Characterization of Genetic Loci That Affect Susceptibility to Inflammatory Bowel Diseases in African Americans

Chengrui Huang; Talin Haritunians; David T. Okou; David J. Cutler; Michael E. Zwick; Kent D. Taylor; Lisa W. Datta; Joseph C. Maranville; Zhenqiu Liu; Shannon Ellis; Pankaj Chopra; Jonathan S. Alexander; Robert N. Baldassano; Raymond K. Cross; Themistocles Dassopoulos; Tanvi A. Dhere; Richard H. Duerr; John S. Hanson; Jason K. Hou; Sunny Z. Hussain; Kim L. Isaacs; Kelly E. Kachelries; Howard Kader; Michael D. Kappelman; Jeffrey Katz; Richard Kellermayer; Barbara S. Kirschner; John F. Kuemmerle; Archana Kumar; John H. Kwon; Mark Lazarev; Peter Mannon; Dedrick E. Moulton; Bankole O. Osuntokun; Ashish Patel; John D. Rioux; Jerome I. Rotter; Shehzad Saeed; Ellen J. Scherl; Mark S. Silverberg; Ann Silverman; Stephan R. Targan; John F. Valentine; Ming Hsi Wang; Claire L. Simpson; S. Louis Bridges; Robert P. Kimberly; Stephen S. Rich; Judy H. Cho; Anna Di Rienzo; Linda W.H. Kao; Dermot P.B. McGovern; Steven R. Brant; Subra Kugathasan

doi:10.1053/j.gastro.2015.07.065

Characterization of Genetic Loci That Affect Susceptibility to Inflammatory Bowel Diseases in African Americans

Chengrui Huang, Talin Haritunians, David T. Okou, David J. Cutler, Michael E. Zwick, Kent D. Taylor, Lisa W. Datta, Joseph C. Maranville, Zhenqiu Liu, Shannon Ellis, Pankaj Chopra, Jonathan S. Alexander, Robert N. Baldassano, Raymond K. Cross, Themistocles Dassopoulos, Tanvi A. Dhere, Richard H. Duerr, John S. Hanson, Jason K. Hou, Sunny Z. HussainKim L. Isaacs, Kelly E. Kachelries, Howard Kader, Michael D. Kappelman, Jeffrey Katz, Richard Kellermayer, Barbara S. Kirschner, John F. Kuemmerle, Archana Kumar, John H. Kwon, Mark Lazarev, Peter Mannon, Dedrick E. Moulton, Bankole O. Osuntokun, Ashish Patel, John D. Rioux, Jerome I. Rotter, Shehzad Saeed, Ellen J. Scherl, Mark S. Silverberg, Ann Silverman, Stephan R. Targan, John F. Valentine, Ming Hsi Wang, Claire L. Simpson, S. Louis Bridges, Robert P. Kimberly, Stephen S. Rich, Judy H. Cho, Anna Di Rienzo, Linda W.H. Kao, Dermot P.B. McGovern, Steven R. Brant, Subra Kugathasan

