A Mendelian Randomization Approach Using 3-HMG-Coenzyme-A Reductase Gene Variation to Evaluate the Association of Statin-Induced Low-Density Lipoprotein Cholesterol Lowering with Noncardiovascular Disease Phenotypes

Importance Observational studies suggest that statins, which inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, may be associated with beneficial effects in many noncardiovascular diseases. Objective To construct a weighted HMG-CoA reductase (HMGCR) gene genetic risk score (GRS) using variants in theHMGCRgene affecting low-density lipoprotein cholesterol as an instrumental variable for mendelian randomization analyses to test associations with candidate noncardiovascular phenotypes previously associated with statin use in observational studies. Design, Setting, and Participants This cohort study included 53 385 unrelated adults of European ancestry with genome-wide genotypes available from BioVU (a practice-based biobank, used for discovery) and 30 444 unrelated adults with European ancestry available in the Electronic Medical Records and Genomics (eMERGE; a research consortium that conducts genetic research using electronic medical records, used for replication). The study was conducted from February 6, 2015, through April 31, 2019; data analysis was performed from August 26, 2019, through December 22, 2020. Interventions AnHMGCRGRS was calculated. Main Outcomes and Measures The association between theHMGCRGRS and the presence or absence of 22 noncardiovascular phenotypes previously associated with statin use in clinical studies. Results Of the 53 385 individuals in BioVU, 29 958 (56.1%) were women; mean (SD) age was 59.9 (15.6) years. The finding between theHMGCRGRS and the noncardiovascular phenotypes of interest in this cohort was significant only for type 2 diabetes. AnHMGCRGRS equivalent to a 10-mg/dL decrease in the low-density lipoprotein cholesterol level was associated with an increased risk of type 2 diabetes (odds ratio [OR], 1.09; 95% CI, 1.04-1.15;P = 5.58 × 10−4). TheHMGCRGRS was not associated with other phenotypes; the closest were increased risk of Parkinson disease (OR, 1.30; 95% CI, 1.07-1.58;P = .007) and kidney failure (OR, 1.18; 95% CI, 1.05-1.34;P = .008). Of the 30 444 individuals in eMERGE, 16 736 (55.0%) were women; mean (SD) age was 68.7 (15.4) years. The association between theHMGCRGRS and type 2 diabetes was replicated in this cohort (OR, 1.09; 95% CI, 1.01-1.17;P = .02); however, theHMGCRGRS was not associated with Parkinson disease (OR, 0.93; 95% CI, 0.75-1.16;P = .53) and kidney failure (OR, 1.18; 95% CI, 0.98-1.41;P = .08) in the eMERGE cohort. Conclusions and Relevance A mendelian randomization approach using variants in theHMGCRgene replicated the association between statin use and increased type 2 diabetes risk but provided no strong evidence for pleiotropic effects of statin-induced decrease of the low-density lipoprotein cholesterol level on other diseases.