Prostate stem cell antigen gene polymorphism is associated with H. pylori-related promoter DNA methylation in non-neoplastic gastric epithelium

Abstract

Genome-wide association study identified two functional single nucleotide polymorphisms associated with gastric cancer (GC) especially the diffuse type. The first was a polymorphism (rs2294008) in prostate stem cell antigen (PSCA), and the other was a polymorphism (rs4072037) in mucin 1 (MUC1). DNA methylation is associated with GC and H. pylori-induced gastritis, while hypermethylation of promoter CpG island (CGI) is a common characteristic of enlarged-fold gastritis induced by H. pylori, a risk factor of diffuse-type GC. We evaluated the association between PSCA and MUC1 polymorphisms with H. pylori-related promoter CGI methylation in the non-neoplastic gastric mucosa. PSCA rs2294008 C/T and MUC1 rs4072037 A/G polymorphisms were genotyped in 410 cancer-free subjects in relation to promoter CGI methylation status of three candidate genes, of which the methylation status is associated with H. pylori infection (IGF2, MYOD1, and SLC16A12). Methylation levels of all three genes were significantly higher in subjects with PSCA rs2294008 T/T compared to the PSCA rs2294008 C/C (all P<0.05). Such associations were more enhanced in H. pylori-positive subjects (all P<0.01). The multivariate analysis demonstrated that PSCA C/T (odds ratio: 2.37, confidence interval: 1.06-5.29, P=0.035) and T/T genotypes (odds ratio: 3.2, confidence interval: 1.41-7.25, P=0.005) were significantly associated with methylation-high gastric mucosa as independent factors. MUC1 rs4072037 A/G polymorphism was not associated with methylation status of all three genes. PSCA C/T and T/T genotypes are associated with H. pylori-related promoter DNA methylation in the gastric mucosa.