Abstract 11954: Metabolomic Profiles Differentiate Arterial and Venous Polygenic Risk

Abstract

Introduction : Genome-wide association studies reveal genetic correlations between venous and arterial cardiovascular phenotypes, such as venous thromboembolism (VTE), coronary artery disease (CAD), and peripheral arterial disease (PAD). The extent to which these diseases share metabolomic signatures has not been established. Methods : Polygenic risk scores (PRS) for CAD, PAD, and VTE were constructed using PRS-CS with external summary statistics and tested on ~120,000 UK Biobank participants with metabolomic profiling. Linear regression adjusted for age, sex, genotyping array, the first five principal components of ancestry, and statin prescription estimated the effect of polygenic disease risk on 249 metabolites among participants free of prevalent cardiovascular disease. For all metabolomic associations common to at least two diseases, bidirectional two-sample Mendelian randomization tested the causal relationship between metabolite and phenotype. Results : We found 206, 201, and 116 metabolites were associated with genetic risk for CAD, PAD, and VTE, respectively, at an adjusted p-value of 0.001 ( Figure ). Metabolomic profiles were similar between CAD and PAD (R = 0.75, P = 1.25E-46) and CAD and VTE (R = 0.76, P = 8.27E-49), but not between VTE and PAD (R = 0.24, P = 1.21E-4). Mendelian randomization revealed 28 metabolites that increased risk for both CAD and PAD and 2 metabolites that increased risk for CAD but decreased risk for VTE. There were no metabolites with shared causal relationship between PAD and VTE. Conclusions : Polygenic risks for arterial and venous disease are associated with unique metabolomic profiles. Mendelian randomization reveals overlap in causal metabolites between CAD and PAD but little overlap between VTE and either CAD or PAD despite moderate genetic correlation.