Mendelian randomization study on simvastatin and gastric cancer: exploring the therapeutic potential of statins in oncology.

Background: Gastric cancer ranks as the fifth most prevalent cancer and the third leading cause of cancer-related mortality worldwide, Statins, renowned for their cholesterol-lowering effects, have garnered interest for their potential roles in cancer prevention and treatment due to their pleiotropic effects, such as anti-proliferative, pro-apoptotic, and anti-inflammatory properties. This study aims to investigate the therapeutic potential of simvastatin, a widely prescribed statin, in the context of gastric cancer using Mendelian randomization (MR) to explore a possible causal relationship between simvastatin use and gastric cancer risk.

Methods: We conducted a two-sample MR analysis utilizing summary statistics from genome-wide association studies (GWAS). Data from the Integrative Epidemiology Unit (IEU) Open GWAS project included 462,933 participants and 9,851,867 single nucleotide polymorphisms (SNPs) for simvastatin, and 476,116 participants with 24,188,662 SNPs for gastric cancer. Instrumental variables screening criteria were stringent, resulting in 41 valid SNPs as instrumental variables. The MR analysis was performed using the inverse variance weighting (IVW), supplemented by MR-Egger, weighted median estimator (WME), weighted mode, and simple mode approaches. Heterogeneity and pleiotropy were assessed using IVW, MR-Egger tests, and the MR-PRESSO method.

Results: The IVW and WME analyses indicated a significant protective effect of simvastatin against gastric cancer [IVW: odds ratio (OR) =0.1459, 95% confidence interval (CI): -3.502 to -0.346, P=0.01; WME: OR =0.0347, 95% CI: -3.521 to 0.1610, P=0.03]. There was no significant difference between the results of the two MR analyses before and after the removal of outliers (P=0.76), and the Egger-intercept for horizontal pleiotropy testing was not significant (P=0.38). Leave-one-out sensitivity analysis supported the robustness of our findings.

Conclusions: This MR study provides evidence for a potential protective effect of simvastatin against gastric cancer, suggesting its consideration as an adjunct to traditional cancer therapies.