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

Abstract

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. 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. 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). Lipid-lowering APOB variants were associated with a decreased risk of thyroid cancer (q<0.05). Our study provides genetic evidence that newer nonstatin lipid-lowering agents have causal effects on decreased risks of several common cancers and cardiometabolic diseases. These data provide genetic insights into the potential benefits of newer nonstatin therapies.