What Loci Determine Susceptibility to IBD in African Americans?
Although many of the same genetic variants determine susceptibility to inflammatory bowel diseases (IBD) in Caucasians and African Americans, researchers report the identification of variants and loci not previously associated with IBD in African American populations. Analyses of these could provide insight into the pathogenesis of IBD, researchers state in the November issue of Gastroenterology.
IBD often develops in multiple members of the same African American families, but little is known about the factors that determine susceptibility. More than 160 IBD susceptibility loci have been reported from studies of Caucasian populations, but only a small number of variants have been evaluated in African Americans, in relatively small studies (a few hundred cases and controls), and only for Crohn’s disease—not ulcerative colitis.
African Americans are a recently admixed population, derived from approximately 80% West African and 20% European ancestries. The prevalence of IBD is lower in African Americans than Caucasian Americans, possibly as a result of genetic and environmental differences. However, African Americans with a sibling with IBD have a relatively high risk for developing the disease (2.5%), indicating a role for genetic factors.
Chengrui Huang et al performed a genetic mapping study, using the Immunochip, to determine whether genetic variants that contribute to IBD susceptibility in Caucasians also affect risk in African Americans, and whether additional loci are involved.
They recruited African Americans with IBD and without IBD (controls) from 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. A total of 130,241 autosomal single-nucleotide polymorphisms (SNPs) were analyzed.
Huang et al found the strongest associations between ulcerative colitis and HLA rs9271366, Crohn’s disease and 5p13.1 rs4286721, and IBD and KAT2A rs730086. KAT2A is a histone acetyltransferase linked to repression of the interferon-beta gene and innate antiviral immunity.
Additional associations were observed between Crohn’s disease and IBD and African-specific SNPs in STAT5A and STAT3 (see figure); between IBD and SNPs in IL23R, IL12B, and C2orf43; and between ulcerative colitis and SNPs near HDAC11 or LINC00994. The latter 3 loci have not been previously associated with IBD.
Established Caucasian associations were replicated in African Americans at NOD2, IL23R, 5p15.3, and IKZF3. Significant admixture was observed for 17q12−17q21.31 (IZKF3 through STAT3), 10q11.23−10q21.2, 15q22.2–15q23, and 16p12.2−16p12.1.
Network analyses showed the highest numbers of variants to occur in genes that encode members of the JAK−STAT, cytokine, and chemokine signaling pathways, as well those involved in pathogenesis of measles, in the African Americans.
The authors state that this is the largest set of cases and controls involved in a genetic analysis of IBD in African Americans and the first genetic study of ulcerative colitis in this population.
The SNP that the authors associated with UC, rs9271366, tags the HLA class II allele DRB1*1502 in other populations. It has been reported to have statistically significant associations with ulcerative colitis genome-wide association studies of Japanese and Korean patients. Interestingly, it is the most associated HLA SNP in systemic lupus erythematosus in African Americans—this disease is 4-fold more frequent in African Americans vs Caucasian Americans.
In an editorial that accompanies the article, Adeyinka O. Laiyemo and Maria T. Abreu say that whereas Caucasians with IBD frequently have polymorphisms in pathways involved in control of Leishmania infection, it was interesting to find that African American patients had polymorphisms in the measles pathway and the African trypanosomiasis pathway. These findings support the role of the immune response to pathogens in development of IBD. Studies of other non-European populations could identify other factors involved in development of IBD.
Laiyemo and Abreu state that although it is not surprising that African Americans and Caucasians share most risk loci for IBD, the subtle differences observed could contribute to different responses to therapy in each patient population. They might also be used to design specific treatments based on genetic features of patients.