Evidence of allelic heterogeneity for associations between the NOD2/CARD15 gene and ulcerative colitis among North Indians

Background: Three common disease susceptibility variants in the NOD2 gene are associated with inflammatory bowel disease in Caucasians, but not in Asians. Aim: To screen for NOD2 variants and examine susceptibility for inflammatory bowel disease in North Indians. Methods: A case-control study was carried out in Punjab, India. Confirmed cases of ulcerative colitis and Crohn's disease and healthy controls matched for age (±10 years) and ethnicity were studied. Besides genotyping the three disease susceptibility variants (SNP8, SNP12 and SNP13), all 12 exons were resequenced to determine other potential single nucleotide polymorphisms. Results: Two hundred and ninety-eight ulcerative colitis, 25 Crohn's disease and 262 controls were investigated. Median age (range) at diagnosis was 39 (7-78) years for ulcerative colitis and 40 (32-58) years for Crohn's disease. All three disease susceptibility variants were either monomorphic or rare in the population. Sequencing (n = 30) revealed two single nucleotide polymorphisms: SNP5 (268 Pro/Ser) and rs2067085 (178 Ser/Ser). The frequency of SNP5 was higher among ulcerative colitis (17% vs. 12% in controls, P = 0.016) and Crohn's disease cases (20% vs. 12%, P = 0.28). SNP5 carriers had elevated risks for ulcerative colitis (OR = 1.72, 95% CI = 1.17-2.52, P = 0.005). Conclusions: The absence of known inflammatory bowel disease susceptibility variants and potential associations between SNP5 and ulcerative colitis in North Indians suggests the presence of allelic heterogeneity for ulcerative colitis susceptibility.