Multicenter Study

. 2015 Nov;149(6):1575-1586.

doi: 10.1053/j.gastro.2015.07.065. Epub 2015 Aug 14.

Characterization of genetic loci that affect susceptibility to inflammatory bowel diseases in African Americans

Chengrui Huang^#¹, Talin Haritunians^#², David T Okou^#³, David J Cutler⁴, Michael E Zwick⁴, Kent D Taylor⁵, Lisa W Datta⁶, Joseph C Maranville⁷, Zhenqiu Liu², Shannon Ellis⁶, Pankaj Chopra⁴, Jonathan S Alexander⁸, Robert N Baldassano⁹, Raymond K Cross¹⁰, Themistocles Dassopoulos¹¹, Tanvi A Dhere¹², Richard H Duerr¹³, John S Hanson¹⁴, Jason K Hou¹⁵, Sunny Z Hussain¹⁶, Kim L Isaacs¹⁷, Kelly E Kachelries⁹, Howard Kader¹⁸, Michael D Kappelman¹⁹, Jeffrey Katz²⁰, Richard Kellermayer²¹, Barbara S Kirschner²², John F Kuemmerle²³, Archana Kumar³, John H Kwon²⁴, Mark Lazarev⁶, Peter Mannon²⁵, Dedrick E Moulton²⁶, Bankole O Osuntokun²⁷, Ashish Patel²⁸, John D Rioux²⁹, Jerome I Rotter⁵, Shehzad Saeed³⁰, Ellen J Scherl³¹, Mark S Silverberg³², Ann Silverman³³, Stephan R Targan², John F Valentine³⁴, Ming-Hsi Wang⁶, Claire L Simpson³⁵, S Louis Bridges³⁶, Robert P Kimberly³⁶, Stephen S Rich³⁷, Judy H Cho³⁸, Anna Di Rienzo⁷, Linda W H Kao¹, Dermot P B McGovern^#², Steven R Brant^#^{1

6}, Subra Kugathasan^#³

Affiliations

¹ Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21231, USA.
² F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90049, USA.
³ Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
⁴ Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
⁵ Institute for Translational Genomics and Population Sciences and Division of Genomic Outcomes, Departments of Pediatrics and Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA,90502, USA.
⁶ Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
⁷ Committee on Clinical Pharmacology and Pharmacogenomics, and the Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA.
⁸ Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA.
⁹ Division of Gastroenterology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
¹⁰ Division of Gastroenterology, University of Maryland, Baltimore, MD 21201, USA.
¹¹ Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
¹² Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
¹³ Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, and Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
¹⁴ Charlotte Gastroenterology and Hepatology, PLLC, Charlotte, NC 28207, USA.
¹⁵ Department of Medicine, Baylor College of Medicine; VA HSR&D Center for Innovations in Quality, Effectiveness and Safety , Michael E. DeBakey VA Medical Center, Houston, TX 77030, USA.
¹⁶ Department of Pediatrics, Willis-Knighton Physician Network, Shreveport, LA 71118, USA.
¹⁷ Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
¹⁸ Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
¹⁹ Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
²⁰ Division of Gastroenterology, Case Western Reserve University, Cleveland, OH 44106, USA.
²¹ Section of Pediatric Gastroenterology, Baylor College of Medicine, Houston, TX, 77030.
²² Department of Pediatrics, University of Chicago Comer Children's Hospital, Chicago, IL 60637, USA.
²³ Departments of Medicine and Physiology and Biophysics, VCU Program in Enteric Neuromuscular Sciences, Medical College of Virginia Campus of Virginia Commonwealth University, Richmond VA 23298, USA.
²⁴ Section of Gastroenterology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
²⁵ Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
²⁶ Division of Gastroenterology, Vanderbilt Children's Hospital, Nashville TN 37212, USA.
²⁷ Department of Pediatrics, Cook Children's Medical Center, Fort Worth, TX 76104, USA.
²⁸ Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
²⁹ Universite de Montreal and the Montreal Heart Institute, Research Center, Montreal, Quebec H1T 1C8, Canada.
³⁰ Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
³¹ Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
³² Departments of Medicine, Surgery, Public Health Sciences, Immunology, and Molecular and Medical Genetics, University of Toronto, Samuel Lunenfeld Research Institute and Mount Sinai Hospital, Toronto General Hospital Research Institute, Toronto, Ontario M5S 2J7, Canada.
³³ Department of Gastroenterology, Henry Ford Health System Detroit, MI 48208, USA.
³⁴ Division of Gastroenterology, Hepatology and Nutrition, University of Utah, Salt Lake City, Utah.
³⁵ Statistical Genetics Section, Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD 21224, USA.
³⁶ Division of Clinical Immunology & Rheumatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
³⁷ Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
³⁸ Department of Medicine and Genetics, Yale University, New Haven, CT 06520, USA.

^# Contributed equally.

PMID: 26278503
PMCID: PMC4685036
DOI: 10.1053/j.gastro.2015.07.065

Multicenter Study

Characterization of genetic loci that affect susceptibility to inflammatory bowel diseases in African Americans

Chengrui Huang et al. Gastroenterology. 2015 Nov.

. 2015 Nov;149(6):1575-1586.

doi: 10.1053/j.gastro.2015.07.065. Epub 2015 Aug 14.

