Determinants of Plasma HDL-Cholesterol Concentrations in Prepubertal Children: Insights from Two Decades of Research in a Spanish Pediatric Cohort

High-density lipoprotein cholesterol (HDL-C) is a well-established cardiovascular risk marker; however, its determinants in childhood remain incompletely understood. The prepubertal period provides a useful window for studying the determinants of HDL-C because it is free of confounders present in other age groups. In this review, we summarize the findings on the plasma HDL-C determinants in Spanish prepubertal children aged 6–8 years from decades of research in the Four Provinces Study. Children with obesity had lower HDL-C concentrations, but BMI was only weakly associated with HDL-C, whereas markers of adipose tissue function, particularly leptin, showed stronger and potential sex-dependent associations. Among common variants in genes directly involved in HDL metabolism, CETP TaqIB emerged as the main genetic predictor, although it explained less than 5% of HDL-C variability. Variants in genes related to adipose-tissue biology (LEP, PLIN1, PLIN2 and DLK1) were also associated with HDL-C in a sex-specific manner, and some associations were modulated by circulating leptin. Dietary intake made only a modest contribution to HDL-C variability, yet fat intake modified the effect of the LIPC −514C>T variant on HDL-C. Overall, these findings support an integrated adipose tissue–HDL axis in childhood and suggest that sex may influence this relationship even before puberty.