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

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

Journal article

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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, …

Gastroenterology (New York, N.Y. 1943), Vol.149(6), pp.1575-1586

11/2015

DOI: https://doi.org/10.1053/j.gastro.2015.07.065

PMCID: PMC4685036

PMID: 26278503

Abstract

Ethnicity

Genetic Variant

Intestinal Inflammation

Race

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. 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. 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. 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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Title: Characterization of Genetic Loci That Affect Susceptibility to Inflammatory Bowel Diseases in African Americans
Creators: Chengrui Huang - Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
Talin Haritunians - F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
David T Okou - Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia
David J Cutler - Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia
Michael E Zwick - Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia
Kent D Taylor - 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, California
Lisa W Datta - Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
Joseph C Maranville - Committee on Clinical Pharmacology and Pharmacogenomics, and the Department of Human Genetics, The University of Chicago, Chicago, Illinois
Zhenqiu Liu - F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
Shannon Ellis - Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
Pankaj Chopra - Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia
Jonathan S Alexander - Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana
Robert N Baldassano - Division of Gastroenterology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
Raymond K Cross - Division of Gastroenterology, University of Maryland, Baltimore, Maryland
Themistocles Dassopoulos - Department of Medicine, Washington University School of Medicine, St Louis, Missouri
Tanvi A Dhere - Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
Richard H Duerr - 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, Pennsylvania
John S Hanson - Charlotte Gastroenterology and Hepatology, PLLC, Charlotte, North Carolina
Jason K Hou - 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, Texas
Sunny Z Hussain - Department of Pediatrics, Willis-Knighton Physician Network, Shreveport, Louisiana
Kim L Isaacs - Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
Kelly E Kachelries - Division of Gastroenterology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
Howard Kader - Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland
Michael D Kappelman - Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
Jeffrey Katz - Division of Gastroenterology, Case Western Reserve University, Cleveland, Ohio
Richard Kellermayer - Section of Pediatric Gastroenterology, Baylor College of Medicine, Houston, Texas
Barbara S Kirschner - Department of Pediatrics, University of Chicago Comer Children's Hospital, Chicago, Illinois
John F Kuemmerle - Departments of Medicine and Physiology and Biophysics, VCU Program in Enteric Neuromuscular Sciences, Medical College of Virginia Campus of Virginia Commonwealth University, Richmond Virginia
Archana Kumar - Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia
John H Kwon - Section of Gastroenterology, Department of Medicine, University of Chicago, Chicago, Illinois
Mark Lazarev - Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
Peter Mannon - Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
Dedrick E Moulton - Division of Gastroenterology, Vanderbilt Children’s Hospital, Nashville, Tennessee
Bankole O Osuntokun - Department of Pediatrics, Cook Children’s Medical Center, Fort Worth, Texas
Ashish Patel - Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas
John D Rioux - Universite de Montreal and the Montreal Heart Institute, Research Center, Montreal, Quebec, Canada
Jerome I Rotter - 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, California
Shehzad Saeed - Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Ellen J Scherl - Department of Medicine, Weill Cornell Medical College, New York, New York
Mark S Silverberg - 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, Canada
Ann Silverman - Department of Gastroenterology, Henry Ford Health System Detroit, Michigan
Stephan R Targan - F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
John F Valentine - Division of Gastroenterology, Hepatology and Nutrition, University of Utah, Salt Lake City, Utah
Ming-Hsi Wang - Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
Claire L Simpson - Statistical Genetics Section, Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland
S. Louis Bridges - Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama
Robert P Kimberly - Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama
Stephen S Rich - Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, Virginia
Judy H Cho - Department of Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York
Anna Di Rienzo - Committee on Clinical Pharmacology and Pharmacogenomics, and the Department of Human Genetics, The University of Chicago, Chicago, Illinois
Linda W.H Kao - Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
Dermot P.B McGovern - F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
Steven R Brant - Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
Subra Kugathasan - Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia
Publication Details: Gastroenterology (New York, N.Y. 1943), Vol.149(6), pp.1575-1586
Date published: 11/2015
Publisher: Elsevier Inc
Grant note: DK062431; DK087694; DK062413; DK046763-19; AI067068; U54DE023789-01; DK062429; DK062422; DK062420; DK062432; DK062423 / National Institutes of Health
Academic Unit: Office of Research and Sponsored Programs; Medicine - Gastroenterology and Hepatology (RWJMS)
Language: English
Resource Type: Journal article
Identifiers: 991031665357904646