LDL-C and TC Mediate the Risk of PNPLA3 Inhibition in Cardiovascular Diseases

作者：Genshan Zhang, Wei Jiang, Fangxun He, Jie Fu, Xiang Xu, Xuelai Luo, Zhixin Cao · 发表于：The Journal of Clinical Endocrinology & Metabolism · 年份：2024 · DOI：10.1210/clinem/dgae264 · 被引用次数：23 · 研究领域：Liver Disease Diagnosis and Treatment、Diabetes, Cardiovascular Risks, and Lipoproteins、Genetic Associations and Epidemiology

CONTEXT: PNPLA3 is a promising target for the treatment of metabolic dysfunction-associated steatotic liver disease. ARO-PNPLA3 is a drug that efficiently lowers PNPLA3 expression in hepatocytes at the mRNA level, resulting in a significant reduction in liver fat in Phase I clinical trials. However, the long-term effects and potential side effects of ARO-PNPLA3 are not well understood. OBJECTIVE: We conducted a 2-sample, 2-step Mendelian randomization analysis to investigate the association between PNPLA3 inhibition and 10 cardiovascular diseases (CVDs), as well as the role of lipid traits as mediators. METHODS: We identified genetic variants near the PNPLA3 gene, which are linked to liver fat percentage, as instrumental variables for inhibiting PNPLA3. Additionally, positive control analyses on liver diseases were conducted to validate the selection of the genetic instruments. RESULTS: Genetically predicted PNPLA3 inhibition significantly increased the risk of coronary atherosclerosis (1.14, 95% CI 1.06, 1.23), coronary heart disease (1.14, 95% CI 1.08, 1.21), and myocardial infarction (1.16, 95% CI 1.08, 1.26). Suggestive associations were observed for increased risk of heart failure (1.09, 95% CI 1.02, 1.17, P = .0143) and atrial fibrillation (1.17, 95% CI 1.00, 1.36, P = .0468). Blood low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) mediated approximately 16% to 25%, 16% to 30%, and 14% to 22% of the associations between PNPLA3 inhibition and coronar...