Genetic Determinants of Metabolic Biomarkers and their Associations with Cardiometabolic Traits in Hispanic/Latino Adolescents

BACKGROUND: Metabolic regulation plays a significant role in energy homeostasis, and adolescence is a crucial life-stage for the development of cardiometabolic disease (CMD). OBJECTIVES: This study aims to investigate the genetic determinants of metabolic biomarkers—adiponectin, leptin, ghrelin, and orexin—and their associations with CMD risk factors. METHODS: We characterized the genetic determinants of the biomarkers among Hispanic/Latino adolescents of the Santiago Longitudinal Study (SLS) and identified the cumulative effects of genetic variants on adiponectin and leptin using biomarker polygenic risk scores (PRS). We further investigated the direct and indirect effect of the biomarker PRS on downstream body fat percent (BF%) and glycemic traits using structural equation modeling. RESULTS: We identified putatively novel genetic variants associated with the metabolic biomarkers. A substantial amount of biomarker variance was explained by SLS-specific PRS, and the prediction was improved by including the putatively novel loci. Fasting blood insulin and insulin resistance were associated with PRS for adiponectin, leptin, and ghrelin, and BF% was associated with PRS for adiponectin and leptin. We found evidence of substantial mediation of these associations by the biomarker levels. CONCLUSION: The genetic underpinnings of metabolic biomarkers can affect the early development of CMD, partly mediated by the biomarkers.