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Abstract

Background and Aims Inflammatory bowel disease (IBD) has familial aggregation in African Americans (AAs), but little is known about the molecular genetic susceptibility. Mapping studies using the Immunochip genotyping array expand the number of susceptibility loci for IBD in Caucasians to 163, but the contribution of the 163 loci and European admixture to IBD risk in AAs is unclear. We performed a genetic mapping study using the Immunochip to determine whether IBD susceptibility loci in Caucasians also affect risk in AAs and identify new associated loci. Methods We recruited AAs with IBD and without IBD (controls) from 34 IBD centers in the United States; additional controls were collected from 4 other Immunochip studies. Association and admixture loci were mapped for 1088 patients with Crohn's disease, 361 with ulcerative colitis, 62 with IBD type unknown, and 1797 controls; 130,241 autosomal single-nucleotide polymorphisms (SNPs) were analyzed. Results The strongest associations were observed between ulcerative colitis and HLA rs9271366 (P = 7.5 × 10^-6), Crohn's disease and 5p13.1 rs4286721 (P = 3.5 × 10^-6), and IBD and KAT2A rs730086 (P = 2.3 × 10^-6). Additional suggestive associations (P < 4.2 × 10^-5) were observed between Crohn's disease and IBD and African-specific SNPs in STAT5A and STAT3; between IBD and SNPs in IL23R, IL12B, and C2orf43; and between ulcerative colitis and SNPs near HDAC11 and near LINC00994. The latter 3 loci have not been previously associated with IBD, but require replication. Established Caucasian associations were replicated in AAs (P < 3.1 × 10^-4) at NOD2, IL23R, 5p15.3, and IKZF3. Significant admixture (P < 3.9 × 10^-4) was observed for 17q12-17q21.31 (IZKF3 through STAT3), 10q11.23-10q21.2, 15q22.2-15q23, and 16p12.2-16p12.1. Network analyses showed significant enrichment (false discovery rate <1 × 10^-5) in genes that encode members of the JAK-STAT, cytokine, and chemokine signaling pathways, as well those involved in pathogenesis of measles. Conclusions In a genetic analysis of 3308 AA IBD cases and controls, we found that many variants associated with IBD in Caucasians also showed association evidence with these diseases in AAs; we also found evidence for variants and loci not previously associated with IBD. The complex genetic factors that determine risk for or protection against IBD in different populations require further study.

Original language	English (US)
Pages (from-to)	1575-1586
Number of pages	12
Journal	Gastroenterology
Volume	149
Issue number	6
DOIs	https://doi.org/10.1053/j.gastro.2015.07.065
State	Published - Nov 2015

All Science Journal Classification (ASJC) codes

Hepatology
Gastroenterology

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10.1053/j.gastro.2015.07.065

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Huang, C., Haritunians, T., Okou, D. T., Cutler, D. J., Zwick, M. E., Taylor, K. D., Datta, L. W., Maranville, J. C., Liu, Z., Ellis, S., Chopra, P., Alexander, J. S., Baldassano, R. N., Cross, R. K., Dassopoulos, T., Dhere, T. A., Duerr, R. H., Hanson, J. S., Hou, J. K., ... Kugathasan, S. (2015). Characterization of Genetic Loci That Affect Susceptibility to Inflammatory Bowel Diseases in African Americans. Gastroenterology, 149(6), 1575-1586. https://doi.org/10.1053/j.gastro.2015.07.065

@article{ab763d2c8095454a8114f27a8aec33dc,

title = "Characterization of Genetic Loci That Affect Susceptibility to Inflammatory Bowel Diseases in African Americans",

abstract = "Background and Aims Inflammatory bowel disease (IBD) has familial aggregation in African Americans (AAs), but little is known about the molecular genetic susceptibility. Mapping studies using the Immunochip genotyping array expand the number of susceptibility loci for IBD in Caucasians to 163, but the contribution of the 163 loci and European admixture to IBD risk in AAs is unclear. We performed a genetic mapping study using the Immunochip to determine whether IBD susceptibility loci in Caucasians also affect risk in AAs and identify new associated loci. Methods We recruited AAs with IBD and without IBD (controls) from 34 IBD centers in the United States; additional controls were collected from 4 other Immunochip studies. Association and admixture loci were mapped for 1088 patients with Crohn's disease, 361 with ulcerative colitis, 62 with IBD type unknown, and 1797 controls; 130,241 autosomal single-nucleotide polymorphisms (SNPs) were analyzed. Results The strongest associations were observed between ulcerative colitis and HLA rs9271366 (P = 7.5 × 10-6), Crohn's disease and 5p13.1 rs4286721 (P = 3.5 × 10-6), and IBD and KAT2A rs730086 (P = 2.3 × 10-6). Additional suggestive associations (P < 4.2 × 10-5) were observed between Crohn's disease and IBD and African-specific SNPs in STAT5A and STAT3; between IBD and SNPs in IL23R, IL12B, and C2orf43; and between ulcerative colitis and SNPs near HDAC11 and near LINC00994. The latter 3 loci have not been previously associated with IBD, but require replication. Established Caucasian associations were replicated in AAs (P < 3.1 × 10-4) at NOD2, IL23R, 5p15.3, and IKZF3. Significant admixture (P < 3.9 × 10-4) was observed for 17q12-17q21.31 (IZKF3 through STAT3), 10q11.23-10q21.2, 15q22.2-15q23, and 16p12.2-16p12.1. Network analyses showed significant enrichment (false discovery rate <1 × 10-5) in genes that encode members of the JAK-STAT, cytokine, and chemokine signaling pathways, as well those involved in pathogenesis of measles. Conclusions In a genetic analysis of 3308 AA IBD cases and controls, we found that many variants associated with IBD in Caucasians also showed association evidence with these diseases in AAs; we also found evidence for variants and loci not previously associated with IBD. The complex genetic factors that determine risk for or protection against IBD in different populations require further study.",

