Impact of loss-of-function in angiopoietin-like 4 on the human phenome

Background Carriers of the E40K loss-of-function variant in Angiopoietin-like 4 (ANGPTL4), have lower plasma triglyceride levels as well as lower rates of coronary artery disease (CAD) and type 2 diabetes (T2D). These genetic data suggest ANGPTL4 inhibition as a potential therapeutic target for cardiometabolic diseases. However, it is unknown whether the association between E40K and human diseases is due to linkage disequilibrium confounding. The broader impact of genetic ANGPTL4 inhibition is also unknown, raising uncertainties about the safety and validity of this target. Methods To assess the impact of ANGPLT4 inhibition, we evaluated whether E40K and other loss-of-function variants in ANGPTL4 influenced a wide range of health markers and diseases using 29 publicly available genome-wide association meta-analyses of cardiometabolic traits and diseases as well as 1589 diseases assessed in electronic health records within FinnGen (n=309,154). To determine whether these relationships were likely causal, and not driven by other correlated variants, we used the Bayesian fine mapping algorithm CoPheScan. Results The CoPheScan posterior probability of E40K being the causal variant for triglyceride levels was 99.99%, validating the E40K to proxy lifelong lower activity of ANGPTL4. The E40K variant was associated with lower risk of CAD (odds ratio [OR]=0.84, 95% CI=0.81 to 0.87, p=3.6e-21) and T2D (OR=0.91, 95% CI=0.87 to 0.95, p=2.8e-05) in GWAS meta-analyses, with results replicated in FinnGen. These significant results were also replicated using other rare loss-of-function variants identified through whole exome sequencing in 488,278 participants of the UK Biobank. Using a Mendelian randomization study design, the E40K variant effect on cardiometabolic diseases was concordant with lipoprotein lipase enhancement (r=0.82), but not hepatic lipase enhancement (r=-0.10), suggesting that ANGPTL4 effects on cardiometabolic diseases are potentially mainly mediated through lipoprotein lipase. After correction for multiple testing, the E40K variant did not significantly increase the risk of any of the 1589 diseases tested in FinnGen. Conclusions ANGPTL4 inhibition may represent a potentially safe and effective target for cardiometabolic diseases prevention or treatment.