上海预防医学2025，Vol.37Issue(7)：569-580,12.DOI:10.19428/j.cnki.sjpm.2025.24938
肥胖相关基因与胃癌发病的遗传易感性
Obesity-related genes and genetic susceptibility to gastric cancer
摘要
Abstract
[Objective]To explore the effects of genetic variation of obesity-related biological pathways and gene-obesity interactions on the incidence of gastric cancer,so as to better understand the pathogenesis of gastric cancer and help identify high-risk populations for individualized prevention of gastric cancer.[Methods]A case-control study based on the Shanghai Suburban Adult Cohort and Biobank study(SSACB)was conducted on the cases with gastric cancer.A total of 267 cases with gastric cancer and 267 healthy controls matched 1∶1 by age and gender using propensity score were included in the study.After genome-wide genotyping,quality control and imputation,19 250 single nucleotide polymorphism(SNP)sites from 115 genes in 4 obesity-related biological pathways were extracted.Univariate and multivariate logistic regression analyses were used to evaluate the association between these SNP sites and the risk of gastric cancer,and false positive report probability(FPRP)was used for multiple test correction.Data from Biobank Japan(BBJ)and FinnGen public accessible databases were used to validate significant SNP sites.For validated sites,expression quantitative trait loci(eQTL)analysis and differentially expressed genes analysis were further performed.Additive and multiplicative interactions were used to evaluate the gene-obesity interactions on the incidence of gastric cancer.Additive interaction evaluation indicators included relative excess risk due to interaction(RERI),attributable proportion due to interaction(AP)and synergy index(SI),while multiplicative interaction evaluation indicators include ORGxE and Pinter.[Results]A total of 41 SNP sites were significantly associated with the onset of gastric cancer(Padj<0.05,FPRP0.1<0.1),among which 7 groups of haplotype blocks were formed.ACACB/rs2268401[SSACB:P=0.005,BBJ:P=0.049],HRAS/rs12785860(SSACB:P<0.001,FinnGen:P=0.045),and PTPN1/rs6095985(SSACB:P<0.001,FinnGen:P=0.023)were significantly associated with the risk of gastric cancer after validation in different populations.Among which,the G allele of HRAS/rs12785860 was correlated with the downregulation of HRAS mRNA expression(P<0.001),and the expression level of HRAS in gastric cancer tissues was higher than that in adjacent normal tissues(P<0.001).Additionaly,JAK1/rs11208559 showed a positive additive interaction with waist circumstance(WC)on the risk of gastric cancer[RERI=2.29(0.06～4.53),AP=0.57(0.23～0.90),SI=4.03(2.20～5.87)].[Conclusion]Obesity-related biological pathway SNP sites and their haplotypes are associated with the risk of gastric cancer,suggesting that genetic variations in obesity pathways may affect gastric cancer.The HRAS/rs12785860 is significantly associated with downregulation of HRAS gene expression,which may serve as a potential genetic marker for gastric cancer.JAK1/rs11208559 interacts with obesity additively on the risk of gastric cancer.Individuals with GC+CC genotypes and pre-central or central obesity have an increased risk of gastric cancer,providing clues and evidences for individualized prevention of gastric cancer.关键词
胃癌/肥胖/通路分析/遗传易感性/交互作用/单核苷酸多态性Key words
gastric cancer/obesity/pathway analysis/genetic susceptibility/interaction/single nucleotide polymorphism分类
医药卫生引用本文复制引用
武文汇,丁诗韵,李竞娆,郑吉,毛嘉宁,朱添忆,吴毅凌,张若昕..肥胖相关基因与胃癌发病的遗传易感性[J].上海预防医学,2025,37(7):569-580,12.基金项目
上海市加强公共卫生体系建设三年行动计划(2023-2025年)重点学科(GWVI-11.1-23) （2023-2025年）
复旦-嘉定公共卫生高质量发展重点学科(GWGZLXK-2023-02) （GWGZLXK-2023-02）
