Lifestyle factors, obesity, and Helicobacter pylori infection in gastric cancer by anatomical subsite: A systematic review and meta-analysis

BACKGROUND Unhealthy lifestyle factors, obesity, and Helicobacter pylori (H.pylori) infection are established risk factors for gastric cancer, however, their differential associations with cardia gastric adenocarcinoma (CGA) and non-CGA (NCGA) remain inconsistent across studies.AIM To evaluate the subsite-and ethnicity-specific associations of lifestyle factors, obesity, and H. pylori infection with CGA and NCGA risk.METHODS We systematically searched MEDLINE, EMBASE, and Web of Science up to November 2025.Study quality was assessed using the Newcastle-Ottawa Scale, and publication bias was evaluated using funnel plots.Pooled odds ratios (OR) and 95% confidence interval (CI) were calculated.Subgroup analyses were conducted by ethnicity (East Asian vs European).RESULTS Twenty-six high-quality studies were included.Smoking was associated with increased risks of CGA (OR =1.99, 95%CI: 1.52-2.61;P < 0.00001) and NCGA (OR = 1.51, 95%CI: 1.25-1.84;P < 0.0001).Alcohol consumption was also associated with an increased risk of CGA (OR = 1.26, 95% CI: 1.04-1.53;P = 0.02), but was not significantly associated with the risk of NCGA (OR = 1.09, 95% CI: 0.77-1.53;P = 0.64).Higher body mass index (BMI) was significantly associated with CGA (OR = 1.43, 95%CI: 1.03-1.98;P = 0.03).H. pylori infection was not significantly associated with overall CGA risk (OR = 0.99, 95%CI: 0.59-1.65;P = 0.96) but significantly increased NCGA risk (OR = 2.49, 95%CI: 1.69-3.66;P < 4 / 36 0.00001).By ethnicity, H. pylori was associated with increased CGA risk in East Asian populations (OR = 2.45, 95%CI: 1.43-4.20;P = 0.001) but decreased it in European populations (OR = 0.46, 95%CI: 0.29-0.72;P = 0.0007), and increased NCGA risk in both groups.CONCLUSION Gastric cancer risk factors show subsite-and ethnicity-specific associations.Smoking significantly increases both CGA and NCGA risks.Alcohol consumption and higher BMI are significantly associated with increased CGA risk but not NCGA risk.H. pylori infection was not significantly associated with overall CGA but showed divergent associations by ethnicity, and consistently increased NCGA risk.These observations may help inform future risk-stratified analyses and generate hypotheses for site-and ethnicity-targeted gastric cancer prevention strategies.