Atorvastatin, simvastatin, rosuvastatin and Amyotrophic lateral sclerosis establishing cause and effect

Background/Objectives: Statins are drugs that lower lipids levels, and widely used to reduce the risk of cardiovascular disease. Previous observational studies and experimental investigations have indicated that statin is associated with Amyotrophic Lateral Sclerosis (ALS). However, the causal relationship remains unclear.The present study employs a two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between atorvastatin, simvastatin, rosuvastatin and ALS at the nenetic level. Methods: The study utilized genome-wide association studies (GWAS) based on single-nucleotide polymorphisms (SNPs) for three statins (atorvastatin, simvastatin, and rosuvastatin), and encompassing data of 462,933 participants obtained from the UK Biobank, 80,610 individuals of ALS in genetic level data from European. The investigation of causal effects implemented five methods: inverse variance weighting (IVW), MR-Egger regression, wighted median, simple mode, and weighted mode. To detect horizontal pleiotropy, the MR-Egger intercept test and MR pleiotropy residual sum and outlier (MR-PRESSO) global test were employed. Instrument heterogeneity was evaluated by Cochran’s Q statistics. Sensitivity analysis was performed via the leave-one-out method. Results: The MR analysis suggest a potential causal relationship between atorvastatin, simvastatin, and rosuvastatin use and the risk of ALS, with the odds ratio (OR) and confidence interval (CI) providing further insight into the strength of this association. The results estimate for three statins use revealed a significantly elevated risk of ALS, atorvastatin (OR = 16.93, 95% CI: 5.42-52.89, p = 1.13E-06), simvastatin (OR = 5.05, 95% CI: 2.92-8.75, p = 7.49E-09), rosuvastatin (OR = 6.93E+5, 95% CI: 247.72-1.94E+9, p = 8.97-05). The sensitivity analysis highlighted the stability and reliability of the casual results. Conclusions: The present study provided genetic evidence that three statins (atorvastatin, simvastatin, rosuvastatin) were associated with the increased risk of ALS. Given the drug's effectiveness and potential side effects, individuals at higher risk of ALS should be cautious about th use of statins. Further investigations and robust reserch are needed to confirm the results, and the findings will provide valuable guidance for the drug use of ALS patients.