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

Abstract

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 the HMGCR gene 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: An HMGCR GRS was calculated.

Main outcomes and measures: The association between the HMGCR GRS 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 the HMGCR GRS and the noncardiovascular phenotypes of interest in this cohort was significant only for type 2 diabetes. An HMGCR GRS 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). The HMGCR GRS 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 the HMGCR GRS and type 2 diabetes was replicated in this cohort (OR, 1.09; 95% CI, 1.01-1.17; P = .02); however, the HMGCR GRS 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 the HMGCR gene 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.

Figure.. Association Between HMGCR Genetic Risk Score (GRS) Quartiles and Candidate Phenotypes

^aIndividuals in the lowest estimated LDL-C level quartile were more likely to have diseases.