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

Abstract

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 six 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 loss-of-function variants revealed that ANGPTL3 inactivation protected against CAD (odds ratio, 0.71 per allele [95%CI,0.62-0.82]). 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.

Characterization of sexual dimorphism in ANGPTL4 levels and function

“…It should be noted, though, that lymphadenopathy appears to be disconnected from the severe chylous ascites and acute phase response ( 75 ). Importantly, in a recent targeted cis-pQTL mendelian randomization analysis ( 76 ), genetically lowered plasma ANGPTL4 levels via the ANGPTL4 p.E40K and p.Cys80 fs variants were not associated with any phenotypes related to lymphadenopathy and malabsorptive states. While these data do not entirely exclude any harmful effects of ANGPTL4 inactivation, they do mitigate safety concerns about the impact of whole-body inactivation of ANGPTL4 in humans.…”