33 The GTPase RAC1 is Associated With Inflammatory Bowel Disease

Background: Several reports have shown an association between Crohn's disease (CD) and SNPs at 10q21. Since reported associations have been with non-coding intergenic SNPs, “causal” variants remain to be identified. Aim: Fine-map the 10q21 region. Methods: We genotyped 86 SNPs across the region of reported association (Chr. 10, position 63,798,139 to 64,219,617) in 1,683 CD cases and 1,049 non-IBD controls. Single marker and conditional analyses were performed using logistic regression (PLINK). ZNF365 isoform D expression was assessed using RT-PCR. Results: Peak association with CD was observed within ZNF365 at rs7076156 and rs7071642, two SNPs in complete linkage disequilibrium (LD) (Table 1). Conditioning on nonsynonymous SNP rs7076156 (Ala62Thr) nullified all other significant associations and the threonine allele protected against CD (p=1.05x10-7; OR 0.71; 23.6% in patients with CD and 30.1% in controls). Four isoforms of ZNF365 (A-D) have previously been identified and rs7076156 is located in an exon unique to ZNF365 isoform D. We further detected expression of this isoform in a terminal ileum resection specimen from a patient with CD. Conclusion: We have demonstrated significant associations between CD and the ZNF365 locus. Conditional analyses suggested that a coding variant (rs7076156; Ala62Thr) confers protection against CD. Furthermore, mRNA for ZNF365 isoform D is expressed in small intestine. Taken together these data suggest that this variant explains the CD association observed at 10q21. ZNF365* SNPs Associated with CD