Towards Early Risk Biomarkers: Serum Metabolic Signature in Childhood Predicts Cardio-Metabolic Risk in Adulthood

Abstract

Background: Cardiovascular diseases may originate in childhood. Biomarkers identifying individuals with increased risk for disease are needed to support early detection and to optimise prevention strategies. Methods: By applying a machine learning approaches to high throughput NMR-based metabolomics data, we identified circulating childhood metabolic predictors of adult cardiovascular risk in a cohort of 396 females, followed from childhood (mean age 11·2 years) to early adulthood (mean age 18·1 years). The results obtained from the discovery cohort were validated in a large longitudinal birth cohort of females and males followed from puberty to adulthood (n = 2664) and in four cross-sectional data sets (n = 6341). Findings: The identified childhood metabolic signature included three circulating biomarkers, glycoprotein acetyls (GlycA), large high-density lipoprotein phospholipids (L-HDL-PL), and the ratio of apolipoprotein B to apolipoprotein A-1 (ApoB/ApoA) that robustly associated with increased cardiovascular risk in early adulthood (AUC = 0·641‒0·802, all p<0·01). These associations were confirmed in all validation cohorts with similar effect estimates both in females (AUC = 0·667‒0·905, all p<0·01) and males (AUC = 0·734‒0·889, all p<0·01) as well as in elderly patients with and without type 2 diabetes (AUC = 0·517‒0·700, all p<0·01). We subsequently applied random intercept cross-lagged panel model analysis, which suggested bidirectional causal relationship between metabolic biomarkers and cardio-metabolic risk score from childhood to early adulthood. Interpretation: These results provide evidence for the utility of a circulating metabolomics panel to identify children and adolescents at risk for future cardiovascular disease, to whom preventive measures and follow-up could be indicated. Funding: This study was financially supported by the Academy of Finland, Ministry of Education of Finland and University of Jyvaskyla, the National Nature Science Foundation of China (Grant 31571219), the 111 Project (B17029), the Shanghai Jiao Tong University Zhiyuan Foundation (Grant CP2014013), China Postdoc Scholarship Council (201806230001). Declaration of Interest: None to declare. Ethical Approval: Written informed consent was obtained from all participants and their parents. The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethic Committee of the Central Hospital of Central Finland and the Finnish National Agency of Medicines (memo 22/8/2008 and 5/2009).