Proteomic signatures of pediatric cardiovascular and cardiometabolic traits demonstrate long-term modifiable drivers of adult disease

While the earliest pathological signs of cardiovascular disease (CVD) emerge before age 20, current adult-based risk thresholds fail to identify a substantial fraction of high-risk children. With the rising prevalence of childhood obesity, the need for early and sensitive detection of cardiovascular-kidney-metabolic disease (CKMD) risk is paramount to enable timely intervention that can prevent the trajectory toward CVD in later life. To identify early accessible molecular biomarkers of CKMD in children, we measured 25 CKMD phenotypes, spanning liver, adipose, vascular, and dysglycemia traits, linked those to the circulating proteome and built a multi-protein signature of composite CKMD, leveraging data from 273 children and adolescents (13.1 +/- 2.7 years; 53% females). We compared these results to the adult CKMD proteome, using data from 685 adults from the same community and 28,257 adults from the UK Biobank. The pediatric CKMD proteome was highly concordant with the adult CKMD proteome, reflecting known and novel mechanisms of pancreatic beta-cell health and insulin sensitivity, liver homeostasis, inflammation, and cholesterol metabolism. Similarly, multi-protein signatures of composite CKMD phenotypes in children were strongly associated with CKMD-related outcomes in both adult populations. Importantly, many proteins linked to pediatric CKMD were modifiable with GLP-1 receptor agonist therapy, associated with adult CKMD-related outcomes in a large-scale proteome-wide association study (PWAS), and exhibited significant variability during development (ages 4-24 years). These findings demonstrate that CKMD develops starting early in life-course continuum, with proteomic profiles linked to future irreversible CVD conditions emerging early in life when they may still be reversible. This highlights a critical opportunity to improve CVD-free longevity through precision medicine diagnosis and intervention in children and adolescents.