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Contribution of higher risk genes and European admixture to Crohn's disease in African Americans

Authors

  • Ming-Hsi Wang MD, PhD,

    1. Lyn P. and Harvey M. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
    2. Department of Medicine, St Agnes Hospital Center, Baltimore, Maryland
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  • Toshihiko Okazaki MD, PhD,

    1. Lyn P. and Harvey M. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Subra Kugathasan MD,

    1. Department of Pediatrics, Emory University, Emory, Georgia
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  • Judy H. Cho MD,

    1. Department of Medicine and Genetics, Yale University, New Haven, Connecticut
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  • Kim L. Isaacs MD,

    1. Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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  • James D. Lewis MD, MSCE,

    1. Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania
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  • Duane T. Smoot MD,

    1. Department of Medicine, Howard University College of Medicine, Washington, DC
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  • John F. Valentine MD,

    1. Division of Gastroenterology, Hepatology & Nutrition, University of Florida, Gainesville, Florida
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  • Howard A. Kader MD,

    1. Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland
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  • Jean G. Ford MD,

    1. Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
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  • Mary L. Harris MD,

    1. Lyn P. and Harvey M. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
    2. Institute for Digestive Health & Liver Disease at Mercy Hospital, Baltimore, Maryland
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  • Maria Oliva-Hemker MD,

    1. Division of Pediatric Gastroenterology and Nutrition, Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Carmen Cuffari MD,

    1. Division of Pediatric Gastroenterology and Nutrition, Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Michael S. Torbenson MD,

    1. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Richard H. Duerr MD,

    1. 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
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  • Mark S. Silverberg MD, PhD,

    1. 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, Canada; Toronto General Hospital Research Institute, Toronto, Ontario, Canada
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  • John D. Rioux PhD,

    1. Université de Montréal and the Montreal Heart Institute, Research Center, Montreal, Quebec, Canada, the Broad Institute of MIT and Harvard, Cambridge, Massachusetts
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  • Kent D. Taylor PhD,

    1. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California
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  • Geoffrey C. Nguyen MD, PhD,

    1. Lyn P. and Harvey M. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
    2. 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, Canada; Toronto General Hospital Research Institute, Toronto, Ontario, Canada
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  • Yuqiong Wu MD,

    1. Lyn P. and Harvey M. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Lisa W. Datta MSc,

    1. Lyn P. and Harvey M. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Stanley Hooker BS,

    1. Section of Genetic Medicine, Department of Medicine, Pritzker School of Medicine, University of Chicago, Chicago, Illinois
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  • Themistocles Dassopoulos MD,

    1. Lyn P. and Harvey M. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
    2. Gastroenterology Division, Washington University School of Medicine, St. Louis, Missouri
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  • Rick A. Kittles PhD,

    1. Section of Genetic Medicine, Department of Medicine, Pritzker School of Medicine, University of Chicago, Chicago, Illinois
    2. Department of Medicine and Division of Epidemiology and Biostatistics, University of Illinois at Chicago, Chicago, Illinois
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  • Linda W.H. Kao PhD,

    1. Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
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  • Steven R. Brant MD

    Corresponding author
    1. Lyn P. and Harvey M. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
    2. Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
    • Gastroenterology Division, Department of Medicine, Johns Hopkins University School of Medicine, 1501 E. Jefferson St., B136, Baltimore, MD 21231
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  • Supported primarily by National Institutes of Health (NIH) grant DK062431 (to S.R.B.) with a supplement to assist with patient recruitment from the NCMHD. Additional funding was from the Harvey M. and Lynn P. Meyerhoff Inflammatory Bowel Disease Center, the Morton Hyatt Family, the Atran Foundation, and the Buford and Linda Lewis family. M.H.W. also received support from St Agnes Hospital and G.N. was supported by an AGA Research Scholar Award; Additional IBDGC support was from DK062429 and DK062422 (to J.H.C.), DK062420 (to R.H.D.), DK062432 (to J.D.R.), DK062423 (to M.S.S.), and DK062413 (to K.T.). No relevant potential conflicts of interest.

Abstract

Background:

African Americans (AAs) are an admixed population of West African (WA) and European ancestry (EA). Crohn's disease (CD) susceptibility genes have not been established. We therefore evaluated the contribution of European admixture and major established risk genes to AA CD.

Methods:

Ninety-seven admixture informative markers were genotyped for ancestry estimates using STRUCTURE. Overall, 354 AA CD cases and 354 ethnicity-matched controls were genotyped for total 21 single nucleotide polymorphisms (SNPs) in ATG16L1, NOD2, IBD5, IL23R and IRGM by TaqMan or direct sequencing. Association was evaluated by logistic regression, adjusted for ancestry.

Results:

Mean EA was similar among the CD cases and controls (20.9% and 20.4%, respectively, P = 0.58). No significant admixture differences were observed among 211 to 227 cases stratified by phenotypic subclassifications including onset, surgery, site, and behavior. CD was associated with NOD2 carrier (6.93% CD, 2.15% Controls, P = 0.007), ATG16L1 Thr300Ala (36.1% CD, 29.3% Controls, P = 0.003), SLC22A4 and SLC22A5 (IBD5 locus) functional SNPs (Leu503Phe [10.5% CD, 7.6% Controls, P = 0.05] and g-207c [41.3% CD, 35.7% Controls, P = 0.03], respectively), and IL23R rs2201841 (18.2% CD, 13.8% Controls, P = 0.03), but not IRGM variants, nor three African ancestral NOD2 nonsynonymous variants. IBD5 risk was recessive. An all-minor allele IBD5 haplotype from EA was associated (P = 0.05), whereas a more common haplotype isolating g-207c was not.

Conclusions:

Specific functional gene variations contribute significantly to AA CD risk. Established NOD2, SLC22A4-A5, and ATG16L1 variants show increased CD risk, with IBD5 recessive. Although CD is more common in whites, European admixture is similar among AA cases and controls. (Inflamm Bowel Dis 2012;)

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