Two-stage candidate gene study of chromosome 3p demonstrates an association between nonsynonymous variants in the MST1R gene and Crohn's disease

Background: Genomewide linkage studies identified chromosome 3p21 as an IBD locus. Genomewide association studies have supported this locus and the Wellcome Trust Case Control Consortium (WTCCC) study narrowed it to a 0.6 Mb region. Our objectives were to perform a 2-stage candidate gene association study of the 3p locus and to identify linkage disequilibrium (LD) between significant single-nucleotide polymorphisms (SNPs) and an Oxfordshire subset (n=282) of the WTCCC as well as the HapMap SNPs. Methods: A total of 197 SNPs in 53 genes from the 3p locus were Genotyped on the Illumina platform in a screening cohort of 469 Crohn's disease (CD) patients and 461 controls. Significant associations were then genotyped on the iPLEX platform in the original as well as a second cohort of 139 CD patients, 670 ulcerative colitis (UC) patients, and 1131 controls. All cases and controls were Caucasian and from the Oxfordshire region of the UK. Results: An intronic SNP rs1128535 in the TRAIP gene was associated with CD in the screening and validation cohorts (combined [n = 6081 P = 0.0004 [corrected 0.0021, odds ratio [OR] 0.77, 95% confidence interval [Cl], 0.67-0.89]). No association was seen for UC. Epistasis was seen with the common CARD15 mutations (P = 0.00003 [corrected 0.0006], OR 0.48, 95% CI, 0.34-0.68). No LD was demonstrated with the WTCCC SNPs. Strong LD was demonstrated with 2 nonsynonymous HapMap SNPs in the MSTIR gene in an adjacent LD block to the peak WTCCC association, suggesting a distinct association signal. Conclusions: The LD with these functional MST1R variants implicate this gene as having a possible role in CD pathogenesis.