Re: Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease.

Abstract

The inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn’s disease (CD) cause significant morbidity and are increasing in prevalence among all populations, including African Americans. More than 200 susceptibility loci have been identified in populations of predominantly European ancestry, but few loci have been associated with IBD in other ethnicities. 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 <i>P</i> < 5.0 × 10⁻⁸ in meta-analysis with a nominal evidence (<i>P</i> < .05) in each scan were considered to have genome-wide significance. We detected SNPs at <i>HLA-DRB1</i>, and African-specific SNPs at <i>ZNF649</i> and <i>LSAMP</i>, with associations of genome-wide significance for UC. We detected SNPs at <i>USP25</i> 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 (<i>P</i> < 1.6 × 10⁻⁶): <i>ADCY3</i>, <i>CXCR6</i>, <i>HLA-DRB1</i> to <i>HLA-DQA1</i> (genome-wide signifi-cance on conditioning), <i>IL12B</i>, <i>PTGER4</i>, and <i>TNC</i> for IBD; <i>IL23R</i>, <i>PTGER4</i>, and <i>SNX20</i> (in strong linkage disequilibrium with <i>NOD2</i>) for CD; and <i>KCNQ2</i> (near <i>TNFRSF6B</i>) for UC. Several of these genes, such as <i>TNC</i> (near <i>TNFSF15), CXCR6</i>, and genes associated with IBD at the HLA locus, contained SNPs with unique association patterns with African-specific alleles. 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.