HNF4α and CDH1 Are Associated with Ulcerative Colitis in a Dutch Cohort

Background: Inflammatory bowel diseases (IBDs), consisting of ulcerative colitis (UC) and Crohn's disease (CD), are complex disorders with multiple genes contributing to disease pathogenesis. A recent genome-wide association scan identified three novel susceptibility loci for UC: HNF4 alpha, CDH1, and LAMB1. We performed an analysis of these three loci in an independent cohort. Methods: In all, 821 UC patients and 1260 healthy controls of central European Caucasian descent were genotyped for single nucleotide polymorphisms (SNPs): rs6017342 (HNF4 alpha), rs1728785 (CDH1), and rs6949033 (LAMB1). Differences in allele and genotype distribution in cases and controls were tested for significance with the chi(2) test. Results: Allelic association analysis showed that SNP rs6017342 in the HNF4 alpha locus was strongly associated with UC (P 1,04 x 10(-11), odds ratio [OR] = 1.56, 95% confidence interval [CI] = 1.37-1.77) and SNP rs1728785 (CDH1) was associated with P = 0.01 (OR = 1.23, 95% CI = 1.05-1.44). SNP rs6949033 in LAMB1 was not associated in our cohort (P = 0.12, OR = 1.11, 95% CI = 0.97-1.26). We found an association for SNP rs6949033 (LAMB1) for disease limited to the rectum (P = 0.02). However, this association was lost after correcting for multiple testing. No further specific subphenotype associations were identified. Conclusions: This is the first independent study to replicate the HNF4 alpha and CDH1 loci as susceptibility loci for UC. The main candidate genes in these risk loci play important roles in the maintenance of the integrity of the epithelial barrier, highlighting the importance of the mucosal barrier function for UC pathogenesis.