Host genetic factors, related to inflammatory response, influence the CpG island methylation status in colonic mucosa in ulcerative colitis

Background: CpG island hypermethylation (CIHM) in gene promoter is frequently observed in the colonic mucosa in ulcerative colitis (UC), and is strongly involved in UC-associated colorectal carcinogenesis (CRC). The influence of common single nucleotide polymorphisms (SNPs) related to inflammatory immune response on the individual susceptibility to CIHM status in the non-neoplastic rectal mucosa in UC patients was evaluated. Patients and Methods: Ten candidate SNPs, multidrug resistance 1 (MDR1) 3435 (C>T), regulated upon activation, normal T-cell expressed and secreted (RANTES)-28 (C>G), heat-shock protein (HSP)70-2 1267 (B>A), NADPH oxidase p22PHOX 242 (C>T), Toll-like receptor (TLR)2-196 to -174 (ins >del), CD14-159 (C>T), Mannan-binding lectin (MBL)2 codon 54 (G>A), tumor necrosis factor-α(TNF-α) -857 (C>T), interleukin-1β(IL-1β)-511 (C>T), and IL-1β -31 (T>C) were genotyped in 58 UC patients without neoplastic lesions, in relation to CIHM in the rectal mucosa of three candidate CpG (p14, p16 and E-cadherin: CDH1) loci, assessed by methylation-specific- polymerase chain reaction (MSP). High CIHM was defined as two or more CpG islands methylated. Results: The CD14-159TT genotype held a significantly higher susceptibility to CIHM of the p16 promoter (OR=3.82, 95%CI=1.06-13.79, p=0.04) A significant association was also found between the IL-1β-31TC genotype and reduced susceptibility to high CIHM (OR=0.14, 95%CI=0.22-0.94, p=0.04). The p22PHOX 242CT genotype and MBL2 codon 54 A carrier (GA+AA) were significantly associated with a lower mean number of CIHM (p=0.029, 0.046, respectively). Conclusion: CD14 -159, 1L-Iβ-31, p22PHOX 242 and MBL2 codon 54 SNPs may influence the CIHM status in the rectal mucosa of UC patients and may therefore be substantially involved in UC- associated carcinogenesis.