Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease.
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Brant Steven R, Okou David T, Simpson Claire L, Cutler David J, Haritunians Talin, Bradfield Jonathan P, Chopra Pankaj, Prince Jarod, Begum Ferdouse, Kumar Archana, Huang Chengrui, Venkateswaran Suresh, Datta Lisa W, Wei Zhi, Thomas Kelly, Herrinton Lisa J, Klapproth Jan-Micheal A, Quiros Antonio J, Seminerio Jenifer, Liu Zhenqiu, Alexander Jonathan S, Baldassano Robert N, Dudley-Brown Sharon, Cross Raymond K, Dassopoulos Themistocles, Denson Lee A, Dhere Tanvi A, Dryden Gerald W, Hanson John S, Hou Jason K, Hussain Sunny Z, Hyams Jeffrey S, Isaacs Kim L, Kader Howard, Kappelman Michael D, Katz Jeffry, Kellermayer Richard, Kirschner Barbara S, Kuemmerle John F, Kwon John H, Lazarev Mark, Li Ellen, Mack David, Mannon Peter, Moulton Dedrick E, Newberry Rodney D, Osuntokun Bankole O, Patel Ashish S, Saeed Shehzad A, Targan Stephan R, Valentine John F, Wang Ming-Hsi, Zonca Martin, Rioux John D, Duerr Richard H, Silverberg Mark S, Cho Judy H, Hakonarson Hakon, Zwick Michael E, McGovern Dermot P B, Kugathasan Subra
Аннотация
METHODS: We performed 2 high-density, genome-wide scans comprising 2345 cases of African Americans with IBD (1646 with CD, 583 with UC, and 116 inflammatory bowel disease unclassified) and 5002 individuals without IBD (controls, identified from the Health Retirement Study and Kaiser Permanente database). Single-nucleotide polymorphisms (SNPs) associated at P < 5.0 × 10-8 in meta-analysis with a nominal evidence (P < .05) in each scan were considered to have genome-wide significance.
RESULTS: We detected SNPs at HLA-DRB1, and African-specific SNPs at ZNF649 and LSAMP, with associations of genome-wide significance for UC. We detected SNPs at USP25 with associations of genome-wide significance for IBD. No associations of genome-wide significance were detected for CD. In addition, 9 genes previously associated with IBD contained SNPs with significant evidence for replication (P < 1.6 × 10-6): ADCY3, CXCR6, HLA-DRB1 to HLA-DQA1 (genome-wide significance on conditioning), IL12B,PTGER4, and TNC for IBD; IL23R, PTGER4, and SNX20 (in strong linkage disequilibrium with NOD2) for CD; and KCNQ2 (near TNFRSF6B) for UC. Several of these genes, such as TNC (near TNFSF15), CXCR6, and genes associated with IBD at the HLA locus, contained SNPs with unique association patterns with African-specific alleles.
CONCLUSIONS: We performed a genome-wide association study of African Americans with IBD and identified loci associated with UC in only this population; we also replicated IBD, CD, and UC loci identified in European populations. The detection of variants associated with IBD risk in only people of African descent demonstrates the importance of studying the genetics of IBD and other complex diseases in populations beyond those of European ancestry.