Increased CpG methylation at the CDH1 locus in inflamed ileal mucosa of patients with Crohn disease

Abstract

Abstract Background E-cadherin, a major actor of cell adhesion in the intestinal barrier, is encoded by the CDH1 gene and associated with susceptibility to Crohn's Disease (CD) and colorectal cancer. Since epigenetic mechanisms are suspected to contribute to the pathogenesis of CD, we studied the methylation of the CpG island (CGI) located in the CDH1 promoter and of 4 CpGs in the 7th enhancer in inflamed ileal mucosa and PBMC of CD patients operated on. Patients who underwent surgery for a non-inflammatory bowel disease provided a macroscopically normal ileal mucosa and PBMC for comparison. Results In ileal mucosa, 90% of the 21 studied CD patients had a methylated CDH1 CGI vs 50% of the 16 control patients (P < 0.01). In PBMC, percentage was comparable in CD (52%) and controls (44%). The methylation of the 4 CpGs in the 7th enhancer of CDH1 was also higher in the CD group for each individual CpG and for the average of the 4 CpGs (45 ± 17% in CD patients vs 36 ± 17% in controls, P < 0.001), while it was comparable in PBMC. The rs16260 SNP known to be associated with CD was not associated with studied CpG methylation. Conclusion Independently of the rs16260 genotype, the methylation of the promoter CGI and 4 enhancer CpGs at the CDH1 locus was increased in the inflamed ileal mucosa of a small cohort of CD patients. We speculate that these local methylation changes may decrease local expression of E-cadherin (not studied) and favor or aggravate ileal CD lesions. Whether CGI methylation could be used as a biomarker of colorectal cancer risk in ileal biopsies will have to be explored in further studies.