Rs2671655 single nucleotide polymorphism modulates the risk for gastric cancer in Helicobacter pylori-infected individuals: a genome-wide association study in the Korean population.

Abstract

ObjectiveTo identify genetic variations which is associated with gastric cancer (GC) risk according to Helicobacter pylori infection.MethodsThis study incorporated 527 GC patients and 441 controls from a cohort at Seoul National University Bundang Hospital. The associations between GC risk and single nucleotide polymorphisms were calculated, stratified by H. pylori status, adjusting for age, sex, and smoking. mRNA expression from non-cancerous gastric mucosae was evaluated using reverse transcription quantitative polymerase chain reaction.ResultsIn the entire cohort, genome-wide association study showed no significant variants reached the genome-wide significance level. In the H. pylori–positive group, rs2671655 (chr17:47,468,020;hg19, GH17J049387 enhancer region) was identified at a genome-wide significance level, which was more pronounced in diffuse type GC. There was no significant variant in the H. pylori–negative group, indicating the effect modification of rs2671655 by H. pylori. Among the target genes of GH17J049387 enhancer (PHB1, ZNF652 and SPOP), PHB1 mRNA was expressed more in cases than in controls, who were not affected by H. pylori. By contrast, an increase in ZNF652 and SPOP in GC was observed only in the H. pylori–negative group (P < 0.05). Mediation analysis showed that PHB1 (P = 0.0238) and SPOP (P = 0.0328) mediated the effect of rs2671655 on GC risk. The polygenic risk score was associated with the number of rs2671655 risk alleles only in the H. pylori–positive group (P = 0.0112).ConclusionAfter H. pylori infection, rs2671655 may increase GC risk, especially in diffuse-type GC, by regulating the expression of several genes that consequently modify susceptibility to GC.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10120-022-01285-x.