RESUMEN
OBJECTIVE: Genome-wide association studies have identified single nucleotide polymorphisms in genes that might influence intestinal barrier function (HNF4A, ECM1, CDH1 and LAMB1) to increase the risk for ulcerative colitis (UC). The aim of our study was to detect causative sequence alterations and provide a functional link to a disturbed intestinal permeability (IP) in UC. METHODS: A total of 19 UC patients with increased IP (lactulose/mannitol ratio measured by sugar drink test) were identified from a large database, and exon/intron boundaries, coding and promoter regions of HNF4A, ECM1, CDH1 and LAMB1 were sequenced. Variants with putative protein alterations were studied for an association with IP in 82 UC patients. A case-control analysis including a genotype phenotype correlation was performed in 743 patients with inflammatory bowel disease (IBD) and 473 healthy controls. RESULTS: In UC patients, we identified 11 missense-mutations, 12 synonymous mutations, one putative promoter variant and three variants in introns close to the intron/exon boundaries (CDH1, HNF4A). For several variants prediction tools revealed damaging protein alterations. None of the studied variants, however, showed an association with an increased IP in UC. In the case-control analysis, the frequency of all investigated variants did not differ between UC or Crohn's disease and healthy controls. Furthermore, no significant association was found to a distinct phenotype. CONCLUSIONS: Despite our large sequencing approach, we could not identify protein altering variants in the genes HNF4A, ECM1, CDH1 and LAMB1 which could explain an impaired intestinal barrier function in UC. The functional relevance of these genes in IBD remains unknown.