Genetic inhibition of angiopoietin-like protein 3, 4, and 8 on cardiovascular disease risk

Abstract Background Angiopoietin-like proteins (ANGPTLs), particularly ANGPTL3, ANGPTL4, and ANGPTL8, play crucial roles in lipid metabolism and have emerged as promising therapeutic targets for managing dyslipidemia. However, their long-term effects on cardiovascular diseases (CVD) are largely unknown. Additionally, the ANGPTL3-ANGPTL8 complex demonstrates significantly stronger inhibition of lipoprotein lipase activity than either protein alone; however, the joint effect of ANGPTL3 and ANGPTL8 on lipid metabolism and cardiovascular risk remains unclear. Objectives This study aims to: 1) investigate the effects of genetic inhibition of ANGPTL3, ANGPTL4, and ANGPTL8 on lipid profiles and CVD risk; 2) analyze the potential mediating effects of lipids profiles; 3) evaluate the effects of joint genetic inhibition of ANGPTL3 and ANGPTL8 on lipid profiles and CVD risk. Methods Genetic scores were constructed separately for ANGPTL3, ANGPTL4, and ANGPTL8 among 401,548 participants from the UK Biobank. Linear regression was used to evaluate the effect of genetic inhibition of ANGPTL3, ANGPTL4, and ANGPTL8, joint genetic inhibition of ANGPTL3 and ANGPTL8 targets on lipid profiles, and logistic regression was used to assess the effects on CVD risk. Mediation analyses were performed to evaluate the contribution of triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C) to observed associations. Results Genetic inhibition of ANGPTL3 was associated with lower TG, LDL-C, apolipoprotein B (ApoB), and high-density lipoprotein cholesterol (HDL-C), but was not associated with CVD risk. Conversely, genetic inhibition of ANGPTL4 was associated with lower TG and higher HDL-C, with no significant effects on LDL-C or ApoB, and was associated with a lower risk of coronary heart disease (OR=0.87, 95%CI: 0.83-0.92). TG mediated about 13.4% of the association between ANGPTL4 inhibition and coronary heart disease, while the association was less likely to depend on LDL-C. Genetic inhibition of ANGPTL8 was associated with lower TG, LDL-C, and ApoB levels, while higher HDL-C, and was associated with lower risks of coronary heart disease (OR=0.94, 95%CI: 0.91-0.96), myocardial infarction (OR=0.94, 95%CI: 0.92-0.97), and ischemic stroke (OR=0.94, 95%CI: 0.90-0.98). Moreover, joint genetic inhibition of ANGPTL3 and ANGPTL8 demonstrated additive effects in reducing TG, LDL-C, and ApoB, with no significant effects on HDL-C, and also demonstrated additive effects in reducing the risks of coronary heart disease (OR=0.92, 95%CI: 0.89-0.96), myocardial infarction (OR=0.93, 95%CI: 0.89-0.97), and heart failure (OR=0.94, 95%CI: 0.89-0.98). Conclusions Genetic inhibition of ANGPTL3, ANGPTL4, and ANGPTL8 differentially modulates lipid profiles and CVD risk, with ANGPTL8 inhibition demonstrating broad cardioprotective effects. Joint genetic inhibition of ANGPTL3 and ANGPTL8further reduces CVD risk, highlighting a potential therapeutic strategy for dyslipidemia and CVD prevention.