nucleotide polymorphism is present in both alleles, 1 if the single nucleotide polymorphism is present in one allele, and 0 if the single nucleotide polymorphism is not present and wherein a subject having a score of more than -1.4350 is or has been selected for treatment with said α4β7 integrin antagonist.

In another embodiment the presence or absence of the single nucleotide polymorphisms rs6671927, rs2088361, rs1556981, rs11205430 and rs1561573 is or has been determined, wherein for example the absence of the single nucleotide polymorphisms rs6671927, rs2088361, rs1556981 and rs11205430 and the presence of the single nucleotide polymorphism rs1561573 is predictive for the subject’s treatment response to said α4β7 integrin antagonist. Preferably, the subject is or has been selected for treatment with the α4β7 integrin antagonist by using the following formula: Score i = (0.2738 * rs1561573)– (0.3913 * rs6671927)– (0.5404 * rs2088361)– (0.7396 * rs1556981)– (0.1912 * rs11205430),

wherein the value for rs1561573, rs6671927, rs2088361, rs1556981 and rs11205430, respectively, is 2 if the single nucleotide polymorphism is present in both alleles, 1 if the single nucleotide polymorphism is present in one allele, and 0 if the single nucleotide polymorphism is not present and wherein a subject having a score of more than -1.3896 is or has been selected for treatment with said α4β7 integrin antagonist.

In still another embodiment the presence or absence of the single nucleotide

polymorphisms rs11205430, rs1561573, rs11211613, rs12061891, and rs11211632 is or has been determined, wherein for example the absence of the single nucleotide polymorphisms

rs11211613, rs12061891, rs11211632 and rs11205430 and the presence of the single nucleotide polymorphism rs1561573 is predictive for the subject’s treatment response to said α4β7 integrin antagonist. Preferably, the subject is or has been selected for treatment with the α4β7 integrin antagonist with the following formula:

Score i = (0.2865 * rs1561573)– (0.3678 * rs11211613)– (1.0079 * rs12061891)– (0.5831 * rs11211632)– (0.2351 * rs11205430),

wherein the value for rs1561573, rs11211613, rs12061891, rs11211632 and rs11205430, respectively, is 2 if the single nucleotide polymorphism is present in both alleles, 1 if the single nucleotide polymorphism is present in one allele, of more than -1.5910 is or has been selected for treatment with said α4β7 integrin antagonist.

In addition to determining the presence or absence of at least one single nucleotide polymorphism in the TRABD2B genomic locus, the presence or absence of at least one single nucleotide polymorphism in at least one genomic locus selected from the group consisting of PDC, NPY, ONECUT1, DLG4 and ELP5 may have been determined.

Preferably, the presence or absence of at least one single nucleotide polymorphism in each of the genomic loci of PDC, NPY, ONECUT1, DLG4 and ELP5 is or has been determined.

For example, the single nucleotide polymorphism in the PDC genomic locus is selected from the group consisting of rs1882926 and rs11801527. For example, the single nucleotide polymorphism in the NPY genomic locus is selected from the group consisting of rs16141 and rs3779477.

For example, the single nucleotide polymorphism in the ONECUT1 genomic locus is selected from the group consisting of rs2440335, rs2440332, rs1899750 and rs7180600.

For example, the single nucleotide polymorphism in the DLG4 genomic locus is selected from the group consisting of rs17203281, rs3826408 and rs1875673.

For example, the single nucleotide polymorphism in the ELP5 genomic locus is rs2106842.

Preferably, the presence or absence of the single nucleotide polymorphisms rs7543124, rs6671927, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs2440335, rs1899750, rs1875673 and rs2106842 is or has been determined. More preferably, the absence of the single nucleotide polymorphisms rs7543124, rs6671927, rs2088361, rs1556981, rs11801527 and rs3779477 and the presence of the single nucleotide polymorphisms rs1882926, rs2440335, rs1899750, rs1875673 and rs2106842 is predictive for the subject’s treatment response to said α4β7 integrin antagonist. Even more preferably, the subject is or has been selected for treatment with the α4β7 integrin antagonist by using the following formula:

Score i = (-0.1797 * rs7543124)– (0.3707 * rs6671927)– (0.5741 * rs2088361)– (0.5848 * rs1556981) + (0.7127 * rs1882926)– (0.7024 * rs11801527)– (0.6841 * rs3779477) + (0.2158 * rs2440335) + (0.6147 * rs1899750) + (0.3475 * rs1875673) + (0.397 * rs2106842),

wherein the value for rs7543124, rs6671927, rs2088361, rs1556981, rs11801527, rs3779477, rs1882926, rs2440335, rs1899750, rs1875673 and rs2106842, respectively, is 2 if the single nucleotide polymorphism is present in both alleles, 1 if the single nucleotide polymorphism is present in one allele, and 0 if the single nucleotide polymorphism is not present and wherein a subject having a score of more than 0.2123 is or has been selected for treatment with said α4β7 integrin antagonist.

Preferably, the presence or absence of the single nucleotide polymorphisms rs7543124, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs1899750 and rs2106842 is or has been determined. More preferably, the absence of the single nucleotide polymorphisms rs7543124, rs2088361, rs1556981, rs11801527 and rs3779477 and the presence of the single nucleotide polymorphisms rs1882926, rs1899750 and rs2106842 is predictive for the subject’s treatment response to said α4β7 integrin antagonist. Even more preferably, the subject is or has been selected for treatment with the α4β7 integrin antagonist with the following formula:

Score i = (-0.2213 * rs7543124)– (0.8735 * rs2088361)– (0.659 * rs1556981) + (0.8567 * rs1882926)– (0.858 * rs11801527)– (0.6935 * rs3779477) + (0.9288 * rs1899750) + (0.7159 * rs2106842)

wherein the value for rs7543124, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs1899750 and rs2106842, respectively, is 2 if the single nucleotide polymorphism is present in both alleles, 1 if the single nucleotide polymorphism is present in one allele, 0 if the single nucleotide polymorphism is not present and wherein a subject having a score of more than 0.6803 is or has been selected for treatment with said α4β7 integrin antagonist. Methods of Predicting Response to Vedolizumab Methods for determining the likelihood that an individual suffering from Crohn’s disease will respond favorably to treatment with an anti-integrin antibody (e.g., vedolizumab, natalizumab, etrolizumab, or AMG181) or an anti-α4β7 ligand antibody (e.g., an antibody that binds MAdCAM-1) including binding agents such as PF-547659 are also provided herein. In some embodiments, the method comprises assaying and/or analyzing a sample from the individual to determine the presence of absence of a TRABD2B variant, a CLDN7 variant, a GABARAP variant, an ELP5 variant, a CTDNEP1 variant, a PDC variant, a DLG4 variant, a MIR324 variant, a ONECUT1 variant, and/or a NPY variant, and determining that the individual is likely to respond favorably to treatment when the individual possesses the TRABD2B variant, the CLDN7 variant, the GABARAP variant, the ELP5 variant, the CTDNEP1 variant, the PDC variant, the DLG4 variant, the MIR324 variant, the ONECUT1 variant, and/or the NPY variant. In some embodiments, the method comprises assaying and/or analyzing a sample from the individual to determine the presence of absence of a C5orf20 variant, a CLN5 variant, a COL24A1 variant, a TIFAB variant, a PLAGL1 variant, a CEP72 variant, a FBXL3 variant, a PAPOLG variant, a SLC47A1 variant, and/or a WRAP53 variant, and determining that the individual is likely to respond favorably to treatment when the individual possesses the C5orf20 variant, the CLN5 variant, the COL24A1 variant, the TIFAB variant, the PLAGL1 variant, the CEP72 variant, the FBXL3 variant, the PAPOLG variant, the SLC47A1 variant, and/or the WRAP53 variant. In some embodiments, the assay is performed in vitro. The sample can be assayed and/or analyzed before, during, and/or after the individual begins treatment for Crohn’s disease. In some embodiments, the sample is obtained prior to treatment with the α4β7 integrin antagonist, such as vedolizumab. In some embodiments, the sample is obtained after the first dose of the α4β7 integrin antagonist, such as vedolizumab. In some embodiments, the sample is obtained after two doses of the α4β7 integrin antagonist, such as vedolizumab. In some embodiments, the sample is obtained during the sixth week of treatment with the α4β7 integrin antagonist, such as vedolizumab. In some embodiments, the methods comprise recording and/or transmitting the result of the assay and/or analysis. In some embodiments, the methods comprise authorizing payment for treatment and/or paying for the treatment.

