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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 This study characterized the genetic underpinnings of four metabolic hormones and investigated their potential influence on adiposity and insulin biology among Hispanic/Latino adolescents. 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. Our findings also highlight the importance of ancestrally diverse populations to facilitate valid studies of the genetic architecture of metabolic biomarker levels.

Background: The contribution of long-term vs. recent-onset obesity to cardiometabolic risk in adolescence remains controversial. Objective: To investigate the association of time of onset and length of obesity with the cardiometabolic profile of adolescence. Methods: Prospective study in 678 16-year-olds. BMI was measured at birth-1-5-10-16y and BMI trajectories were interpolated using cubic splines. BMI >2 sd at

Background: We aimed to determine the sensitivity and specificity of selected anthropometric indicators as predictors of cardiovascular risk in adolescents. Methods: Cross-sectional study in 678 adolescents (16.8y ± 0.3) from an infancy cohort. Weight, height, waist circumference (WC) and hip circumference were measured. Body-Mass Index (BMI), waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR) were estimated. MetS was diagnosed with IDF/AHA/NHLBI. Optimal cutoffs of BMI, WC, WHR and WHtR for diagnosing MetS were determined using ROC analysis. Results: In males, WHtR (0.96) had the greatest area under the ROC curve, followed by WC (0.95) and BMI (0.93). In females, BMI (0.84) had the greatest area under the ROC curve (0.84), followed by WHtR (0.83) and WC (0.83). In both sexes, the optimal WHtR cutoff for MetS diagnosis was 0.54. A BMI of 26.9 in males and 26.3 in females were the optimal cutoffs for diagnosing MetS. Finally, WC values of 92 and 81.6 cm in males and females, respectively, were the optimal cutoffs for MetS diagnosis. Conclusions: In both sexes, a WHtR value of 0.54 was a good predictor of MetS. In males and females, the optimal cutoff of BMI for Mets diagnosis was below the values for diagnosing obesity.

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.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.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.The genetic underpinnings of metabolic biomarkers can affect the early development of CMD, partly mediated by the biomarkers.This study characterized the genetic underpinnings of four metabolic hormones and investigated their potential influence on adiposity and insulin biology among Hispanic/Latino adolescents. 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. Our findings also highlight the importance of ancestrally diverse populations to facilitate valid studies of the genetic architecture of metabolic biomarker levels.