3-Hydroxy-3-methylglutaryl-CoA reductase variants strongly associated with low-density lipoprotein cholesterol levels and diabetes mellitus risk in a Taiwanese population: A Mendelian randomization study

Objectives: 3-Hydroxy-3-methylglutaryl-CoA reductase (HMGCR) is a rate-limiting enzyme involved in cholesterol synthesis. The common HMGCR variants are associated with low-density lipoprotein cholesterol (LDL-C) levels. We aimed to identify novel HMGCR variants influencing the lipid profiles of Taiwanese and assess the causal links between LDL-C levels and diabetic risk based on HMGCR genotypes. Materials and Methods: Genome-wide genotyping of 108,880 participants from Taiwan Biobank was used for the association studies and Mendelian randomization (MR) analysis. Results: Regional association and stepwise linear regression analyses showed HMGCR rs3064191, rs150454634, and rs13354746 variants were independently associated with total cholesterol (TC), LDL-C, and non-high-density lipoprotein cholesterol (non-HDL-C) levels with the former two variants in strong linkage disequilibrium with HMGCR rs3846662, a variant influencing exonal alternative splicing, and HMGCR rs191835914 (p.Y311S), an Asian-specific nonsynonymous mutation, respectively. Multivariate MR analyses showed significant associations between weighted genetic risk scores using LDL-C-determining HMGCR variants and using genome-wide association study identifying LDL-C-determining 47 variants and the prevalence of diabetes mellitus (DM) (P = 0.0011 and P = 1.66 × 10⁻⁸, respectively). Conclusion: The HMGCR variants exhibited significant associations with TC, LDL-C, and non-HDL-C levels as well as causally with DM risk in our Taiwanese population. HMGCR genotypes may play an important role and serve as a reference for the prevention and treatment of cardiovascular diseases in the clinical settings.