In some embodiments, the methods comprise assaying and/or analyzing a sample from the individual to determine the presence of absence of a TRABD2B variant and/or a PDC variant and/or NPY variant positive and/or a ONECUT1 variant and/or a DLG4 variant and/or a CLDN7 variant and/or a ELP5 variant in nucleic acids from the individual, and determining that the individual is likely to respond favorably to treatment with vedolizumab when the individual possesses a TRABD2B variant and/or a PDC variant and or a NPY variant and/or a ONECUT1 variant and/or a DLG4 variant and/or a CLDN7 variant and/or a ELP5 variant.

The present invention also relates to a method for predicting a treatment response to an α4β7 integrin antagonist in a subject with Crohn’s disease, said method comprising the step of determining the presence or absence of at least one single nucleotide polymorphism in the TRABD2B genomic locus in a nucleic acid sample obtained from said subject, wherein the presence or absence of the at least one single nucleotide polymorphism in the TRABD2B genomic locus is predictive for the treatment response to said α4β7 integrin antagonist.

Preferably, the α4β7 integrin antagonist is vedolizumab. As used herein,“predicting a treatment response” means that based on the result of the analysis of at least one single nucleotide polymorphism as disclosed herein a subject is considered to be likely to respond to the treatment with a α4β7 integrin antagonist.

Accuracy, sensitivity, precision, specificity and negative predictive value are exemplary statistical measures of the performance of the prediction method. In the following, examples are given for determining the performance of the prediction methods described herein.

As used herein, accuracy may be calculated as (number of true positives + number of true negatives) / (number of true positives + number of false positives + number of true negatives + number of false negatives), e.g. (number of patients correctly diagnosed as responding to α4β7 integrin antagonist + number of patients correctly diagnosed as not responding to α4β7 integrin antagonist) / (number of patients correctly diagnosed as responding to α4β7 integrin antagonist + number of patients wrongly diagnosed as responding to α4β7 integrin antagonist + number of patients correctly diagnosed as not responding to α4β7 integrin antagonist + number of patients wrongly diagnosed as not responding to α4β7 integrin antagonist). The accuracy of prediction may e.g. be at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 90 to 99% or 95 to 99%.

As used herein, sensitivity may be calculated as (true positives) / (true positives + false negatives), e.g.: (number of patients correctly diagnosed as responding to α4β7 integrin antagonist) / (number of patients correctly diagnosed as responding to α4β7 integrin antagonist + number of patients wrongly diagnosed as not responding to α4β7 integrin antagonist). The sensitivity of prediction may be at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 90 to 99% or 95 to 99%.

As used herein, precision (also referred to as positive predictive value) may be calculated as (true positives) / (true positives + false positives), e.g.: (number of patients correctly diagnosed as responding to α4β7 integrin antagonist) / (number of patients correctly diagnosed as responding to α4β7 integrin antagonist + number of patients wrongly diagnosed as responding to α4β7 integrin antagonist). The precision of prediction may be at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 90 to 99% or 95 to 99%. As used herein, specificity is calculated as (true negatives) / (true negatives + false positives), e.g.: (number of patients correctly diagnosed as not responding to α4β7 integrin antagonist) / (number of patients correctly diagnosed as not responding to α4β7 integrin antagonist + number of patients wrongly diagnosed as responding to α4β7 integrin antagonist). The specificity of prediction may be at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 90 to 99% or 95 to 99%.

As used herein, negative predictive value is calculated as (true negatives) / (true negatives + false negatives), e.g.: (number of patients correctly diagnosed as not responding to α4β7 integrin antagonist) / (number of patients correctly diagnosed as not responding to α4β7 integrin antagonist + number of patients wrongly diagnosed as not responding to α4β7 integrin antagonist). The negative predictive value may be at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 90 to 99% or 95 to 99%.

Other statistical measures useful for describing the performance of the prediction methods described herein include geometric mean of sensitivity and specificity, geometric mean of positive predictive value and negative predictive value, F-measure and area under ROC curve, and the positive and negative likelihood ratios, the false discovery rate and Matthews correlation coefficient. These measures and method for their determination are well known in the art.

For a prediction whether a patient is likely to respond to the treatment with a α4β7 integrin antagonist the prediction method described herein may include determining a number of SNPs and/or combinations of SNPs sufficient to achieve a prediction sensitivity and/or precision of at least 55%, optionally at least 80%.

For the prediction whether it is unlikely that a patient responds to the treatment with a α4β7 integrin antagonist the prediction method described herein may include determining a number of SNPs and/or combinations of SNPs sufficient to achieve a prediction specificity and/or negative predictive value of at least 55%, optionally at least 80%.

For a prediction whether a patient responds to a treatment with α4β7 integrin antagonists or not the prediction method described herein may include determining a number of SNPs and/or combinations of SNPs sufficient to achieve sensitivity and/or precision and/or specificity and/or negative predictive value of at least 55%, optionally at least 80%.

In exemplary embodiments, the at least one single nucleotide polymorphism in the TRABD2B genomic locus is selected from the group consisting of rs7543124, rs6671927, rs12134443, rs11211624, rs2088361, rs1556981, rs11205430, rs1561573, rs11211613, rs12061891, rs11211632, rs17103939 and rs6684538.

In exemplary embodiments, the presence or absence of the single nucleotide

polymorphisms rs2088361 and rs1556981 is determined, wherein for examplethe absence of the single nucleotide polymorphisms rs2088361 and rs1556981 is predictive for the subject’s treatment response to said α4β7 integrin antagonist.

In another embodiment, the presence or absence of the single nucleotide polymorphisms rs6671927, rs2088361, rs1556981 and rs1561573 can be determined, wherein for example the absence of the single nucleotide polymorphisms rs6671927, rs2088361 and rs1556981 and the presence of the single nucleotide polymorphism rs1561573 is predictive for the treatment response to said α4β7 integrin antagonist. In an exemplary embodiment, a subject that is likely to respond to α4β7 integrin antagonist therapy is identified with the following formula:

Score i = (0.32 * rs1561573)– (0.4502 * rs6671927)– (0.6524 * rs2088361)– (0.8948 * rs1556981),

wherein the value for rs1561573, rs6671927, rs2088361 and rs1556981, respectively, is 2 if the single nucleotide polymorphism is present in both alleles, 1 if the single nucleotide polymorphism is present in one allele, and 0 if the single nucleotide polymorphism is not present and wherein a subject having a score of more than -1.4350 is likely to respond to α4β7 integrin antagonist therapy.

In another embodiment, the presence or absence of the single nucleotide polymorphisms rs6671927, rs2088361, rs1556981, rs11205430 and rs1561573 can be determined, wherein for example the absence of the single nucleotide polymorphisms rs6671927, rs2088361, rs1556981 and rs11205430 and the presence of the single nucleotide polymorphism rs1561573 is predictive for the treatment response to said α4β7 integrin antagonist. Preferably, a subject that is likely to respond to α4β7 integrin antagonist therapy is identified with the following formula:

Score i = (0.2738 * rs1561573)– (0.3913 * rs6671927)– (0.5404 * rs2088361)– (0.7396 * rs1556981)– (0.1912 * rs11205430),

wherein the value for rs1561573, rs6671927, rs2088361, rs1556981 and rs11205430, respectively, is 2 if the single nucleotide polymorphism is present in both alleles, 1 if the single nucleotide polymorphism is present in one allele, and 0 if the single nucleotide polymorphism is not present and wherein a subject having a score of more than -1.3896 is likely to respond to α4β7 integrin antagonist therapy.

