Potential role for the common cystic fibrosis AF508 mutation in Crohn's disease

Background: Inflammatory bowel disease (IBD1) is an epithelial barrier disease that is thought to result from a dysregulated interaction with bacteria in the intestine of genetically predisposed individuals. The cystic fibrosis transmembrane conductance regulator (CFTR), which is mutated in the autosomal recessive disease cystic fibrosis, modulates gut permeability, mucus production, and epithelial interactions with bacteria. The cystic fibrosis Delta F508 mutation is commonly found in the general Population and has been shown to result in a reduced number of CFTR molecules at the surface of epithelial cells. Given the important biological functions of CFTR in the intestine, we tested whether this mutation is of relevance to IBD. Methods: Using DNA heleroduplex analysis, we investigated the distribution of Delta F508 heterozygosity in 2568 subjects from three independent cohorts of Italian, Swedish, and Scottish IBD patients and controls. Results: In all three cohorts an association between Delta F508 and Crohn's disease (CD) was observed. Specifically, Delta F508 heterozygosity was markedly underrepresented in CD patients from Italy and Sweden (P = 0.021 and 0.027 Versus controls, respectively). while stratification for disease location revealed an absence of Delta F508 carriers among Scottish CD patients with right-sided colitis (P = 0.023 versus all other locations). Conclusions: Delta F508 heterozygosity might exert a protective effect in CD.