Lung‑An Hsua†, Ming‑Sheng Tengb†, De‑Min Duanc, Kuan‑Hung Yehc,d, Semon Wue, Yu‑Lin Kob,c,d*
aThe First Cardiovascular Division, Department of Internal Medicine, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan, bDepartment of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan, cDivision of Cardiology, Department of Internal Medicine and The Cardiovascular Medical Center, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan, dSchool of Medicine, Tzu Chi University, Hualien, Taiwan, eDepartment of Life Science, Chinese Culture University, Taipei, Taiwan
†Both authors contributed equally to this work.
Open Access funded by Buddhist Compassion Relief Tzu Chi Foundation
Abstract
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.
Keywords: 3‑Hydroxy‑3‑methylglutaryl‑CoA reductase, Diabetes mellitus, Low‑density lipoprotein cholesterol, Mendelian randomization, Nonsynonymous mutation