In another embodiment, the presence or absence of the single nucleotide polymorphisms rs11205430, rs1561573, rs11211613, rs12061891, rs11211632 can be determined, wherein for example the absence of the single nucleotide polymorphisms rs11211613, rs12061891, rs11211632 and rs11205430 and the presence of the single nucleotide polymorphism rs1561573 is predictive for the treatment response to said α4β7 integrin antagonist. Preferably, a subject that is likely to respond to α4β7 integrin antagonist therapy is identified with the following formula: Score i = (0.2865 * rs1561573)– (0.3678 * rs11211613)– (1.0079 * rs12061891)– (0.5831 * rs11211632)– (0.2351 * rs11205430),

wherein the value for rs1561573, rs11211613, rs12061891, rs11211632 and rs11205430, respectively, is 2 if the single nucleotide polymorphism is present in both alleles, 1 if the single nucleotide polymorphism is present in one allele, and 0 if the single nucleotide polymorphism is not present and wherein a subject having a score of more than -1.5910 is likely to respond to α4β7 integrin antagonist therapy.

In exemplary embodiments, the presence or absence of at least one single nucleotide polymorphism in at least one genomic locus selected from the group consisting of PDC, NPY, ONECUT1, DLG4 and ELP5 can additionally be determined.

In exemplary embodiments, the presence or absence of at least one single nucleotide polymorphism in each of the genomic loci of PDC, NPY, ONECUT1, DLG4 and ELP5 is determined. In an exemplary embodiment, the single nucleotide polymorphism in the PDC genomic locus is selected from the group consisting of rs1882926 and rs11801527, the single nucleotide polymorphism in the NPY genomic locus is selected from the group consisting of rs16141 and rs3779477, the single nucleotide polymorphism in the ONECUT1 genomic locus is selected from the group consisting of, rs2440335, rs2440332, rs1899750 and rs7180600, the single nucleotide polymorphism in the DLG4 genomic locus is selected from the group consisting of rs17203281, rs3826408 and rs1875673 and/or the single nucleotide polymorphism in the ELP5 genomic locus is rs2106842.

In a specific embodiment, the presence or absence of the single nucleotide

polymorphisms rs7543124, rs6671927, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs2440335, rs1899750, rs1875673 and rs2106842 can be determined, wherein for example the absence of the single nucleotide polymorphisms rs7543124, rs6671927, rs2088361, rs1556981, rs11801527 and rs3779477and the presence of the single nucleotide polymorphisms rs1882926, rs2440335, rs1899750, rs1875673 and rs2106842 is predictive for the treatment response to said α4β7 integrin antagonist. Preferably a subject that is likely to respond to α4β7 integrin antagonist therapy is identified with the following formula:

Score i = (-0.1797 * rs7543124)– (0.3707 * rs6671927)– (0.5741 * rs2088361)– (0.5848 * rs1556981) + (0.7127 * rs1882926)– (0.7024 * rs11801527)– (0.6841 * rs3779477) + (0.2158 * rs2440335) + (0.6147 * rs1899750) + (0.3475 * rs1875673) + (0.397 * rs2106842),

wherein the value for rs7543124, rs6671927, rs2088361, rs1556981, rs11801527, rs3779477, rs1882926, rs2440335, rs1899750, rs1875673 and rs2106842, respectively, is 2 if the single nucleotide polymorphism is present in both alleles, 1 if the single nucleotide polymorphism is present in one allele, and 0 if the single nucleotide polymorphism is not present and wherein a subject having a score of more than 0.2123 is likely to respond to α4β7 integrin antagonist therapy.

In another embodiment the presence or absence of the single nucleotide polymorphisms rs7543124, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs1899750 and rs2106842 can be determined, wherein for example the absence of the single nucleotide polymorphisms rs7543124, rs2088361, rs1556981, rs11801527 and rs3779477 and the presence of the single nucleotide polymorphisms rs1882926, rs1899750 and rs2106842 is predictive for the treatment response to said α4β7 integrin antagonist. Preferably, a subject that is likely to respond to α4β7 integrin antagonist therapy is identified with the following formula:

Score i = (-0.2213 * rs7543124)– (0.8735 * rs2088361)– (0.659 * rs1556981) + (0.8567 * rs1882926)– (0.858 * rs11801527)– (0.6935 * rs3779477) + (0.9288 * rs1899750) + (0.7159 * rs2106842)

wherein the value for rs7543124, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs1899750 and rs2106842, respectively, is 2 if the single nucleotide polymorphism is present in both alleles, 1 if the single nucleotide polymorphism is present in one allele, and 0 if the single nucleotide polymorphism is not present and wherein a subject having a score of more than 0.6803 is likely to respond to α4β7 integrin antagonist therapy.In some embodiments, determining whether an individual is TRABD2B variant positive, PDC variant positive, NPY variant positive, ONECUT1 variant positive, DLG4 variant positive, CLDN7 variant positive, and/or ELP5 variant positive or predicting a treatment response to an α4β7 integrin antagonist as discussed above involves obtaining a biological sample from an individual.

A sample, e.g., a biological sample, can be any substance that contains nucleic acids from the individual, such as a body fluid sample, a tissue sample, a stool sample, cells from the individual, and/or isolated nucleic acids from the individual. Exemplary body fluid samples include blood, plasma, serum, cerebrospinal fluid, bile and saliva. Exemplary tissue samples include tissue biopsy samples, such as an intestinal biopsy sample (e.g., from colon tissue or ileum tissue). Exemplary cell samples include buccal swabs or cells obtained from biological samples taken from the individual. Methods of extracting nucleic acids from samples are well known in the art and can be readily adapted to obtain a sample that is compatible with the system utilized. In some embodiments, the samples are enriched and/or stabilized. In some embodiments, the samples are centrifuged through Ficoll. Automated sample preparation systems for extracting nucleic acids from a test sample are commercially available, e.g., Roche Molecular Systems’ (Pleasanton, CA, USA) COBAS AmpliPrep System, Qiagen's (Venlo, Netherlands) BioRobot 9600, and Applied Biosystems' (Watham, MA, USA) PRISM™ 6700 sample preparation system.

As used herein,“isolated nucleic acids” means nucleic acid that is removed to at least some extent from the cellular material from which they originated. However,“isolated” does not require that the nucleic acid be completely pure and free of any other components. Examples of isolated nucleic acid are those obtained using commercial nucleic extraction kits.

In some embodiments, a sample from an individual contains DNA and/or RNA from the individual. In some embodiments, assaying a sample involves extracting nucleic acids from a biological sample to determine that the individual is positive for any of the variants described herein. For example, some embodiments comprise extracting nucleic acids from a biological sample to determine that the individual is TRABD2B variant positive and/or PDC variant positive and/or NPY variant positive and/or ONECUT1 variant positive and/or DLG4 variant positive and/or CLDN7 variant positive and/or ELP5 variant positive. Various methods of extraction are suitable for isolating DNA or RNA. Suitable methods include phenol and chloroform extraction. See Maniatis et al., Molecular Cloning, A Laboratory Manual, 2d, Cold Spring Harbor Laboratory Press, page 16.54 (1989). Numerous commercial kits also yield DNA and/or RNA. However, nucleic acid extraction is not essential and a sample, such as blood or saliva, may be assayed directly to determine that the individual is TRABD2B variant positive and/or PDC variant positive and/or NPY variant positive and/or ONECUT1 variant positive and/or DLG4 variant positive and/or CLDN7 variant positive and/or ELP5 variant positive without extracting nucleic acids from the sample.

In some embodiments, assaying a sample comprises reverse transcribing RNA to produce cDNA.

In some embodiments, assaying a sample comprises amplifying nucleic acids in the sample or nucleic acids derived from nucleic acids in the sample (e.g. cDNA). Amplification methods which may be used include variations of RT-PCR, including quantitative RT-PCR, for example as adapted to the method described by Wang, A. M. et al., Proc. Natl. Acad. Sci. USA 86:9717-9721, (1989), or by Karet, F. E., et al., Analytical Biochemistry 220:384-390, (1994). Another method of nucleic acid amplification or mutation detection which may be used is ligase chain reaction (LCR), as described by Wiedmann, et al., PCR Methods Appl.3:551-564, (1994). An alternative method of amplification or mutation detection is allele specific PCR (ASPCR). ASPCR which utilizes matching or mismatching between the template and the 3' end base of a primer well known in the art. See e.g., U.S. Pat. No.5,639,611, which is incorporated herein by reference and made a part hereof.

