Abstract 12056: Angiopoietin-Like Protein 3 Blood Levels and Cardiometabolic Traits and Diseases: A Mendelian Randomization Study

Abstract

Introduction: Angiopoietin-like 3 (ANGPTL3) is a key regulator of blood lipid levels. ANGPTL3 inhibitors are currently under investigation for their impact on metabolic and cardiovascular health. Our objective was to investigate the causal effect of genetically-predicted blood ANGPTL3 levels on cardiometabolic traits and diseases using Mendelian randomization (MR). Methods: We performed a series of two-sample MR studies using cis-acting variants on ANGPTL3 blood levels measured using aptamers in 35,559 participants of the deCODE study. We used inverse-variance weighted-MR to assess the effect of genetically-predicted blood ANGPTL3 levels on lipid and apolipoprotein B levels (from the UK Biobank, n = 441,016 participants), non-alcoholic fatty liver disease (from a genome-wide association meta-analysis [GWAS] of 8434 cases and 770,614 controls of European ancestry), type 2 diabetes (from the DIAGRAM consortium, 74,124 cases and 824,006 controls), acute pancreatitis (from a GWAS of 7832 cases and 793,427 controls of European ancestry) and coronary artery disease (from the CARDIoGRAMplusC4D and UK Biobank GWAS meta-analysis [34,541 cases and 261,984 controls of European ancestry]). Results: We selected 27 independent variants near or in the ANGPTL3 region associated with ANGPTL3 blood levels (R2<0.1, p<5x10 -08 ). Genetically-predicted ANGPTL3 levels were strongly and significantly associated with triglyceride and apolipoprotein B levels (beta [SE] = 0.156 [0.032], p-value = 1.05x10 -06 , and beta [SE] = 0.058 [0.013], p-value = 8.16x10 -06 , respectively) but were not associated with non-alcoholic fatty liver disease, type 2 diabetes or coronary artery disease (all p-values > 0.05). Genetically-predicted ANGPTL3 levels were however significantly associated with acute pancreatitis (beta [SE] = 0.071 [0.025], and p-value = 0.004). Conclusions: Our two-sample MR study revealed that blood ANGPTL3 levels may be causally-related to lipid-lipoprotein levels, but not with cardiometabolic diseases. Blood ANGPTL3 levels were however associated with acute pancreatitis, thereby suggesting that ANGPTL3 inhibition might warrant further investigation in the prevention of acute pancreatitis.