Causal effects of drug exposure on gastric cancer risk: a Mendelian randomization study involving 23 commonly used medications in the European population

Abstract Background Previous studies have indicated potential associations between some drugs and cancer risk, but the causal relationship with gastric cancer remains unclear. This study aimed to explore the causality between 23 medications and gastric cancer using Mendelian randomization (MR) analysis. Methods A two-sample MR analysis was conducted to assess the causal effects of medications on gastric cancer risk. Primary causal estimates were derived using the inverse variance weighted method, complemented by weighted median, MR-Egger, simple mode, and weighted mode methods. Sensitivity analyses (MR-PRESSO, MR-Egger regression, Cochran’s Q test, leave-one-out analysis, Steiger filtering) validated the robustness of significant findings. Furthermore, enrichment analysis was used to analyze the biological functions of medication-related genes. Results After Bonferroni correction, anti-migraine formulations (OR, 0.83 [95% CI, 0.70–0.98]; p = 0.0253), drugs acting on the renin-angiotensin system (OR, 0.83 [95% CI, 0.73–0.94]; p = 0.0035), and adrenergic drugs/inhalants (OR, 0.86 [95% CI, 0.76–0.98]; p = 0.0212) were found to be suggestively associated with a reduced risk of gastric cancer in European populations. Sensitivity analyses revealed no significant heterogeneity or horizontal pleiotropy (all p > 0.05), and the Steiger filtering excluded reverse causality-related bias, collectively supporting the robustness of the primary findings. No significant causal relationship was found between the remaining 20 medications and gastric cancer risk. The causal association between 23 medications and gastric cancer differed between East Asian and European populations, indicating that the applicability of the causalities to non-European populations remains limited. Conclusion This study revealed negative genetically proxied associations related to drug targets of anti-migraine formulations, drugs acting on the renin-angiotensin system, and adrenergic drugs/inhalants with gastric cancer risk. These hypothesis-generating findings may help inform future mechanistic and clinical investigations.