In some embodiments, the methods comprise determining the presence of a genetic variant with nucleic acid sequencing. Sequencing can be performed using any number of methods, kits or systems known in the art. One example is using dye terminator chemistry and an ABI sequencer (Applied Biosystems, Foster City, Calif.). Sequencing also may involve single base determination methods such as single nucleotide primer extension ("SNapShot® " sequencing method) or allele or mutation specific PCR. The SNaPshot® Multiplex System is a primer extension-based method that enables multiplexing up to 10 SNPs (single nucleotide polymorphisms). The chemistry is based on the dideoxy single-base extension of an unlabeled oligonucleotide primer (or primers). Each primer binds to a complementary template in the presence of fluorescently labeled ddNTPs and AmpliTaq® DNA Polymerase, FS. The polymerase extends the primer by one nucleotide, adding a single ddNTP to its 3' end. SNaPshot® Multiplex System is commercially available (ABI PRISM. SNaPshot® Multiplex kit, Applied Biosystems Foster City, Calif.). Products generated using the ABI PRISM® SNaPshot® Multiplex kit can be analyzed with GeneScan® Analysis Software version 3.1 or higher using ABI PRISM® 310 Genetic Analyzer, ABI PRISM® 3100 Genetic Analyzer or ABI PRISM® 3700 DNA Analyzer.

A person skilled in the art will recognize that, based on the SNP and associated sequence information disclosed herein, detection reagents can be developed and used to assay any SNP of the present technology individually or in combination, and that such detection reagents can be incorporated into a kit.

The term "kit" as used herein in the context of SNP detection reagents, refers to such things as combinations of multiple SNP detection reagents, or one or more SNP detection reagents in combination with one or more other types of elements or components (e.g., other types of biochemical reagents, containers, packages such as packaging intended for commercial sale, substrates to which SNP detection reagents are attached, electronic hardware components, etc.).

Accordingly, the present technology further provides SNP detection kits and systems, including but not limited to, packaged probe and primer sets (e.g., TaqMan probe/primer sets), arrays/microarrays of nucleic acid molecules, and beads that contain one or more probes, primers, or other detection reagents for detecting one or more SNPs described herein. The kits can optionally include various electronic hardware components. For example, arrays ("DNA chips") and microfluidic systems ("lab-on-a-chip" systems) provided by various manufacturers typically comprise hardware components. Some kits (e.g., TaqMan probe/primer sets) may not include electronic hardware components, but may be comprised of, for example, one or more SNP detection reagents (along with other optional biochemical reagents) packaged in one or more containers.

In some embodiments, a SNP detection kit contains one or more detection reagents and other components (e.g., buffers, reagents, enzymes having polymerase activity, enzymes having polymerase activity and lacking 5' ^3' exonuclease activity or both 5' ^3' and 3' ^5' exonuclease activity, ligases, enzyme cofactors such as magnesium or manganese, salts, chain extension nucleotides such as deoxynucleoside triphosphates (dNTPs) or biotinylated dNTPs, and in the case of Sanger-type DNA sequencing reactions, chain terminating nucleotides (i.e., dideoxynucleoside triphosphates (ddNTPs), positive control sequences, negative control sequences, and the like) to carry out an assay or reaction, such as amplification and/or detection of a SNP-containing nucleic acid molecule. In some embodiments, a kit contains a means for determining the amount of a target nucleic acid, determining whether an individual is heterozygous or homozygous for a polymorphism, detecting a gene transcript, and/or comparing the amount with a standard. In some embodiments, the kit comprises instructions for using the kit to detect the SNP-containing nucleic acid molecule of interest. In some embodiments, the kits contain reagents to carry out one or more assays to detect one or more SNPs disclosed herein. In some embodiments, SNP detection kits are in the form of nucleic acid arrays or compartmentalized kits, including microfluidic/lab-on-a-chip systems.

The kits may further comprise one or more of: wash buffers and/or reagents, hybridization buffers and/or reagents, labeling buffers and/or reagents, and detection means. The buffers and/or reagents can be optimized for the particular amplification/detection technique for which the kit is intended. Protocols for using these buffers and reagents for performing different steps of the procedure may also be included in the kit.

In some embodiments, the SNP detection kits comprise at least one set of primers (e.g., comprising one matched allele-specific primer and one mismatched allele-specific primer) and, optionally, a non-extendable oligonucleotide probe. Each kit can comprise reagents which render the procedure specific. Thus, a kit intended to be used for the detection of a particular SNP can comprise a matched and mismatched allele-specific primers set specific for the detection of that particular SNP, and optionally, a non-extendable oligonucleotide probe. A kit intended to be used for the multiplex detection of a plurality of SNPs comprises a plurality of primer sets, each set specific for the detection of one particular SNP, and, optionally, a plurality of corresponding non-extendable oligonucleotide probes.

In some embodiments, the SNP detection kits comprise multiple pairs of primers for one or more target SNP loci, wherein said primers are designed so that the lengths of said PCR products from different SNP loci or from different alleles of the same SNP locus are sufficiently distinguishable from each other in capillary electrophoresis analysis, thus making them suitable to multiplex PCR. The SNP detection kit can further comprise a fluorescently labeled single- base extension⁄termination reagent, i.e., ddNTPs, to label the primers during the multiplex PCR reaction (e.g., SNaPshot Multiplex). The chemistry of the SNP detection kit can be based on the dideoxy single-base extension of the unlabeled primers. Each primer can bind to its target SNP loci in the presence of fluorescently labeled ddNTPs and the polymerase extends the primer by one nucleotide, adding a single ddNTP to its 3´ end. The identity of the incorporated nucleotide can be determined by the fluorescence color readout. In some embodiments, the kits comprise multiple pairs of primers for simultaneously detecting at least one SNP locus having two or more different alleles. In some embodiments, the kits comprise multiple pairs of primers for simultaneously detecting different genotypes among 1-8 different SNP loci. In some embodiments, the SNP detection kit comprises multiple pairs of primers that have the annealing temperatures designed to be used in a single amplification reaction. In some embodiments, the kits further comprise an internal control polynucleotide and/or multiple control primers for conducting multiplex PCR using the internal control polynucleotide as a template.

In some embodiments, SNP detection kits may contain, for example, one or more probes, or pairs of probes, that hybridize to a nucleic acid molecule at or near each target SNP position. Multiple pairs of allele-specific probes may be included in the kit to simultaneously assay multiple SNPs, at least one of which is a SNP disclosed herein. In certain embodiments, multiple pairs of allele-specific probes are included in the kit to simultaneously assay all of the SNPs described herein. In some embodiments, the kit includes capture primers and optionally extension primers for the detection of one or a plurality of SNPs of one or more genes selected from the group consisting of TRABD2B, PDC, NPY, ONECUT1, DLG4, CLDN7, ELP5, GABARAP, CTDNEP1, MIR324, C5orf20, CLN5, COL24A1, TIFAB, PLAGL1, CEP72, FBXL3, PAPOLG, SCL47A1, and WRAP53.

In some embodiments, the SNP detection kits comprise at least one set of pre-selected nucleic acid sequences that act as capture probes for the extension products. The pre-selected nucleic acid sequences (allele-specific probes) may be immobilized on an array or beads (e.g., coded beads), and can be used to detect at least 1, 4, 10, 11, all, or any combination of the SNPs disclosed herein. By way of example only, the kits may include polystyrene microspheres that are internally dyed with two spectrally distinct fluorescent dyes (e.g., x-MAP™ microbeads, Luminex Corp. (Austin, Tex.)). Using precise ratios of these fluorophores, a large number of different fluorescent bead sets can be produced (e.g., a set of 100). Each set of beads can be distinguished by its code (or spectral signature) and can be used to detect a large number of different extension products in a single reaction vessel. These sets of fluorescent beads with distinguishable codes can be used to label extension products. Labeling (or attachment) of extension products to beads can be by any suitable means including, but not limited to, chemical or affinity capture, cross-linking, electrostatic attachment, and the like. In some embodiments, labeling of extension products is carried out through hybridization of the allele-specific primers and the tag probe sequences. The magnitude of the biomolecular interaction that occurs at the microsphere surface is measured using a third fluorochrome that acts as a reporter (e.g., biotinylated dNTPs). Because each of the different extension products is uniquely labeled with a fluorescent bead, the captured extension product (indicative of one allele of a SNP of interest) can be distinguishable from other different extension products (including extension products indicative of other alleles of the same SNP and extension products indicative of other SNPs of interest). Following hybridization, the microbeads can be analyzed using methods such as flow cytometry. In embodiments where the primer extension reaction is carried out in the presence of biotinylated dNTPs, the reaction between beads and extension products may be quantified by fluorescence after reaction with fluorescently-labeled streptavidin (e.g., Cy5-streptavidin conjugate) using instruments such as the Luminex® 100™ Total System, Luminex® 100™ IS Total System, Luminex™ High Throughput Screening System).

