Paediatric proteomic signatures of cardiometabolic disease-associated traits predict adult disease outcomes

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Abstract
While the earliest pathological signs of cardiovascular–kidney–metabolic disease (CKMD) emerge before age 20, current adult-based risk thresholds fail to identify a substantial fraction of children at high risk. With increasing childhood obesity, early, sensitive detection of CKMD risk is critical to timely intervention. We linked 25 CKMD phenotypes spanning liver, adipose, vascular and dysglycaemia traits to the circulating proteome in 273 Hispanic or Latino children and adolescents (13.1 ± 2.7 years; 53% female). Here we show that proteome signatures of CKMD in children are strongly associated with clinical CKMD outcomes in adults. In 685 adults from the same community and 28,256 adults from UK Biobank, we observe high concordance between the paediatric and adult CKMD phenotype–proteome relationships, related to pancreatic beta-cell health and insulin sensitivity, liver homeostasis, inflammation and cholesterol metabolism. Many proteins linked to paediatric CKMD were modifiable with glucagon-like peptide-1 receptor agonist therapy in adults and are linked to genetic liability to CKMD. These findings support an early origin of CKMD disease liability embedded in the human proteome in children, underscoring the value of precision prevention to forestall metabolic disease long before its clinical manifestation.
Funding Information
  • National Institutes of Health (U01DK140952)
  • National Institutes of Health (T32HG008341)
  • National Institutes of Health (U01CA288325)
  • National Institutes of Health (K23HL179316)
  • National Institutes of Health (R01DK139598)
  • National Institutes of Health (R01HL142302)
  • National Institutes of Health (R01HL142302)
  • National Institutes of Health (T32GM145734)
  • National Institutes of Health (R01HL156975)
  • National Institutes of Health (U24DK132715)
  • National Institutes of Health (R01AG078452)
  • National Institutes of Health (P60DK020593)
  • National Institutes of Health (U01CA288325)
  • National Institutes of Health (U01CA288325)
  • National Institutes of Health (R01DK139598)
  • National Institutes of Health (R01DK139598)
  • National Institutes of Health (R01DK139598)
  • Importantly, all relevant funding sources for all authors are listed in the manuscript.

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