Gastroenterology

Gastroenterology

Volume 149, Issue 6, November 2015, Pages 1575-1586
Gastroenterology

Original Research
Full Report: Basic and Translational—Alimentary Tract
Characterization of Genetic Loci That Affect Susceptibility to Inflammatory Bowel Diseases in African Americans

https://doi.org/10.1053/j.gastro.2015.07.065Get rights and content

Background & 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.

Section snippets

Study Population and Phenotyping

The study population included unrelated self-identified non-Hispanic AA volunteers recruited from 3 coordinating centers: (1) Johns Hopkins: Multicenter African American IBD Study (MAAIS) coordinated by Johns Hopkins IBD Genetics Research Center (GRC) of the National Institutes of Diabetes and Digestive and Kidney Diseases IBD Genetics Consortium (IBDGC) with recruitment from 13 collaborating IBD centers and 4 other IBDGC GRCs,5 and additional AA control samples from the controls from

Results

After quality-control measures were performed, 3308 samples (1511 IBD cases and 1797 controls) and 130,241 unique autosomal SNPs remained for association and admixture analyses (Supplementary Figures 1 and 2). Mean YRI was higher in controls than in cases (81.7% ± 9.7% vs 80.0% ± 10.3%; P < 1 × 10-5), and also differed by coordinating centers (P < 1 × 10-10), with YRI proportion lowest for AAs from the American west coast, similar to other genetic studies24 (Supplementary Table 1).

Five

Discussion

In this study of IBD genetics in the AA population, we assembled the largest set of cases and controls (more than 4 times larger than any prior AA IBD study and the first genetic study of AA UC), evaluated for replication the of majority of established IBD associations, and we interrogated the majority of known IBD loci for novel associations. We also performed pathway and eQTL analyses to further inform about the nature of AA IBD genetics. Although our genotyping platform (not being GWA)

Acknowledgments

The authors are grateful to all of the patients and the controls that volunteered to join this study. This study is dedicated to Dr Linda Kao, who helped plan and direct the study, and passed away just before the study’s completion.

Ming-Hsi Wang's current affiliaton is, Department of Gastroenterology and Hepatology, Mayo Clinic Florida, Jacksonville, Florida.

IBDGC sample recruitment was from the Meyerhoff Inflammatory Bowel Disease Center at The Johns Hopkins Hospital and Johns Hopkins

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    Conflicts of interest The authors disclose no conflicts.

    Funding This work supported by National Institutes of Health (NIH) grants DK062431 (S.R.B.), DK087694 (S.K.), DK062413 (D.P.B.M and K.T), DK046763-19, AI067068, and U54DE023789-01 (D.P.B.M.), DK062429 and DK062422 (J.H.C.), DK062420 (R.H.D.), DK062432 (J.D.R.), and DK062423 (M.S.S.). Additional support from Harvey M. and Lynn P. Meyerhoff Inflammatory Bowel Disease Center, the Morton Hyatt Family, the Buford and Linda Lewis family (S.R.B.); endowed professorship from Marcus foundation (S.K.); The Joshua L and Lisa Z Greer Endowed Chair, HS021747 from the Agency for Healthcare Research and Quality, grant 305479 from the European Union, and The Leona M. and Harry B. Helmsley Charitable Trust (D.P.B.M.); from the Veterans Administration HSR&D Center for Innovations in Quality, Effectiveness and Safety (#CIN 13-413) and the Michael E. DeBakey VA Medical Center (J.K.H.). PARC control samples supported by NIH/National Heart, Lung, and Blood Institute grant HL06957 (Ronald M. Krauss, principal investigator). Rheumatoid arthritis control samples recruited and supported by the Consortium for the Longitudinal Evaluation of African-Americans with Early Rheumatoid Arthritis (CLEAR), NIH grants N01-AR-02247 and AR-6-2278 (S.L.B.) and the University of Alabama General Clinical Research Center (M01-RR-00032); systemic lupus erythematosus control samples recruited and supported by the PROFILE Study group coordinated at the University of Alabama Birmingham and supported by NIH grants P01-AR49084 (R.P.K.) and M01-RR-00032; type 1 diabetes control samples recruited and supported by the Type 1 Diabetes Genetics Consortium U01 DK062418 (S.S.R.), and sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Allergy and Infectious Diseases, National Center for Human Genome Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the Juvenile Diabetes Research Foundation. C.L.S. is supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health.

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