Abstract
Background
Metabolic regulation plays a significant role in energy homeostasis, and adolescence is a crucial life stage for the development of cardiometabolic disease (CMD). 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.
Conclusions
The genetic underpinnings of metabolic biomarkers can affect the early development of CMD, partly mediated by the biomarkers.
Impact
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This study characterized the genetic underpinnings of four metabolic hormones and investigated their potential influence on adiposity and insulin biology among Hispanic/Latino adolescents.
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Fasting blood insulin and insulin resistance were associated with polygenic risk score (PRS) for adiponectin, leptin, and ghrelin, with evidence of some degree of mediation by the biomarker levels. Body fat percent (BF%) was also associated with PRS for adiponectin and leptin. This provides important insight on biological mechanisms underlying early metabolic dysfunction and reveals candidates for prevention efforts.
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Our findings also highlight the importance of ancestrally diverse populations to facilitate valid studies of the genetic architecture of metabolic biomarker levels.
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Acknowledgements
We thank the participants of the Santiago Longitudinal Study, the San Antonio Family Heart Study and the San Antonio Family Diabetes/Gallbladder Study for their continued cooperation and participation in our research programs.
Funding
This work was funded in part by University of North Carolina Nutrition Research Institute internal pilot grant, AHA grant 15GRNT25880008, and NIH award K99/R00HL130580-02. We thank the participants and their family members from the Santiago Longitudinal Study (SLS) (R01 HL088530, R01 HD33487). K.E.N. is additionally supported by R01HL151152 and R01 DK122503. Work for the validation study was supported in part by National Institutes of Health (NIH) grants P01 HL045522, R01 DK047482, DK053889, R01 HL113323, R37 MH059490, and T2D-GENES Consortium grants (U01 DK085524, U01 DK085584, U01 DK085501, U01 DK085526, and U01 DK085545).
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D.K. and K.E.N. designed the study and drafted the initial manuscript; E.B. and R.B. collected the data; A.E.J., G.C., M.G., and Y.W. carried out genetic data cleaning; D.K., M.G., A.G.H., Y.W., R.R., and V.L.B. conducted statistical analysis; M.A., J.P., D.M.L., J.E.C., A.G.C., R.D., and J.B. were involved in the validation study; D.K., K.E.N., M.G., A.G.H., A.E.J., and G.C. were involved in interpretation of the results; all authors revised the manuscript and contributed to the content and approved the submission and publication of the paper.
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Kim, D., Justice, A.E., Chittoor, G. et al. Genetic determinants of metabolic biomarkers and their associations with cardiometabolic traits in Hispanic/Latino adolescents. Pediatr Res 92, 563–571 (2022). https://doi.org/10.1038/s41390-021-01729-7
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DOI: https://doi.org/10.1038/s41390-021-01729-7
