Causal effects of lipid-lowering therapies on aging-related outcomes and risk of cancers: a drug-target Mendelian randomization study

作者：Han Chen, Xinyu Tang, Wei Su, Shuo Li, Ruoyun Yang, Hong Cheng, Guoxin Zhang, Xiaoying Zhou · 发表于：Aging · 年份：2023 · DOI：10.18632/aging.205347 · 被引用次数：8 · 研究领域：Cancer, Lipids, and Metabolism、Lipoproteins and Cardiovascular Health、Genetic Associations and Epidemiology

Background: Despite the widespread use of statins, newer lipid-lowering drugs have been emerging. It remains unclear how the long-term use of novel lipid-lowering drugs affects the occurrence of cancers and age-related diseases. Methods: A drug-target Mendelian randomization study was performed. Genetic variants of nine lipid-lowering drug-target genes (HMGCR, PCKS9, NPC1L1, LDLR, APOB, CETP, LPL, APOC3, and ANGPTL3) were extracted as exposures from the summary data of Global Lipids Genetics Consortium Genome-Wide Association Studies (GWAS). GWAS summary data of cancers and noncancerous diseases were used as outcomes. The inverse-variance weighted method was applied as the main statistical approach. Sensitivity tests were conducted to evaluate the robustness, pleiotropy, and heterogeneity of the results. Results: In addition to marked effects on decreased risks of atherosclerotic cardiovascular diseases, genetically proxied lipid-lowering variants of PCKS9, CETP, LPL, LDLR, and APOC3 were associated with longer human lifespans (q<0.05). Lipid-lowering variants of ANGPTL3 and LDLR were associated with reduced risks of colorectal cancer, and ANGPTL3 was also associated with lower risks of gastric cancer (q<0.05). Lipid-lowering LPL variants were associated with decreased risks of hypertension, type 2 diabetes, nonalcoholic fatty liver disease, and bladder cancer (q<0.05). Lipid-lowering variants of PCKS9 and HMGCR were associated with decreased risks of osteoporosis (q<0.05). L...