Characterization of genetic loci that affect susceptibility to inflammatory bowel diseases in African Americans.
OBJECTIVE
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.
Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21231, USA.
Chengrui
C
Huang
F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90049, USA.
Talin
T
Haritunians
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
David T
DT
Okou
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
David J
DJ
Cutler
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
Michael E
ME
Zwick
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.
Kent D
KD
Taylor
Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Lisa W
LW
Datta
Committee on Clinical Pharmacology and Pharmacogenomics, and the Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA.
Joseph C
JC
Maranville
F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90049, USA.
Zhenqiu
Z
Liu
Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Shannon
S
Ellis
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
Pankaj
P
Chopra
Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA.
Jonathan S
JS
Alexander
Division of Gastroenterology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Robert N
RN
Baldassano
Division of Gastroenterology, University of Maryland, Baltimore, MD 21201, USA.
Raymond K
RK
Cross
Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
Themistocles
T
Dassopoulos
Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Tanvi A
TA
Dhere
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.
Richard H
RH
Duerr
Charlotte Gastroenterology and Hepatology, PLLC, Charlotte, NC 28207, USA.
John S
JS
Hanson
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.
Jason K
JK
Hou
Department of Pediatrics, Willis-Knighton Physician Network, Shreveport, LA 71118, USA.
Sunny Z
SZ
Hussain
Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
Kim L
KL
Isaacs
Division of Gastroenterology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Kelly E
KE
Kachelries
Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Howard
H
Kader
Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
Michael D
MD
Kappelman
Division of Gastroenterology, Case Western Reserve University, Cleveland, OH 44106, USA.
Jeffrey
J
Katz
Section of Pediatric Gastroenterology, Baylor College of Medicine, Houston, TX, 77030.
Richard
R
Kellermayer
Department of Pediatrics, University of Chicago Comer Children's Hospital, Chicago, IL 60637, USA.
Barbara S
BS
Kirschner
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.
John F
JF
Kuemmerle
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
Archana
A
Kumar
Section of Gastroenterology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
John H
JH
Kwon
Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Mark
M
Lazarev
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Peter
P
Mannon
Division of Gastroenterology, Vanderbilt Children's Hospital, Nashville TN 37212, USA.
Dedrick E
DE
Moulton
Department of Pediatrics, Cook Children's Medical Center, Fort Worth, TX 76104, USA.
Bankole O
BO
Osuntokun
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Ashish
A
Patel
Universite de Montreal and the Montreal Heart Institute, Research Center, Montreal, Quebec H1T 1C8, Canada.
John D
JD
Rioux
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.
Jerome I
JI
Rotter
Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Shehzad
S
Saeed
Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
Ellen J
EJ
Scherl
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.
Mark S
MS
Silverberg
Department of Gastroenterology, Henry Ford Health System Detroit, MI 48208, USA.
Ann
A
Silverman
F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90049, USA.
Stephan R
SR
Targan
Division of Gastroenterology, Hepatology and Nutrition, University of Utah, Salt Lake City, Utah.
John F
JF
Valentine
Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Ming-Hsi
MH
Wang
Statistical Genetics Section, Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD 21224, USA.
Claire L
CL
Simpson
Division of Clinical Immunology & Rheumatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
S Louis
SL
Bridges
Division of Clinical Immunology & Rheumatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Robert P
RP
Kimberly
Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
Stephen S
SS
Rich
Department of Medicine and Genetics, Yale University, New Haven, CT 06520, USA.
Judy H
JH
Cho
Committee on Clinical Pharmacology and Pharmacogenomics, and the Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA.
Anna Di
AD
Rienzo
Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21231, USA.
Linda W H
LWH
Kao
F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90049, USA.
Dermot P B
DPB
McGovern
Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21231, USA.|Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Steven R
SR
Brant
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
Subra
S
Kugathasan
D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D003093:Colitis, Ulcerative / Q000235:genetics; D003424:Crohn Disease / Q000235:genetics; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D014481:United States / Q000208:ethnology; D044465:White People / Q000235:genetics*; D055815:Young Adult
Ethnicity; Genetic Variant; Intestinal Inflammation; Race