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In this study, we conducted a cross\u2010sectional study with 1800 participants to identify plasma metabolite signatures associated with environmental risk factors of gastric cancer. Subsequently, we evaluated the association between these signatures and gastric cancer risk in a nested case\u2013control study involving 326 gastric cancer cases and 326 matched cancer\u2010free controls. We conducted mediation analyses to elucidate the potential impact of metabolites on the association between environmental factors and gastric cancer. In the cross\u2010sectional study, we identified 46 metabolites associated with <jats:italic>Helicobacter pylori (H. pylori)<\/jats:italic> infection, 365 with alcohol drinking, and 154 with smoking status. In the nested case\u2013control study, 60 plasma metabolites, comprising 30 lipids, 15 amino acids, 6 xenobiotics, 3 nucleotides, 2 cofactors and vitamins, 2 carbohydrate, 1 energy, and 1 peptide, were associated with gastric cancer risk. A one\u2010standard deviation increment in the <jats:italic>H. pylori<\/jats:italic> infection\u2010related metabolomic signature was associated with an increased risk of gastric cancer (OR\u2009=\u20091.66, 95% CI: 1.32\u20132.09, <jats:italic>p<\/jats:italic>\u2009=\u20091.62\u2009\u00d7\u200910<jats:sup>\u22125<\/jats:sup>). Furthermore, the effect of <jats:italic>H. pylori<\/jats:italic> infection on gastric cancer was partially mediated by the metabolomic signature (23.28%, 95% CI: 0.09\u20130.56) or adenine (13.69%, 95% CI: 0.05\u20130.31). In conclusion, we have identified metabolites associated with environmental factors and demonstrated the association between the <jats:italic>H. pylori<\/jats:italic> infection signature and gastric cancer risk. The findings provide novel insights into characterizing high\u2010risk population for gastric cancer.<\/jats:p>","DOI":"10.1002\/mc.23851","type":"journal-article","created":{"date-parts":[[2024,12,4]],"date-time":"2024-12-04T14:32:47Z","timestamp":1733322767000},"page":"463-474","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Plasma Metabolomic Signatures of <i>H. pylori<\/i> Infection, Alcohol Drinking, Smoking, and Risk of Gastric Cancer"],"prefix":"10.1002","volume":"64","author":[{"given":"Yuhui","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Epidemiology, State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University Nanjing 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