Drug-target Mendelian randomization analysis supports lowering plasma ANGPTL3, ANGPTL4, and APOC3 levels as strategies for reducing cardiovascular disease risk

Background and Aims APOC3, ANGPTL3, and ANGPTL4 are circulating proteins that are actively pursued as pharmacological targets to treat dyslipidemia and reduce the risk of atherosclerotic cardiovascular disease. Here, we used human genetic data to compare the predicted therapeutic and adverse effects of APOC3, ANGPTL3, and ANGPTL4 inactivation. Methods We conducted drug-target Mendelian randomization analyses using variants in proximity to the genes associated with circulating protein levels to compare APOC3, ANGPTL3, and ANGPTL4 as drug targets. We obtained exposure and outcome data from large-scale genome-wide association studies and used generalized least squares to correct for linkage disequilibrium-related correlation. We evaluated five primary cardiometabolic endpoints and screened for potential side effects across 694 disease-related endpoints, 43 clinical laboratory tests, and 11 internal organ MRI measurements. Results Genetically lowering circulating ANGPTL4 levels reduced the odds of coronary artery disease (CAD) (odds ratio, 0.57 per s.d. protein [95%CI,0.47–0.70]) and type 2 diabetes (T2D) (odds ratio, 0.73 per s.d. protein [95%CI,0.57–0.94]). Genetically lowering circulating APOC3 levels also reduced the odds of CAD (odds ratio, 0.90 per s.d. protein [95%CI,0.82–0.99]). Genetically lowered ANGPTL3 levels via common variants were not associated with CAD. However, meta-analysis of deleterious variants revealed that ANGPTL3 inactivation protected against CAD (odds ratio, 0.79 per allele [95%CI, 0.69–0.90]). Analysis of lowered ANGPTL3, ANGPTL4, and APOC3 levels did not identify important safety concerns. Conclusion Human genetic evidence suggests that therapies aimed at reducing circulating levels of ANGPTL3, ANGPTL4, and APOC3 reduce the risk of CAD. ANGPTL4 lowering may also reduce the risk of T2D. STRUCTURED GRAPHICAL ABSTRACT Key Question Does human genetics support that triglyceride-lowering drugs targeting ANGPTL3, ANGPTL4, and APOC3 will reduce the risk of cardiometabolic disease without causing side effects? Key Finding Genetically lowered circulating ANGPTL4 reduced coronary artery disease and type 2 diabetes risk. Genetically lowered ANGPTL3 and APOC3 also reduced coronary artery disease risk, but no impact on type 2 diabetes risk was observed. Take-home Message Human genetics suggest that ANGPTL3, ANGPTL4, and APOC3-lowering medications may prevent CAD. Medicines targeting ANGPTL4 may have added benefits for patients with type 2 diabetes. Graphical abstract summarizing the study’s methods and findings. Graphical abstract summarizing the overall study design. The ‘Key Findings’ figure provides a summary of the results categorized into three groups. The term ‘improves’ denotes a statistically significant association with a clinically relevant effect magnitude. The term ‘weak’ refers to a statistically significant association with no clinically significant effect. ‘ASCVD’ denotes atherosclerotic cardiovascular disease. ‘T2D’ denotes type 2 diabetes.