Clustering of youth metabolic profiles and their association with health outcomes and methylation changes in individuals and offspring

Cardiometabolic diseases are a major global health threat that are primarily prevented and treated through lifestyle modifications.Emerging evidence suggests that the origins of these diseases can be traced back to early life stages or even to parental health and exposures.Early metabolic disturbances may already predict adult disease risk, and some of these effects may be mediated through epigenetic mechanisms such as DNA methylation, potentially transmitting across generations.This study evaluated the suitability of different clustering methods for analysing youth cardiometabolic data and their ability to identify data-driven profiles of metabolic health.It was based on longitudinal data from the Cardiovascular Risk in Young Finns Study (YFS), which enabled the biological assessment of clustering results and the investigation of associations between youth metabolic markers, adult health outcomes, and DNA methylation patterns.The most suitable approach was hierarchical clustering using Ward's (D2) distance metric, which produced two distinct and biologically plausible clusters.The high-risk cluster was characterized by higher levels of BMI, adiposity, blood pressure, insulin, and triglycerides, and lower HDL cholesterol compared with the more favourable profile.In the association analyses, cluster membership was significantly associated with adult cardiometabolic health outcomes and with offspring health outcomes, although intergenerational analyses were limited by small sample size.Epigenome-wide association analyses identified several CpG sites with significant methylation differences, some of which at loci previously linked to cardiometabolic health.Within the same generation, the most notable finding was hypomethylation in the promoter region of the SQLE gene, associated with the less favourable metabolic cluster.The gene's role in cholesterol synthesis and lipid metabolism supports its potential function as a link between youth metabolic state and adult cardiometabolic health.In offspring, differential methylation at cg11927004 within the SLC24A4 gene was associated with paternal cluster membership, indicating possible sex-specific epigenetic inheritance related to glucose metabolism and type 2 diabetes.The findings align with evidence that the metabolic state in youth has long-term effects on adult cardiometabolic health, possibly mediated by epigenetic modifications, and that some of these effects may extend to the next generation.The study highlights the importance of childhood and adolescent health in preventing cardiometabolic diseases and provides new insight into epigenetic connections in health development across the life course and generations.