author = "Chengrui Huang and Talin Haritunians and Okou, {David T.} and Cutler, {David J.} and Zwick, {Michael E.} and Taylor, {Kent D.} and Datta, {Lisa W.} and Maranville, {Joseph C.} and Zhenqiu Liu and Shannon Ellis and Pankaj Chopra and Alexander, {Jonathan S.} and Baldassano, {Robert N.} and Cross, {Raymond K.} and Themistocles Dassopoulos and Dhere, {Tanvi A.} and Duerr, {Richard H.} and Hanson, {John S.} and Hou, {Jason K.} and Hussain, {Sunny Z.} and Isaacs, {Kim L.} and Kachelries, {Kelly E.} and Howard Kader and Kappelman, {Michael D.} and Jeffrey Katz and Richard Kellermayer and Kirschner, {Barbara S.} and Kuemmerle, {John F.} and Archana Kumar and Kwon, {John H.} and Mark Lazarev and Peter Mannon and Moulton, {Dedrick E.} and Osuntokun, {Bankole O.} and Ashish Patel and Rioux, {John D.} and Rotter, {Jerome I.} and Shehzad Saeed and Scherl, {Ellen J.} and Silverberg, {Mark S.} and Ann Silverman and Targan, {Stephan R.} and Valentine, {John F.} and Wang, {Ming Hsi} and Simpson, {Claire L.} and Bridges, {S. Louis} and Kimberly, {Robert P.} and Rich, {Stephen S.} and Cho, {Judy H.} and {Di Rienzo}, Anna and Kao, {Linda W.H.} and McGovern, {Dermot P.B.} and Brant, {Steven R.} and Subra Kugathasan",

note = "Publisher Copyright: {\textcopyright} 2015 AGA Institute.",

year = "2015",

month = nov,

doi = "10.1053/j.gastro.2015.07.065",

language = "English (US)",

volume = "149",

pages = "1575--1586",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders",

number = "6",

}

Huang, C, Haritunians, T, Okou, DT, Cutler, DJ, Zwick, ME, Taylor, KD, Datta, LW, Maranville, JC, Liu, Z, Ellis, S, Chopra, P, Alexander, JS, Baldassano, RN, Cross, RK, Dassopoulos, T, Dhere, TA, Duerr, RH, Hanson, JS, Hou, JK, Hussain, SZ, Isaacs, KL, Kachelries, KE, Kader, H, Kappelman, MD, Katz, J, Kellermayer, R, Kirschner, BS, Kuemmerle, JF, Kumar, A, Kwon, JH, Lazarev, M, Mannon, P, Moulton, DE, Osuntokun, BO, Patel, A, Rioux, JD, Rotter, JI, Saeed, S, Scherl, EJ, Silverberg, MS, Silverman, A, Targan, SR, Valentine, JF, Wang, MH, Simpson, CL, Bridges, SL, Kimberly, RP, Rich, SS, Cho, JH, Di Rienzo, A, Kao, LWH, McGovern, DPB, Brant, SR & Kugathasan, S 2015, 'Characterization of Genetic Loci That Affect Susceptibility to Inflammatory Bowel Diseases in African Americans', Gastroenterology, vol. 149, no. 6, pp. 1575-1586. https://doi.org/10.1053/j.gastro.2015.07.065

