Identification of modifiable plasma protein markers of cardiometabolic risk in children and adolescents with obesity.

Pediatric obesity is linked to multi-organ inflammation and an increased risk of cardiometabolic and steatotic liver disease. To identify circulating biomarkers of cardiometabolic risk, we performed proximity extension assay proteomics, to quantify 149 inflammation- and cardiovascular-related proteins in a cross-sectional study of 4024 children and adolescents (2377 with obesity and 1647 with normal weight). We identified protein signatures linked to obesity, dyslipidemia, insulin resistance, hyperglycemia, hypertension, and related cardiometabolic phenotypes. Using machine learning, a three-protein panel (CDCP1, FGF21, HAOX1) combined with liver enzymes improved prediction of steatotic liver disease versus liver enzymes alone (receiver operating characteristic-area under the curve (ROC-AUC) = 0.83 vs. 0.77; DeLong's test, P < 0.05). During a 1-year non-pharmacological obesity intervention (n = 184), reductions in adiposity were associated with decreased inflammatory cytokines (including CDCP1, FGF21), which correlated with improvements in cardiometabolic risk profiles. Here we show that circulating proteomic signatures may mediate obesity-related cardiometabolic risk in youth.