Some embodiments provide methods of identifying the SNPs disclosed herein in a biological sample comprising incubating a test sample of nucleic acids obtained from the subject with an array comprising one or more probes corresponding to at least one SNP position disclosed herein, and assaying for binding of a nucleic acid from the test sample with one or more of the probes. Conditions for incubating a test sample with a SNP detection reagent from a kit that employs one or more such SNP detection reagents can vary. Incubation conditions depend on factors such as the format employed in the assay, the detection methods employed, and the type and nature of the detection reagents used in the assay. One skilled in the art will recognize that any one of the commonly available hybridization, amplification and array assay formats can readily be adapted to detect the SNPs disclosed herein.

In some embodiments, the SNP detection kits of the present technology include control analytes for spiking into a sample, buffers, including binding, washing and elution buffers, solid supports, such as beads, protein A or G or avidin coated sepharose or agarose, etc., and a matrix- assisted laser desorption/ionization (MALDI) sample plate. The kit may also contain a database, which may be a table, on paper or in electronic media, containing information for one or a plurality of SNPs of one or more genes selected from the group consisting of TRABD2B, PDC, NPY, ONECUT1, DLG4, CLDN7, ELP5, GABARAP, CTDNEP1, MIR324, C5orf20, CLN5, COL24A1, TIFAB, PLAGL1, CEP72, FBXL3, PAPOLG, SLC47A1, and WRAP53. In some embodiments, the kits contain programming to allow a robotic system to perform the present methods, e.g., programming for instructing a robotic pipettor or a contact or inkjet printer to add, mix and remove reagents. The various components of the kit may be present in separate containers or certain compatible components may be precombined into a single container, as desired.

In some embodiments, the kits include one or more other reagents for preparing or processing an analyte sample for matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF). The reagents may include one or more matrices, solvents, sample preparation reagents, buffers, desalting reagents, enzymatic reagents, denaturing reagents, where calibration standards such as positive and negative controls may be provided as well. As such, the kits may include one or more containers such as vials or bottles, with each container containing a separate component for carrying out a sample processing or preparing step and/or for carrying out one or more steps of a MALDI-TOF protocol.

In addition to above-mentioned components, the kits can include instructions for using the components of the kit, e.g., to prepare a MALDI-TOF sample plate and/or assess a sample. The instructions, such as for preparing or assessing a sample via MALDI-TOF, are generally recorded on a suitable recording medium. For example, the instructions may be printed on a substrate, such as paper or plastic, etc. As such, the instructions may be present in the kits as a package insert, in the labeling of the container of the kit or components thereof (i.e., associated with the packaging or subpackaging) etc. In some embodiments, the instructions are present as an electronic storage data file present on a suitable computer readable storage medium. In some embodiments, the actual instructions are not present in the kit, but means for obtaining the instructions from a remote source, e.g. via the internet, are provided. An example of this embodiment is a kit that includes a web address where the instructions can be viewed and/or from which the instructions can be downloaded. As with the instructions, this means for obtaining the instructions is recorded on a suitable substrate. In addition to the database, programming and instructions, the kits may also include one or more control analyte mixtures, e.g., two or more control samples for use in testing the kit.

Sequencing can be performed using any number of methods, kits or systems known in the art. One example is using dye terminator chemistry and an ABI sequencer (Applied Biosystems, Foster City, Calif.). Sequencing also may involve single base determination methods such as single nucleotide primer extension ("SNapShot® " sequencing method) or allele or mutation specific PCR. The SNaPshot® Multiplex System is a primer extension-based method that enables multiplexing up to 10 SNPs (single nucleotide polymorphisms). The chemistry is based on the dideoxy single-base extension of an unlabeled oligonucleotide primer (or primers). Each primer binds to a complementary template in the presence of fluorescently labeled ddNTPs and AmpliTaq® DNA Polymerase, FS. The polymerase extends the primer by one nucleotide, adding a single ddNTP to its 3' end. SNaPshot® Multiplex System is commercially available (ABI PRISM. SNaPshot® Multiplex kit, Applied Biosystems Foster City, Calif.). Products generated using the ABI PRISM® SNaPshot® Multiplex kit can be analyzed with GeneScan® Analysis Software version 3.1 or higher using ABI PRISM® 310 Genetic Analyzer, ABI PRISM® 3100 Genetic Analyzer or ABI PRISM® 3700 DNA Analyzer.

Next generation sequencing (NGS) may be used to determine an individual’s genotype. Next generation sequencing is a high throughput, massively parallel sequencing method that can generate multiple sequencing reactions of clonally amplified molecules and of single nucleic acid molecules in parallel. This allows increased throughput and yield of data. NGS methods include, for example, sequencing-by-synthesis using reversible dye terminators, and sequencing-by- ligation. Non-limiting examples of commonly used NGS platforms include Miseq/Nextseq/HiSeq (Illumina, Inc.), Roche 454 TM GS FLX TM -Titanium (Roche Diagnostics), XMAP ® (Luminex Corp.), IONTORRENT™ (Life Technologies Corp.) and ABI SOLiD TM System (Applied Biosystems, Foster City, CA). Some embodiments as described herein are directed to kits comprising: (i) at least one pair of primers that specifically hybridizes to a genetic variant as described herein, and (ii) a detectably labeled probe that hybridizes to the genetic variant. In some embodiments, the kits comprise at least one pair of primers that specifically hybridizes to a genetic variant independently selected from the group consisting of rs7543124, rs6671927, rs12134443, rs11211624, rs2088361, rs1556981, rs11205430, rs1561573, rs11211613, rs12061891, rs11211632, rs17103939, rs6684538, rs1882926, rs11801527, rs12407957, rs10798041, rs16141, rs3779477, rs16129, rs2440335, rs2440332, rs1899750, rs7180600, rs2456507, rs2456525, rs17203281, rs3826408, rs1875673, rs739669, rs2017365, rs929229, rs2106842, exm1286317, rs2074217, and rs222843.

Some embodiments are directed to kits comprising: (i) at least one pair of primers that specifically hybridizes to a genetic variant independently selected from the group consisting of rs1556981, rs2088361, rs1561573, and rs6671927, and (ii) a detectably labeled probe that hybridizes to the genetic variant.

Some embodiments are directed to kits comprising: a pair of primers that specifically hybridizes to rs1556981; a pair of primers that specifically hybridizes to rs2088361; a pair of primers that specifically hybridizes to rs1561573; and a pair of primers that specifically hybridizes to rs6671927.

Some embodiments are directed to kits comprising: a pair of primers that specifically hybridizes to rs1556981; a pair of primers that specifically hybridizes to rs2088361; a pair of primers that specifically hybridizes to rs1561573; a pair of primers that specifically hybridizes to rs6671927; and a pair of primers that specifically hybridizes to rs11205430.

Some embodiments are directed to kits comprising: (i) at least one pair of primers that specifically hybridizes to a genetic variant independently selected from the group consisting of rs1561573, rs11211613, rs12061891, rs11211632, and rs11205430, and (ii) a detectably labeled probe that hybridizes to the genetic variant.

Some embodiments are directed to kits comprising: (i) at least one pair of primers that specifically hybridizes to a genetic variant independently selected from the group consisting of rs7543124, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs1899750, and rs2106842, and (ii) a detectably labeled probe that hybridizes to the genetic variant.