TY - JOUR

T1 - Characterization of Genetic Loci That Affect Susceptibility to Inflammatory Bowel Diseases in African Americans

AU - Huang, Chengrui

AU - Haritunians, Talin

AU - Okou, David T.

AU - Cutler, David J.

AU - Zwick, Michael E.

AU - Taylor, Kent D.

AU - Datta, Lisa W.

AU - Maranville, Joseph C.

AU - Liu, Zhenqiu

AU - Ellis, Shannon

AU - Chopra, Pankaj

AU - Alexander, Jonathan S.

AU - Baldassano, Robert N.

AU - Cross, Raymond K.

AU - Dassopoulos, Themistocles

AU - Dhere, Tanvi A.

AU - Duerr, Richard H.

AU - Hanson, John S.

AU - Hou, Jason K.

AU - Hussain, Sunny Z.

AU - Isaacs, Kim L.

AU - Kachelries, Kelly E.

AU - Kader, Howard

AU - Kappelman, Michael D.

AU - Katz, Jeffrey

AU - Kellermayer, Richard

AU - Kirschner, Barbara S.

AU - Kuemmerle, John F.

AU - Kumar, Archana

AU - Kwon, John H.

AU - Lazarev, Mark

AU - Mannon, Peter

AU - Moulton, Dedrick E.

AU - Osuntokun, Bankole O.

AU - Patel, Ashish

AU - Rioux, John D.

AU - Rotter, Jerome I.

AU - Saeed, Shehzad

AU - Scherl, Ellen J.

AU - Silverberg, Mark S.

AU - Silverman, Ann

AU - Targan, Stephan R.

AU - Valentine, John F.

AU - Wang, Ming Hsi

AU - Simpson, Claire L.

AU - Bridges, S. Louis

AU - Kimberly, Robert P.

AU - Rich, Stephen S.

AU - Cho, Judy H.

AU - Di Rienzo, Anna

AU - Kao, Linda W.H.

AU - McGovern, Dermot P.B.

AU - Brant, Steven R.

AU - Kugathasan, Subra

PY - 2015/11

Y1 - 2015/11

N2 - Background and Aims Inflammatory bowel disease (IBD) has familial aggregation in African Americans (AAs), but little is known about the molecular genetic susceptibility. Mapping studies using the Immunochip genotyping array expand the number of susceptibility loci for IBD in Caucasians to 163, but the contribution of the 163 loci and European admixture to IBD risk in AAs is unclear. We performed a genetic mapping study using the Immunochip to determine whether IBD susceptibility loci in Caucasians also affect risk in AAs and identify new associated loci. Methods We recruited AAs with IBD and without IBD (controls) from 34 IBD centers in the United States; additional controls were collected from 4 other Immunochip studies. Association and admixture loci were mapped for 1088 patients with Crohn's disease, 361 with ulcerative colitis, 62 with IBD type unknown, and 1797 controls; 130,241 autosomal single-nucleotide polymorphisms (SNPs) were analyzed. Results The strongest associations were observed between ulcerative colitis and HLA rs9271366 (P = 7.5 × 10-6), Crohn's disease and 5p13.1 rs4286721 (P = 3.5 × 10-6), and IBD and KAT2A rs730086 (P = 2.3 × 10-6). Additional suggestive associations (P < 4.2 × 10-5) were observed between Crohn's disease and IBD and African-specific SNPs in STAT5A and STAT3; between IBD and SNPs in IL23R, IL12B, and C2orf43; and between ulcerative colitis and SNPs near HDAC11 and near LINC00994. The latter 3 loci have not been previously associated with IBD, but require replication. Established Caucasian associations were replicated in AAs (P < 3.1 × 10-4) at NOD2, IL23R, 5p15.3, and IKZF3. Significant admixture (P < 3.9 × 10-4) was observed for 17q12-17q21.31 (IZKF3 through STAT3), 10q11.23-10q21.2, 15q22.2-15q23, and 16p12.2-16p12.1. Network analyses showed significant enrichment (false discovery rate <1 × 10-5) in genes that encode members of the JAK-STAT, cytokine, and chemokine signaling pathways, as well those involved in pathogenesis of measles. Conclusions In a genetic analysis of 3308 AA IBD cases and controls, we found that many variants associated with IBD in Caucasians also showed association evidence with these diseases in AAs; we also found evidence for variants and loci not previously associated with IBD. The complex genetic factors that determine risk for or protection against IBD in different populations require further study.

