Genetic and Metabolic Determinants of Plasma Levels of ANGPTL8.

ANGPTL8 (A8) plays a key role in determining the tissue fate of circulating triglycerides (TGs). Plasma A8 levels are associated with several parameters of glucose and TG metabolism, but the causality of these relationships and the contribution of genetic variants to differences in A8 levels have not been explored.To characterize the frequency distribution of plasma A8 levels in a diverse population using a newly-developed ELISA and to identify genetic factors contributing to differences in plasma A8 levels.Population-based sample of Dallas County.Individuals in the Dallas Heart Study (DHS-1, n=3,538; DHS-2, n=3,283), including 2,131 individuals with repeated measurements 7-9 years apart (age 18-85 years; >55% female; 52% Black; 29% White; 17% Hispanic; and 2% other).Associations of A8 levels with body-mass index (BMI), plasma levels of glucose, insulin, lipids, hepatic TG and DNA variants identified by exome-wide sequencing.A8 levels varied over a 150-fold range (2.1 - 318 ng/mL; median, 13.3 ng/mL) and differed between racial/ethnic groups (Blacks > Hispanics > Whites). A8 levels correlated with BMI, fasting glucose, insulin and TG levels. A variant in A8, R59W, accounted for 17% of the inter-individual variation in A8 levels but was not associated with the metabolic parameters correlated with plasma A8 concentrations.A8 levels were strongly associated with indices of glucose and TG metabolism, but the lack of association of genetic variants at the A8 locus that impact A8 levels with these parameters indicates that differences in A8 levels are not causally related to the associated metabolic phenotypes.

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Authors: Federico Oldoni, Kevin Bass, Julia Kozlitina, Hannah Hudson, Lisa M Shihanian, Viktoria Gusarova, Jonathan C Cohen, Helen H Hobbs