MAFK Polymorphisms Located in 3′-UTR are Associated with Severity of Atrophy and CDKN2A Methylation Status in the Gastric Mucosa

Abstract

Objective:

This study was designed to clarify the association of the MAFK polymorphisms (rs4268033, rs3735656, and rs10226620) with the degree of gastric mucosal atrophy and CDKN2A CpG methylation status.

Methods:

A total of 491 subjects were enrolled in this study. Genotypes and methylation status were determined by polymerase chain reaction (PCR)-single-stranded conformation polymorphism and methylation-specific PCR (Fujita Health University, HM18-094).

Methods:

A total of 491 subjects were enrolled in this study. Genotypes and methylation status were determined by polymerase chain reaction (PCR)-single-stranded conformation polymorphism and methylation-specific PCR (Fujita Health University, HM18-094).

Results:

Both rs3735656 and rs10226620, located in the 3′-UTR of MAFK, were significantly associated with the severity of gastric mucosal atrophy using a dominant genetic model (odds ratio [OR], 2.10; p = 0.0012, and OR, 1.98; p = 0.0027, respectively). Under a recessive genetic model, no significant association was found between three polymorphisms and gastric mucosal atrophy. The serum pepsinogen I/II ratio was significantly lower in subjects with minor alleles of rs3735656 and rs10226620 than in subjects that were homozygous WT (p = 0.018 and 0.013, respectively). In a subgroup including 400 of the 491 subjects, the CpG of p14^ARF and p16 ^INK4a were methylated in 132 and 112 subjects, respectively. Fifty subjects had both CpG methylations and 206 subjects had neither methylation. When comparing the groups with both and neither methylations, there were no significant associations between any of the three polymorphisms and CDKN2A methylation under a dominant genetic model. However, all polymorphisms investigated in this study (rs4268033, rs3735656, and rs10226620) were significantly associated with CDKN2A methylation in a recessive genetic model (OR, 3.58; p = 0.0071, OR, 4.49; p = 0.0004, and OR, 3.45; p = 0.0027, respectively).

Conclusions:

Our results indicate that possession of either of the minor allele MAFK polymorphisms that are located in the 3′UTR increase the risk of severe gastric mucosal atrophy; furthermore CDKN2A CpG methylation may develop in subjects who are homozygous for the minor alleles of the these MAFK 3′ UTR SNPs