Drug target Mendelian randomization supports apolipoprotein C3-lowering for lipoprotein-lipid levels reductions and cardiovascular diseases prevention

Background and aims Inhibitors of apolipoprotein C-III (apoC3) are currently approved for the reduction of triglyceride levels in patients with Familial Chylomicronemia Syndrome. We used drug target Mendelian randomization (MR) to assess the effect of genetically predicted decrease in APOC3 blood protein levels on cardiometabolic traits and diseases. Methods We quantified lifelong reductions in APOC3 blood levels by selecting all genome wide significant and independent ( r 2 <0.1) single nucleotide polymorphisms (SNPs) in the APOC3 gene region ±1Mb, from three genome-wide association studies (GWAS) of apoC3 blood protein levels (deCODE, n = 35,378, Fenland, n = 10,708 and ARIC, n = 7,213). We included the largest GWASes on 18 cardiometabolica traits and 9 cardiometabolic diseases as study outcomes. Results A one standard deviation lowering in apoC3 blood protein levels was associated with lower triglycerides, apolipoprotein B, density lipoprotein cholesterol, alanine aminotransferase, and glomerular filtration rate as well as higher high-density lipoprotein cholesterol levels. APOC3 lowering was also associated with lower risk of acute pancreatitis (odds ratio [OR] = 0.91 95% CI=0.82 to 1.00), aortic stenosis (OR = 0.82 95% CI=0.73 to 0.93), and coronary artery disease (OR = 0.86 95% CI=0.80 to 0.93), and was associated with increased parental lifespan (0.06 95% CI=0.03 to 0.09 years). These results were concordant across robust MR methods, the three protein datasets and upon adjustment for APOA1, APOA4 and APOA5 using a multivariable MR framework. Conclusions These results provide evidence that apoC3 lowering could result in widespread benefits for cardiometabolic health and encourage the launch of trials on apoC3 inhibition for coronary artery disease prevention.