Cis-Mendelian randomisation study using individual-level data from UK Biobank, Lifelines, and publicly available GWAS sources, examining 13 lipid-related drug targets (including ACLY, ANGPTL3/4, APOB, APOC3, CETP, HMGCR, LDLR, LIPG, LPA, MTTP, NPC1L1, and PCSK9). Lipid modification via HMGCR (statins) was predicted to reduce CAD risk but increase type 2 diabetes risk — a known statin side-effect. Modification via APOC3, LDLR, LPA, MTTP, NPC1L1, and PCSK9 reduced CAD risk without changing T2D risk. ANGPTL4 and CETP reduced risk of both CAD and T2D. For ACLY, ANGPTL3, APOB, and LIPG, no genetic evidence was found for either CAD or T2D effects. The findings suggest substantial variation in diabetes risk between lipid-lowering classes and may guide future drug development and individual therapy decisions.
This cis-Mendelian randomization study used individual level data from the UK Biobank, Lifelines, and publicly available genome-wide association data. We identified loci that are either targeted directly with drugs, or alternatively, targeting their gene products (mRNA and/or protein). Included are, in alphabetical order, the loci ACLY, ANGPTL3, ANGPTL4, APOB, APOC3, CETP, HMGCR, LDLR, LIPG, LPA, MTTP, NPC1L1, and PCSK9. We used cis-genetic instruments weighted for LDL-C, HDL-C, triglycerides, and apolipoproteins as downstream proxies for the drug targets. Main outcomes were prevalent and incident T2D, with CAD as a contrast outcome.
Lipid modification through HMGCR is predicted to reduce CAD risk and increase T2D risk. Modification through targeting APOC3, LDLR, LPA, MTTP, NPC1L1, and PCSK9 is predicted to reduce CAD risk without a change in T2D risk. Modification through ANGPTL4 and CETP is predicted to reduce risk of both CAD and T2D. For ACLY, ANGPTL3, APOB, and LIPG, we found evidence for neither CAD nor T2D.
This study provides genetic evidence for variation in diabetes-related side-effects of different lipid-modifying drugs, with potential relevance for future clinical trials and individual treatment decisions.