Some embodiments are directed to kits comprising: (i) at least one pair of primers that specifically hybridizes to a genetic variant independently selected from the group consisting of rs7543124, rs6671927, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs2440335, rs1899750, rs1875673, and rs2106842, and (ii) a detectably labeled probe that hybridizes to the genetic variant. EXAMPLES Example 1– Identification of SNPs Associated with Clinical Remission or Enhanced Clinical Response Whole genome genotyping data on 1,390 samples from two clinical trials (C13007 and C13011) was assayed for 964,193 variants using an Illumina HumanOmniExpressExome Beadchip array. Genotypic quality control was performed using per-sample and per-variant quality control procedures, which narrowed the raw dataset of 1,390 samples and 964,193 variants to 1,365 samples and 811,254 variants. See Figure 1A. Baseline characteristics of the patients are shown in Figure 1B.

Following quality control, the top 10 gene regions associated with clinical remission or enhanced clinical response at a 6-week endpoint were identified using a region test-based linear mixed model framework. The top 10 genes associated with clinical remission are shown in Figures 2A-D, where Figure 2A shows results in all patients; Figure 2B shows results from clinical trial C13007; Figure 2C shows results from clinical trial C13011; and Figure 2D shows results in all Caucasian patients. The top 10 genes associated with enhanced clinical response are shown in Figures 3A-D, where Figure 3A shows results in all patients; Figure 3B shows results in clinical trial C13007; Figure 3C shows results in clinical trial C13011; and Figure 3D shows results in all Caucasian patients. Association Testing of Genomic Features

The following types of genomic features based on genetic variants (e.g. single nucleotide polymorphisms, i.e. SNPs; insertions; or deletions) were considered in the present study: (i) A SNP with Minor Allele Frequency (MAF)≥ 5%; and (ii) a gene of interest, which was defined as the region between the transcription start and end positions plus 5kb upstream and downstream of the transcription start and end positions.

For all single variant analyses, a genotypic or dominant model was considered for variants that passed genotypic QC. Specifically, the following genetic models were used to accommodate single variant analyses: (a) A genotypic model (i.e. a model with g-1 degrees of freedom (d.f.), where g = the number of observed genotypes) was considered for common variants (i.e. MAF≥ 5%) with genotype counts of at least 5 for all genotype categories; and (ii) a dominant model (i.e. a model with 1 d.f., where presence vs. absence of the minor allele was modeled) was used for common variants with less than 5 observations for any of the genotypes. A variant was omitted from single variant testing if the variant had less than 5 observations in the heterozygous and rare homozygous groups combined. For multi-variant analyses, each variant was coded as the number of minor alleles (i.e.0, 1, or 2).

A tiered approach was employed to prioritize the genomic regions of interest in association testing. Tier 1 genomic regions were defined in part as genes/SNPs residing in regions covered by the Immunochip.

A two-stage approach was utilized to identify genes or single variants predictive of response to Vedolizumab treatment in clinical remission at week 6 in trials C13007 and C13011.

In Stage 1, the effect of genetic variation (SNP or gene) on clinical remission at week 6 was assessed in patients treated by Vedolizumab or placebo in trials C13007 and C13011. Single variants or genes with an unadjusted P-value < 0.1 were carried forward into the second stage.

In stage 2, the interaction between genetic variation (SNP or gene) and the treatment (i.e. Vedolizumab vs. placebo) was assessed on clinical remission at week 6 using samples treated by Vedolizumab or placebo in trials C13007 and C13011. Multiplicity adjustment was considered by tier. A flexible regression framework was considered for gene-level association testing or single variant association testing. For the stage 1 analysis, the following logistic regression model was considered for testing gene/SNP main effect on clinical remission at week 6: w here denotes the probability of response, ^^ and ^^ were the ^th subject’s covariate vector and biomarker vector, ^^ denotes an indicator variable for treatment assignment for subject ^ (i.e.^ ^^ =1 if Vedolizumab treated), and was the coefficient vector for the covariate vector. The top 3 Principal Components derived from a Principal Component Analysis as well as a baseline CDAI score, prior treatment, geographic region, treatment were included in the model as covariates.

For the stage 2 analysis, the following interaction model was considered for clinical remission:

(2) The biomarker vector ^ ^ was a general placeholder that represented the corresponding biomarker. Subgroup Identification

Subgroup identification was considered for the primary endpoint week 6 clinical remission. A subgroup ^ was assumed to exhibit enhanced treatment effect of Vedolizumab as compared to placebo. The problem of subgroup identification was written in the logistic regression framework as

w here denoted enhanced treatment effect in a subgroup ^ that was added to the treatment main effect. Since true subgroup membership cannot be observed, biomarkers were used as surrogates to infer subgroup membership.

A multi-marker composite score approach was used in the development of a genetic signature that could be used to infer subgroup membership. A subgroup was identified using a two-stage approach: Stage 1: Develop a composite score using a subset of biomarkers (i.e. genetic variants) via a penalized regression approach; and Stage 2: Find a composite score cutoff that defines a subgroup. The composite score was derived by fitting a working model contained interaction terms of the treatment with each biomarker. The composite score was then defined as , in which increasing values of the composite score would be indicative of a benefit (i.e., increasing Odds Ratio). The model above was fit using the elastic net (Zou and Hastie, J. R. Statist. Soc. B, 67: 301-320 (2005)), which performed feature selection through penalized regression. For biomarkers that did not contribute significantly to the composite score, the corresponding parameter estimates could be shrunk to zero in the composite score calculation and subsequently only biomarkers with non-zero parameter estimates were used in the definition of a genetic signature.

A subgroup of patients was defined using the estimated composite scores

for n patients. Given a threshold the subgroup was defined as i To choose the optimal value and the corresponding subgroup a grid search was used to consider all possible s in the designated range of 25-75% and

to choose the optimal value maximizing a t statistic. To account for the multiple testing performed when searching for the optimal threshold, significance of the treatment-by- subgroup interaction at the optimal cutoff was evaluated using a parametric bootstrap approach. Example 2– 19 SNP Model Common variants located in the top 10 genes identified in the Genome-Wide Association Study were employed to build a second model for subgroup identification. After genotypic QC, 90 common variants located in the top 10 genes were identified. LD pruning was performed to eliminate high-LD structures among the SNPs (r 2 threshold = 0.8). 59 out of the 90 variants survived LD-pruning and were selected as candidate variants for constructing genetic composite scores in subgroup identification. A penalized regression approach (Zou and Hastie, 2005) was employed to select the 19 SNPs set forth in Table 1. Table 1A.19 SNPs Selected by Penalized Regression from the Top 10 Genes

Table 1B: 19-SNP Model– Flanking Sequences

Table 1A shows genes and gene combinations whose genotypes can be combined in multigene models that significantly correlate with clinical remission in adult patients treated with vedolizumab, and Table 1B shows flanking sequences (based on dbSNP from NCBI) for the SNPs in the multigene model. The 19-variant (19-SNP) model shows statistically significant evidence for a treatment-specific effect. A subgroup identified via the genetic signature set forth in Figure 4 showed statistically significant enhanced treatment effect in adult Crohn’s Disease patients treated with vedolizumab. See Figure 4, where the left markings for vedolizumab and placebo represent patients“not in the subgroup” and the right markings in each category represent patients“in the subgroup.” Moreover, the subjects outside the subgroup showed a significant non-response effect. See Figure 4. The distribution of a Biomarker+ subgroup (in the subgroup) and a Biomarker– subgroup (not in the subgroup) in vedolizumab- and placebo-treated CD patients is shown in Table 2. The subgroup showing enhanced treatment effect was identified using a parametric bootstrapping approach, similar to that set forth in Li et al.,“A multi-marker molecular signature approach for treatment-specific subgroup identification with survival outcomes,” The Pharmacogenomics Journal, 14(5): 439-45 (2014), which is incorporated herein by reference and made a part hereof. In particular, the dataset was bootstrapped multiple times, and each bootstrapped dataset was used to re-estimate a score using elastic net. Using this approach, a coefficient for each SNP was estimated. Using these coefficients, for each signature, the patient’s score is calculated as:

where j indicates the jth SNP, and the patient’s membership is

In the equation, G is 0, 1, or 2, depending on the number of patient’s minor allele and coefficient β is selected for each particular variant. Using this equation, responders were identified using the following formula, where the optimal cutoff was

Score i = (rs7543124 coefficient) * rs7543124 + (rs6671927 coefficient) * rs6671927 + (rs12134443 coefficient) * rs12134443 + (rs11211624 coefficient) * rs11211624 + (rs2088361 coefficient) * rs2088361 + (rs1556981 coefficient) * rs1556981 + (rs11205430 coefficient) * rs11205430 + (rs1882926 coefficient) * rs1882926 + (rs11801527 coefficient) * rs11801527 + (rs16141 coefficient) * rs16141 + (rs3779477 coefficient) * rs3779477 + (rs2440335 coefficient) * rs2440335 + (rs2440332 coefficient) * rs2440332 + (rs1899750 coefficient) * rs1899750 + (rs7180600 coefficient) * rs7180600 + (rs17203281 coefficient) * rs17203281 + (rs3826408 coefficient) * rs3826408 + (rs1875673 coefficient) * rs1875673 + (rs2106842 coefficient) * rs2106842. Table 2: Distribution of biomarker+ subgroup (in the subgroup) and biomarker– subgroup (Not in the subgroup) CD patients in the 19-SNP model.