Authors

Affiliations

¹ Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21231, USA.
² F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90049, USA.
³ Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
⁴ Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
⁵ Institute for Translational Genomics and Population Sciences and Division of Genomic Outcomes, Departments of Pediatrics and Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA,90502, USA.
⁶ Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
⁷ Committee on Clinical Pharmacology and Pharmacogenomics, and the Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA.
⁸ Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA.
⁹ Division of Gastroenterology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
¹⁰ Division of Gastroenterology, University of Maryland, Baltimore, MD 21201, USA.
¹¹ Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
¹² Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
¹³ Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, and Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
¹⁴ Charlotte Gastroenterology and Hepatology, PLLC, Charlotte, NC 28207, USA.
¹⁵ Department of Medicine, Baylor College of Medicine; VA HSR&D Center for Innovations in Quality, Effectiveness and Safety , Michael E. DeBakey VA Medical Center, Houston, TX 77030, USA.
¹⁶ Department of Pediatrics, Willis-Knighton Physician Network, Shreveport, LA 71118, USA.
¹⁷ Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
¹⁸ Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
¹⁹ Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
²⁰ Division of Gastroenterology, Case Western Reserve University, Cleveland, OH 44106, USA.
²¹ Section of Pediatric Gastroenterology, Baylor College of Medicine, Houston, TX, 77030.
²² Department of Pediatrics, University of Chicago Comer Children's Hospital, Chicago, IL 60637, USA.
²³ Departments of Medicine and Physiology and Biophysics, VCU Program in Enteric Neuromuscular Sciences, Medical College of Virginia Campus of Virginia Commonwealth University, Richmond VA 23298, USA.
²⁴ Section of Gastroenterology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
²⁵ Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
²⁶ Division of Gastroenterology, Vanderbilt Children's Hospital, Nashville TN 37212, USA.
²⁷ Department of Pediatrics, Cook Children's Medical Center, Fort Worth, TX 76104, USA.
²⁸ Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
²⁹ Universite de Montreal and the Montreal Heart Institute, Research Center, Montreal, Quebec H1T 1C8, Canada.
³⁰ Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
³¹ Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
³² Departments of Medicine, Surgery, Public Health Sciences, Immunology, and Molecular and Medical Genetics, University of Toronto, Samuel Lunenfeld Research Institute and Mount Sinai Hospital, Toronto General Hospital Research Institute, Toronto, Ontario M5S 2J7, Canada.
³³ Department of Gastroenterology, Henry Ford Health System Detroit, MI 48208, USA.
³⁴ Division of Gastroenterology, Hepatology and Nutrition, University of Utah, Salt Lake City, Utah.
³⁵ Statistical Genetics Section, Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD 21224, USA.
³⁶ Division of Clinical Immunology & Rheumatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
³⁷ Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
³⁸ Department of Medicine and Genetics, Yale University, New Haven, CT 06520, USA.

^# Contributed equally.

PMID: 26278503
PMCID: PMC4685036
DOI: 10.1053/j.gastro.2015.07.065

Abstract

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.

Keywords: Ethnicity; Genetic Variant; Intestinal Inflammation; Race.

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Figures

**Figure 1**
Comparison of log₂(Odds ratios) estimated in this study with those in *Caucasian Immunochip Study* (*CIS*) for 110 IBD-general (correlation=0.78), 26 CD-specific (correlation=0.77) and 23 UC-specific (correlation=0.61) *Maximal-CIS SNPs*.

**Figure 2**
Association mapping (left) and admixture (right) mapping p-values (in −log10) for IBD (top panel), CD (middle panel) and UC (bottom panel).

**Figure 3**
Comparison of log₁₀(Odds Ratios) at the risk alleles by chromosomal position (in Mb, Genome Build 37) between Caucasian (*black*), East Asian (*green*) and African American (*red*) loci for IBD (*hatched*), CD (*solid*) and UC (*stippled*). Bars with *black outlines* represent loci with reported genome-wide significant association evidence in the CIS (*black,* limited to OR≥1.1) or in East Asian studies (*green*). Bars *without outlines* are present for AA or East Asian replications (at p<3.1e-4) of CIS-Maximal SNPs, or for SNPs evaluated in these populations with *suggestive evidence for association* at established CIS loci (p<4.2e-5) or borderline of genome-wide significance for novel loci (p≤1e-6). *Asterisks* denote the same associated SNPs in AA and additional populations. *Red arrows* denote overlaps between significant admixture regions and association loci.

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Comment in

Reducing colorectal cancer risk among African Americans.
Kupfer SS, Carr RM, Carethers JM. Kupfer SS, et al. Gastroenterology. 2015 Nov;149(6):1302-4. doi: 10.1053/j.gastro.2015.08.033. Epub 2015 Aug 22. Gastroenterology. 2015. PMID: 26302487 Free PMC article. No abstract available.
Deciphering the genetic code of gastrointestinal diseases among African Americans.
Laiyemo AO, Abreu MT. Laiyemo AO, et al. Gastroenterology. 2015 Nov;149(6):1323-6. doi: 10.1053/j.gastro.2015.09.029. Epub 2015 Sep 28. Gastroenterology. 2015. PMID: 26416331 Free PMC article. No abstract available.

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Characterization of genetic loci that affect susceptibility to inflammatory bowel diseases in African Americans

Affiliations

Characterization of genetic loci that affect susceptibility to inflammatory bowel diseases in African Americans

Authors

Affiliations

Abstract

Figures

Comment in

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Molecular Biology Databases

Research Materials

Miscellaneous