Abstract 13874: A Mitochondrial Polygenic Risk Score is Associated With Metabolite Levels Implicated in Heart Failure

Introduction: Heart failure (HF) is characterized by metabolic inflexibility in fuel substrate selection and results in dysregulation of downstream mitochondrial processes. Prior work has identified greater plasma concentrations of circulating long-chain acylcarnitines (LCAC) in HF. LCAC are metabolites reporting on impaired mitochondrial fatty acid catabolism and predict incident adverse events in HF. Hypothesis: We hypothesized that a polygenic risk score (PRS) of genetic variation in mitochondrially-associated genes may be associated with circulating LCAC as well as HF phenotypes. Methods: The study population consisted of 2277 European-ancestry participants from the CATHGEN (CATHeterization GENetics) cohort, consisting of sequential individuals undergoing cardiac catheterization at Duke University. Using PRSice software, a PRS was generated from variants in 1462 nuclear genes implicated in mitochondrial function; weights were derived from the HERMES HF GWAS meta-analysis. Linear regression was used to test the association between the mitochondrial function PRS and plasma metabolite levels, as well as HF phenotypes, in models adjusting for ancestry principal components and batch. Results: The analysis cohort included 515 participants with HF, with 39% females and a mean age 61.2 11.8 years. The mitochondrial PRS was associated with three LCAC: C10, C10:1 and C12:1 (nominal p-values 0.02-0.008, 18-70 variants). The PRS was not associated with prevalent cardiomyopathy (p=0.097) or HF (p=0.16). Conclusions: We have generated a focused PRS inclusive of mitochondrial nuclear genetic variants weighted on HF association and found it to be associated with relevant circulating metabolites of mitochondrial fatty acid metabolism. These results highlight the utility of a novel biology-focused PRS in cardiovascular disease traits.