AB - Background and Aims Inflammatory bowel disease (IBD) has familial aggregation in African Americans (AAs), but little is known about the molecular genetic susceptibility. Mapping studies using the Immunochip genotyping array expand the number of susceptibility loci for IBD in Caucasians to 163, but the contribution of the 163 loci and European admixture to IBD risk in AAs is unclear. We performed a genetic mapping study using the Immunochip to determine whether IBD susceptibility loci in Caucasians also affect risk in AAs and identify new associated loci. Methods We recruited AAs with IBD and without IBD (controls) from 34 IBD centers in the United States; additional controls were collected from 4 other Immunochip studies. Association and admixture loci were mapped for 1088 patients with Crohn's disease, 361 with ulcerative colitis, 62 with IBD type unknown, and 1797 controls; 130,241 autosomal single-nucleotide polymorphisms (SNPs) were analyzed. Results The strongest associations were observed between ulcerative colitis and HLA rs9271366 (P = 7.5 × 10-6), Crohn's disease and 5p13.1 rs4286721 (P = 3.5 × 10-6), and IBD and KAT2A rs730086 (P = 2.3 × 10-6). Additional suggestive associations (P < 4.2 × 10-5) were observed between Crohn's disease and IBD and African-specific SNPs in STAT5A and STAT3; between IBD and SNPs in IL23R, IL12B, and C2orf43; and between ulcerative colitis and SNPs near HDAC11 and near LINC00994. The latter 3 loci have not been previously associated with IBD, but require replication. Established Caucasian associations were replicated in AAs (P < 3.1 × 10-4) at NOD2, IL23R, 5p15.3, and IKZF3. Significant admixture (P < 3.9 × 10-4) was observed for 17q12-17q21.31 (IZKF3 through STAT3), 10q11.23-10q21.2, 15q22.2-15q23, and 16p12.2-16p12.1. Network analyses showed significant enrichment (false discovery rate <1 × 10-5) in genes that encode members of the JAK-STAT, cytokine, and chemokine signaling pathways, as well those involved in pathogenesis of measles. Conclusions In a genetic analysis of 3308 AA IBD cases and controls, we found that many variants associated with IBD in Caucasians also showed association evidence with these diseases in AAs; we also found evidence for variants and loci not previously associated with IBD. The complex genetic factors that determine risk for or protection against IBD in different populations require further study.

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UR - http://www.scopus.com/inward/citedby.url?scp=84945529572&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2015.07.065

DO - 10.1053/j.gastro.2015.07.065

M3 - Article

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AN - SCOPUS:84945529572

SN - 0016-5085

VL - 149

SP - 1575

EP - 1586

JO - Gastroenterology

JF - Gastroenterology

IS - 6

ER -

Characterization of Genetic Loci That Affect Susceptibility to Inflammatory Bowel Diseases in African Americans

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