Abstract
Genome-Wide Association studies (GWAS) of both Crohn's Disease (CD) and Ulcerative Colitis (UC) have unearthed over 40 risk conferring variants. Recently, a meta-analysis on UC revealed several loci, most of which were either previously associated with UC or CD susceptibility in populations of European origin. In this study, we attempted to replicate these findings in an ethnically distinct north Indian UC cohort. 648 UC cases and 850 controls were genotyped using Infinium Human 660W-quad. Out of 59 meta-analysis index SNPs, six were not in the SNP array used in the study. Of the remaining 53 SNPs, four were found monomorphic. Association (p<0.05) at 25 SNPs was observed, of which 15 were CD specific. Only five SNPs namely rs2395185 (HLA-DRA), rs3024505 (IL10), rs6426833 (RNF186), rs3763313 (BTNL2) and rs2066843 (NOD2) retained significance after Bonferroni correction. These results (i) reveal limited replication of Caucasian based meta-analysis results; (ii) reiterate overlapping molecular mechanism(s) in UC and CD; (iii) indicate differences in genetic architecture between populations; and (iv) suggest that resources such as HapMap need to be extended to cover diverse ethnic populations. They also suggest a systematic GWAS in this terrain may be insightful for identifying population specific IBD risk conferring loci and thus enable cross-ethnicity fine mapping of disease loci.
Highlights
Ulcerative colitis (UC) and Crohn’s disease (CD), the two subphenotypes of inflammatory bowel diseases (IBDs), are polygenic conditions that are suspected to result from dysregulated activation of immune mechansism to commensal microbes in genetically predisposed individuals
Of the remaining 49 index SNPs, associations were replicated with 25 SNPs (p,0.05) with 15 of them previously identified as CD specific (Table 1)
In this study we investigated the contribution of these IBD specific loci in our ethnically heterogeneous north Indian UC cohort in order to define its genetic architecture more conclusively
Summary
Ulcerative colitis (UC) and Crohn’s disease (CD), the two subphenotypes of inflammatory bowel diseases (IBDs), are polygenic conditions that are suspected to result from dysregulated activation of immune mechansism to commensal microbes in genetically predisposed individuals. Some loci showed specific association with CD (ATG16L1) [10] or UC (IL10, ECM1, HERC2) [13], a substantial overlap in genetic risk factors between the phenotypes have been observed with genes such as IL23R at the forefront [6,14,15]. Discovery of these susceptibility genes, common as well as unique, has provided valuable insights into the link between the innate and adaptive immunity vis-a-vis risk for IBD
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