Vasorin as a multi-omic biomarker of cardiometabolic health in paediatric obesity

<title>Abstract</title> <p> <bold>Background</bold> Effective early stratification of cardiometabolic risk in children with obesity remains a major clinical challenge. Existing classification approaches rely largely on indirect indicators, limiting their utility for timely personalized preventive strategies. <bold>Methods</bold> We conducted a multi-omic study integrating leukocyte genomic and epigenomic (DNA methylation and genotype arrays), whole-blood transcriptomic (bulk RNA-seq), and circulating protein data from three independent paediatric populations aged 3–18 years. The study included a prospective discovery population of 138 individuals with and without obesity, and a cross-sectional validation population of 237 children with overweight or obesity. Additionally, gene expression was profiled in visceral adipose tissue (VAT) samples from a third independent population of 13 children. <bold>Results</bold> We identified vasorin (VASN) as a consistent biomarker of metabolic health across multiple molecular layers, populations and tissues. Pubertal DNA methylation at the <italic>VASN</italic> locus (cg00041083) was positively associated with several cardiometabolic risk factors consistently in both the discovery and validation populations, including BMI z-score (β = 0.40, FDR &lt; 0.001; β = 0.20, p &lt; 0.05) and blood pressure z-score (β = 0.36, FDR &lt; 0.05; β = 0.19, p &lt; 0.05), and functioned as a cis-eQTM for <italic>VASN</italic> expression in whole-blood (β = -0.71, p &lt; 0.05). Circulating VASN protein levels during puberty were inversely associated with fat mass index (β =-0.30, p &lt; 0.05) in the discovery population and positively associated with HDL-c in the validation population (β = 0.23, p &lt; 0.05). In pooled analyses, pubertal VASN protein levels showed inverse associations with HOMA-IR (β =-0.11, p &lt; 0.05) and FMI (β =-0.22, p &lt; 0.05), mainly driven by males (β =-0.30, FDR &lt; 0.05) and but not in females (β =-0.10, p &gt; 0.05). In VAT samples from the third population, <italic>VASN</italic> expression was significantly downregulated in prepubertal children with obesity compared to normal-weight controls (p &lt; 0.05), supporting its relevance in this metabolically active tissue. <bold>Conclusion</bold> VASN emerges as a novel biomarker of cardiometabolic health in paediatric obesity. Its reproducible associations with cardiometabolic risk factors across molecular layers, populations and tissues support its potential utility for early risk stratification in precision prevention strategies. </p>