Example 3– 11 SNP Model The 19-SNP model was refined to construct an 11-SNP model. Table 3 shows genes and gene combinations whose expression levels can be combined in multigene models that significantly correlate with clinical remission in adult Crohn’s Disease patients treated with vedolizumab.

Table 3: 11 variants used in genetic signature

The 11-variant (11-SNP) model shows statistically significant evidence for a treatment- specific effect. A subgroup identified via the genetic signature in Table 3 showed a statistically significant clinical remission treatment effect. See Figure 5A, where the left markings for vedolizumab and placebo represent patients“not in the subgroup,” the middle markings in each category represent the“treatment main effect,” and the right markings in each category represent patients“in the subgroup.” Moreover, subjects outside the subgroup showed a statistically significant non-response effect. See Figure 5A. The subgroup showing enhanced treatment effect was identified using the parametric bootstrapping methods set forth in Example 2. In particular, responders were identified using the following formula, where the optimal cutoff was

Score i = (rs7543124 coefficient) * rs7543124 + (rs6671927 coefficient) * rs6671927 + (rs2088361 coefficient) * rs2088361 + (rs1556981 coefficient) * rs1556981 + (rs1882926 coefficient) * rs1882926 + (rs11801527 coefficient) * rs11801527 + (rs3779477 coefficient) * rs3779477 + (rs2440335 coefficient) * rs2440335 + (rs1899750 coefficient) * rs1899750 + (rs1875673 coefficient) * rs1875673 + (rs2106842 coefficient) * rs2106842. The specific algorithm used was as follows:

Score i = -0.1797 * rs7543124– 0.3707 * rs6671927– 0.5741 * rs2088361– 0.5848 * rs1556981 + 0.7127 * rs1882926– 0.7024 * rs11801527– 0.6841 * rs3779477 + 0.2158 * rs2440335 + 0.6147 * rs1899750 + 0.3475 * rs1875673 + 0.397 * rs2106842, where the value for rs7543124, rs6671927, rs2088361, rs1556981, rs1882926, rs11801527, rs3779477, rs2440335, rs1899750, rs1875673, and rs2106842, respectively, is 0, 1, or 2, depending on the number of the patient’s minor allele. The distribution of Biomarker+ subgroup (In the subgroup) and Biomarker– subgroup (not in the subgroup) in vedolizumab- and placebo-treated CD patients is shown in Table 4. Table 4: Distribution of Biomarker+ subgroup (in the subgroup) and Biomarker– subgroup (Not in the subgroup) CD patients in the 11-SNP model

Figures 5B and 5C show clinical remission over time during the induction phase in the C13007 and C13011 trials, respectively.

Figure 5D shows a statistically significant enhanced clinical response treatment effect. See Figure 5D, where the left markings for vedolizumab and placebo represent patients“not in the subgroup,” the middle markings in each category represent the overall“treatment main effect” and the right markings in each category represent patients“in the subgroup.” Moreover, subjects outside the subgroup showed a statistically significant non-response effect. See Figure 5D. Figure 5E and 5F show enhanced clinical response over time in the C13007 and C13011 trials, respectively. Figure 5G shows plots of CDAI scores versus genetic biomarker scores for both vedolizumab treatment and placebo treatment in the 11-SNP model. Figure 5H shows observed vs. predicted CDAI scores for the 11-SNP model. Example 4– 8 SNP Model The 19-SNP model was refined to construct an 8-SNP model. Table 5 shows genes and gene combinations whose genotypes can be combined in multigene models that significantly correlate with clinical remission in adult Crohn’s Disease patients treated with vedolizumab. Table 5: 8 variants used in genetic signature

The 8-variant (8-SNP) model shows statistically significant evidence for a treatment- specific effect. A subgroup identified via the genetic signature in Table 5 showed a statistically significant clinical remission treatment effect. See Figure 6, where the left markings for vedolizumab and placebo represent patients“not in the subgroup” and the right markings in each category represent patients“in the subgroup.” Moreover, subjects outside the subgroup showed a statistically significant non-response effect. See Figure 6. The subgroup showing enhanced treatment effect was identified using the parametric bootstrapping methods set forth in Example 2. In particular, responders were identified using the following formula, where the optimal cutoff was ^ = 0.6803: Score i = (rs7543124 coefficient) * rs7543124 + (rs2088361 coefficient) * rs2088361 + (rs1556981 coefficient) * rs1556981 + (rs1882926 coefficient) * rs1882926 + (rs11801527 coefficient) * rs11801527 + (rs3779477 coefficient) * rs3779477 + (rs1899750 coefficient) * rs1899750 + (rs2106842 coefficient) * rs2106842. The specific algorithm used was as follows:

Score i = -0.2213 * rs7543124– 0.8735 * rs2088361– 0.659 * rs1556981 + 0.8567 * rs1882926– 0.858 * rs11801527– 0.6935 * rs3779477 + 0.9288 * rs1899750 + 0.7159 * rs2106842, where the value for rs7543124, rs2088361, rs1556981, rs1882926, rs11801527, rs1899750, and rs2106842, respectively, is 0, 1, or 2, depending on the number of the patient’s minor allele. The distribution of Biomarker+ subgroup (In the subgroup) and Biomarker– subgroup (not in the subgroup) in vedolizumab- and placebo-treated CD patients is shown in Table 6. Table 6: Distribution of Biomarker+ subgroup (in the subgroup) and Biomarker– subgroup (Not in the subgroup) CD patients in the 8-SNP model

Example 5– 4 SNP Model Common variants located in the TRABD2B gene were of interest for subgroup identification based on association testing results. 45 common variants located in this gene passed genotypic QC. A penalized regression approach (Zou and Hastie, 2005) was employed to select the 13 SNPs set forth in Table 7. The 13-SNP model was found to significantly identify a responder subgroup.

Table 7. SNPs Selected by Penalized Regression from TRABD2B

6 SNPs were removed from these 13 SNPs to eliminate high LD structure using an r 2 threshold of 0.8: rs11211613, rs11211624, rs6684538, rs12061891, rs11211632, and rs17103939. A model refinement approach was then applied to the 7 remaining SNPs, and 4 SNPs were selected to construct a final model based on model performance. These 4 SNPs (Table 8) significantly defined a subgroup of size 73.24% (within the Vedolizumab arm) that showed statistical evidence (bootstrap adjusted p-value = 0.0010) of enhanced treatment effect on week 6 clinical remission. Table 8. The 4-SNP Model. The 4-variant (4-SNP) model shows statistically significant evidence for a treatment- specific effect. A subgroup identified via the genetic signature in Table 8 showed a statistically significant clinical remission treatment effect. See Figure 7A, where the left markings for vedolizumab and placebo represent patients“not in the subgroup,” the middle markings in each category represent the“treatment main effect,” and the right markings in each category represent patients“in the subgroup.” Moreover, subjects outside the subgroup showed a statistically significant non-response effect. See Figure 7A. The subgroup showing enhanced treatment effect was identified using the parametric bootstrapping methods set forth in Example 2. In particular, responders were identified using the following formula, where the optimal cutoff was ^ = -1.4350: Score i = (rs1561573 coefficient) * rs1561573 + (rs6671927 coefficient) * rs6671927 + (rs2088361 coefficient) * rs2088361 + (rs1556981 coefficient) * rs1556981 The specific algorithm used was as follows:

Score i = 0.32 * rs1561573– 0.4502 * rs6671927– 0.6524 * rs2088361– 0.8948 * rs1556981,

where the value for rs1561573, rs6671927, rs2088361, rs1556981, respectively, is 0, 1, or 2, depending on the number of the patient’s minor allele. The distribution of Biomarker+ subgroup (In the subgroup) and Biomarker– subgroup (not in the subgroup) in vedolizumab- and placebo-treated CD patients is shown in Table 9. Table 9: Distribution of Biomarker+ subgroup (in the subgroup) and

Biomarker– subgroup (Not in the subgroup) CD patients

Figures 7B and 7C show clinical remission over time during the induction phase in the C13007 and C13011 trials, respectively.

