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
Authors: Ge Liu, Mingjian Shi, Jonathan D. Mosley, Chunhua Weng, Yanfei Zhang, Ming Ta Michael Lee, Gail P. Jarvik, Hakon Hakonarson, Bahram Namjou-Khales, Patrick Sleiman, Yuan Luo, Frank Mentch, Joshua C. Denny, MacRae F. Linton, Wei-Qi Wei, C. Michael Stein, QiPing Feng
Journal: JAMA Network Open (2021)

<h3>Importance</h3> 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. <h3>Objective</h3> To construct a weighted HMG-CoA reductase (<i>HMGCR</i>) gene genetic risk score (GRS) using variants in the<i>HMGCR</i>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. <h3>Design, Setting, and Participants</h3> 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. <h3>Interventions</h3> An<i>HMGCR</i>GRS was calculated. <h3>Main Outcomes and Measures</h3> The association between the<i>HMGCR</i>GRS and the presence or absence of 22 noncardiovascular phenotypes previously associated with statin use in clinical studies. <h3>Results</h3> 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<i>HMGCR</i>GRS and the noncardiovascular phenotypes of interest in this cohort was significant only for type 2 diabetes. An<i>HMGCR</i>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;<i>P</i> = 5.58 × 10<sup>−4</sup>). The<i>HMGCR</i>GRS was not associated with other phenotypes; the closest were increased risk of Parkinson disease (OR, 1.30; 95% CI, 1.07-1.58;<i>P</i> = .007) and kidney failure (OR, 1.18; 95% CI, 1.05-1.34;<i>P</i> = .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<i>HMGCR</i>GRS and type 2 diabetes was replicated in this cohort (OR, 1.09; 95% CI, 1.01-1.17;<i>P</i> = .02); however, the<i>HMGCR</i>GRS was not associated with Parkinson disease (OR, 0.93; 95% CI, 0.75-1.16;<i>P</i> = .53) and kidney failure (OR, 1.18; 95% CI, 0.98-1.41;<i>P</i> = .08) in the eMERGE cohort. <h3>Conclusions and Relevance</h3> A mendelian randomization approach using variants in the<i>HMGCR</i>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.