Mendelian Randomization-Based Analysis of Causal Effects Between Statins and Common Upper Gastrointestinal Diseases

Statins are widely used for cardiovascular disease prevention and exhibit multiple pleiotropic effects, including anti-inflammatory properties. However, conclusions from observational studies regarding the causal relationship between statin use and upper gastrointestinal diseases (such as gastric cancer, gastric ulcer, and functional dyspepsia) remain controversial. This study is aimed at systematically evaluating the causal association between statin-targeted gene (HMGCR)-mediated reductions in low-density lipoprotein cholesterol (LDL-C) levels and common upper gastrointestinal diseases using drug-targeted Mendelian randomization (MR). This approach seeks to uncover potential unintended effects.

We extracted genetic variants associated with the HMGCR gene region from genome-wide association studies (GWAS) as instrumental variables to simulate the lipid-lowering effects of statins. Outcome data were derived from large-scale GWAS meta-analyses covering gastric cancer (n = 202,308), gastroenteritis (n = 7651), gastric ulcer (n = 361,194), gastroesophageal reflux disease (n = 462,933), and functional dyspepsia (n = 84,572). The primary analysis employed inverse variance weighting (IVW), with sensitivity assessments for heterogeneity and pleiotropy conducted via MR-Egger, weighted median, and MR-PRESSO methods.

Genetically predicted HMGCR-mediated LDL-C reduction was associated with reduced risk of gastric cancer (OR = 0.588, 95% CI: 0.423-0.816, p = 0.002), gastroenteritis (OR = 0.257, 95% CI: 0.086-0.766, p = 0.015), and gastric ulcer (OR = 0.996, 95% CI: 0.993-0.998, p = 0.003). However, analysis indicated a potential increased risk of functional dyspepsia (OR = 1.437, 95% CI: 1.014-2.036, p = 0.042). No significant causal association was found between statin use and gastroesophageal reflux disease (OR = 0.999, 95% CI: 0.992-1.006, p = 0.773). Sensitivity analyses confirmed the robustness of the results, with no evidence of significant level-specific multiplicity.

This study provides genetic evidence supporting the potential protective effects of statins against gastric cancer, gastritis, and gastric ulcers, which may be associated with their anti-inflammatory properties. However, the potential increased risk of functional dyspepsia suggests the complexity of the drug's effects. These findings provide scientific basis for the repositioning of statins in gastrointestinal diseases and their safety assessment.