Figure 7D shows a statistically significant enhanced clinical response treatment effect. See Figure 7D, where the left markings for vedolizumab and placebo represent patients“not in the subgroup,” the middle markings in each category represent the“treatment main effect,” and the right markings in each category represent patients“in the subgroup.” Moreover, subjects outside the subgroup showed a statistically significant non-response effect. See Figure 7D. Figure 7E and 7F show enhanced clinical response over time in the C13007 and C13011 trials, respectively.

Figure 7G shows plots of CDAI scores versus genetic composite biomarker scores for both vedolizumab treatment and placebo treatment in the 4-SNP model. Figure 7H shows observed vs. predicted CDAI scores for the 4-SNP model.

Initial follow-up analysis on the 4-SNP model (conducted on a second cohort of the C13007 study that was not included in the initial analysis) was not consistent with the 4-SNP model being predictive of enhanced clinical response or clinical remission following treatment with vedolizumab. However, the follow-up analysis did trend toward showing a predictive effect at week 6 on clinical remission (p = 0.071), though it is possible this trend was driven by a negative effect of the placebo in the Biomarker+ group.. Example 6– 5 SNP Models Table 10 shows genes and gene combinations whose expression levels can be combined in multigene models that significantly correlate with clinical remission in adult Crohn’s Disease patients treated with vedolizumab.

Table 10: 5 variants used in genetic signature.

The 5-variant (5-SNP) model shows statistically significant evidence for a treatment- specific effect. A subgroup identified via the genetic signature in Table 10 showed a statistically significant clinical remission treatment effect. See Figure 8A, where the left markings for vedolizumab and placebo represent patients“not in the subgroup” and the right markings in each category represent patients“in the subgroup.” Moreover, subjects outside the subgroup showed a statistically significant non-response effect. See Figure 8A. The subgroup showing enhanced treatment effect was identified using the parametric bootstrapping methods set forth in Example 2. In particular, responders were identified using the following formula, where the optimal cutoff was ^ = -1.3896: Score i = (rs1561573 coefficient) * rs1561573 + (rs6671927 coefficient) * rs6671927 + (rs2088361 coefficient) * rs2088361 + (rs1556981 coefficient) * rs1556981 + (rs11205430 coefficient) * rs11205430 The specific algorithm used was as follows:

Score i = 0.2738 * rs1561573– 0.3913 * rs6671927– 0.5404 * rs2088361– 0.7396 * rs1556981– 0.1912 * rs11205430,

where the value for rs1561573, rs6671927, rs2088361, rs1556981, and rs11205430, respectively, is 0, 1, or 2, depending on the number of the patient’s minor allele.

The distribution of Biomarker+ subgroup (in the subgroup) and Biomarker– subgroup (not in the subgroup) in vedolizumab- and placebo-treated CD patients is shown in Table 11. Table 11: Distribution of Biomarker+ subgroup (in the subgroup) and Biomarker– subgroup (N t in the subgroup) CD patients in a first 5-SNP model

A second 5-variant (5-SNP) model also shows statistically significant evidence for a treatment-specific effect. A subgroup identified via the genetic signature in Table 12 showed a statistically significant clinical remission treatment effect. See Figure 8B, where the left markings for vedolizumab and placebo represent patients“not in the subgroup” and the right markings in each category represent patients“in the subgroup.” Moreover, subjects outside the subgroup showed a statistically significant non-response effect. See Figure 8B. Table 12: 5 variants used in genetic signature.

The subgroup showing enhanced treatment effect was identified using the parametric bootstrapping methods set forth in Example 2. In particular, responders were identified using the following formula, where the optimal cutoff was ^ = -1.59103: Score i = (rs1561573 coefficient) * rs1561573 + (rs11211613 coefficient) * rs11211613 + (rs12061891 coefficient) * rs12061891 + (rs11211632 coefficient) * rs11211632 + (rs11205430 coefficient) * rs11205430 The specific algorithm used was as follows:

Score i = 0.2865 * rs1561573– 0.3678 * rs11211613– 1.0079 * rs12061891– 0.5831 * rs11211632– 0.2351 * rs11205430,

where the value for rs1561573, rs11211613, rs12061891, rs11211632, and rs11205430, respectively, is 0, 1, or 2, depending on the number of the patient’s minor allele. The distribution of Biomarker+ subgroup (in the subgroup) and Biomarker– subgroup (not in the subgroup) in vedolizumab- and placebo-treated CD patients is shown in Table 13. Table 13: Distribution of Biomarker+ subgroup (in the subgroup) and Biomarker– subgroup (Not in the subgroup) CD patients in a second 5-SNP model

Example 7– 11 SNP Model Validation Study A validation analysis was conducted with the 11-SNP model set forth in Example 3. The analysis was conducted using data from a 2 nd cohort of the C13007 study (i.e., data not used in Example 3). The data from the 2 nd cohort was compared against placebo data discussed in Example 3, because the 2 nd cohort of the C13007 did not contain placebo data. A logistical regression model was used to test for the difference in treatment effect in Biomarker+ and Biomarker- subgroups.

Patients used in the validation analysis had some differences in their demographic and clinical characteristics from the patients in Example 3: the validations analysis (i) had more White and fewer Asian patients, and more patients from North America, (ii) had more patients that failed anti-TNF treatment prior to treatment with vedolizumab, and (iii) had a higher response rate for clinical remissions and enhanced clinical response at week 6. Demographic and clinical characteristic are compared in Figures 9A-C. Sample sizes in the respective studies were as shown in Table 14: Table 14: Sample Sizes for C13007 Induction Phase Subpopulations

Validation analysis of the 11-SNP model showed a nominally significant predictive effect at week 6 on clinical remission. See Figure 10, where the left markings for vedolizumab and placebo represent patients“not in the subgroup,” and the right markings in each category represent patients“in the subgroup,” and the center markings in each categoty represent the total number of analyzed patients. There is nevertheless a possibility that the interaction effect may be driven by the placebo arm. The observed predictive effect is summarized in Table 15. Table 15: Summary of subgroup predictive effect at week 6 comparing cohort 2 and the placebo arm of cohort 1

The distribution of Biomarker+ (in the subgroup) and Biomaker- (not in the subgroup) in the vedolizumab and placebo-treated CD patients is shown in Table 16. Table 16: Distribution of Bioamer+ subgroup and Biomaker- subgroup CD patients in the 11- SNP validation analysis:

When placebo data is excluded from the validation analysis, the 11-SNP model still trended towards a treatment effect in the Biomarker+ subgroup with respect to clinical remission and clinical response. In the placebo-excluded analysis on clinical remission, the mean response rate in the treatment arm in the Biomarker+ subgroup was 0.172 (0.122, 0.238), and the mean response rate in the treatment arm in the Biomarker- subgroup was 0.151 (0.117, 0.193) (p-value = 0.5276, pseudo R 2 = 0.087). Subjects in the Biomarker+ subgroup were 1.141 times more likely to respond to treatment than subjects in the Biomarker- subgroup (using a different statistical model that accounts for the placebo arm, the response rate for subjects in the Biomarker+ subgroup was 1.146 times higher than for subjects in the Biomarker- subgroup). A summary of the placebo-excluded analysis is shown in Table 17. Table 17: Summary of subgroup main effect at week 6 in cohort 2 using 11-SNP model