Environmental factors, seven GWAS-identified susceptibility loci, and risk of gastric cancer and its precursors in a Chinese population.

Meng Cai,Shuyang Dai,Jun Qi,Xiaohang Zhao,Lingeng Lu,Changfa Xia,Meilin Wang,Hongmei Zeng,Fuhua Lei,Shuguang Dai,Lanping Zhou,Tingting Zuo,Wanqing Chen,Minjie Wang

doi:10.1002/cam4.1038

Abstract

Gene–environment interactions may increase gastric cancer (GC) risk. Seven susceptibility loci identified by genome‐wide association studies (GWASs) suggest that genetic factors play a role in gastric carcinogenesis. Meanwhile, Helicobacter pylori (H. pylori) infection, smoking, and alcohol drinking are also important environmental factors for gastric cancer. However, studies to explore the role of gene–environment interactions in gastric carcinogenesis, and particularly the relationship between the seven susceptibility loci and their potential interactions with H. pylori infection, smoking, and alcohol drinking in risk of GC, and severe intestinal metaplasia (IM)/dysplasia, have been inconclusive. A total of 1273 subjects in a Chinese population were recruited, and genotyping was carried out using the competitive allele‐specific PCR (KASP) method. Unconditional logistic regression was applied to model the associations between genetic polymorphisms and the disease risk. Effect modifications by H. pylori infection, smoking and alcohol drinking were evaluated. PSCA rs2294008/rs2976392 showed a significant, multiplicative interaction with H. pylori infection in risk of GC. Meanwhile, PRKAA1 rs13361707 had an additive interaction with H. pylori infection. SLC52A3 rs13042395 showed an interaction with alcohol drinking in risk of GC. Moreover, three SNPs, MUC1 rs4072037, ZBTB20 rs9841504 and PRKAA1 rs13361707, were associated with precancerous gastric lesions (severe IM/dysplasia). Our data suggest that genetic predisposition factors identified by GWAS may interact with environmental risk factors, Particularly for H. pylori infection and alcohol consumption, to increase the risk of GC.

Highlights

Gastric cancer (GC) is one of the most common cancers worldwide and more than 40% of GC cases occur in China
We found that individuals with at least one variant allele of the six polymorphisms had an altered risk of GC (OR: 1.48, 95% confidence intervals (CIs): 1.09–1.99 for PLCE1 rs2274223; Odds ratios (ORs): 1.41, 95% CI: 1.05–1.89 for PSCA rs2294008; OR: 1.41, 95% CI: 1.05–1.89 for PSCA rs2976392; OR: 0.59, 95% CI: 0.42–0.81 for MUC1 rs4072037; OR: 0.70, 95% CI: 0.52–0.93 for SLC52A3 rs13042395; and OR: 0.43, 95% CI: 0.31–0.61 for PRKAA1 rs13361707)
We found that the ZBTB20 rs9841504, CG/GG genotype was associated with a protective effect against risk of severe intestinal metaplasia (IM)/dysplasia, with an adjusted OR of 0.69

Summary

Introduction

Gastric cancer (GC) is one of the most common cancers worldwide and more than 40% of GC cases occur in China. The carcinogenesis of GC is a multifactorial process, resulting from the combined consequences of genetic predisposition and environmental risk factors including Helicobacter pylori (H. pylori) infection, smoking, alcohol drinking, and dietary factors [2]. Among the environmental risk factors for GC, it is widely recognized that H. pylori is a major etiological factor [3]. Only a small proportion of H. pylori-infected individuals progress to GC [5], suggesting that environmental factors other than H. pylori infection, such as smoking and alcohol drinking, and genetic predisposition may influence the outcome of gastric pathogenesis [6]. Several studies have found that H. pylori cytotoxin-associated gene A (CagA)+ and/or vacuolating cytotoxin gene A (VacA)+ strains can increase the risk of developing gastric diseases. VacA is a secreted protein that stimulates epithelial cell apoptosis and induces vacuole formation in eukaryotic cells [10]

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