The association of childhood HDL cholesterol with atherosclerotic CVD events in adults: findings from the International Childhood Cardiovascular Cohort Consortium

Eur J Prev Cardiol. 2025 Mar 5:zwaf117. doi: 10.1093/eurjpc/zwaf117. Online ahead of print.

Authors

Jing Wang^{1

2}, Noora Kartiosuo^{3

4

5}, Olli Raitakari^{3

4

6}, Jorma Viikari⁷, Markus Juonala⁷, Lydia Bazzano⁸, Alan R Sinaiko⁹, Julia Steinberger¹⁰, Stephen R Daniels^{11

12}, Alison Venn¹³, Costan Magnussen^{3

4

14}, Jessica G Woo¹⁵, Rema Ramakrishnan¹⁶, Elaine M Urbina¹⁵, Mika Kähönen¹⁷, David R Jacobs¹⁸, Terence Dwyer^{1

2

16

19}

Affiliations

¹ Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia.
² Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia.
³ Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland.
⁴ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
⁵ Department of Mathematics and Statistics, University of Turku, Turku, Finland.
⁶ Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
⁷ Department of Medicine, University of Turku and Turku University Hospital, Turku, Finland.
⁸ School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA.
⁹ Department of Pediatrics, Division of Pediatric Nephrology, University of Minnesota, USA.
¹⁰ Department of Pediatrics, Division of Pediatric Cardiology, University of Minnesota, Minneapolis, MN, USA.
¹¹ Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA.
¹² Children's Hospital Colorado, Anschutz Medical Campus, Aurora, CO, USA.
¹³ Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
¹⁴ Baker Heart and Diabetes Institute, Melbourne, Australia.
¹⁵ Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, USA.
¹⁶ Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford, UK.
¹⁷ Department of Clinical Physiology, Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital, Tampere, Finland.
¹⁸ Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
¹⁹ Oxford Martin School, University of Oxford, Oxford, UK.

PMID: 40042879
DOI: 10.1093/eurjpc/zwaf117

Abstract

Aims: The role of adult HDL-C in atherosclerotic cardiovascular disease (ASCVD) faces challenges from Mendelian randomisations and drug trials. However, the association between childhood HDL-C and its changes and adult ASCVD remains undefined. This study aimed to determine this association.

Methods: Participants: Children in the International Childhood Cardiovascular Cohort (i3C) Consortium with childhood HDL-C and adult ASCVD follow-up. Age- and sex-standardized HDL-C z-scores were calculated for childhood (3-19 years), early childhood (3-11 years), and adolescence (12-19 years); Low HDL-C defined as <1.03mmol/L; Participants classified as consistently normal, low-to-normal, normal-to-low, and consistently low based on HDL-C status at early childhood and adolescence. ASCVD events: Identified using self-reports adjudicated by medical records or death registries. Analysis: Cox proportional hazards models quantified the associations between childhood HDL-C and adult ASCVD.

Results: The study included 38,589 participants (49.7% males, mean age in 2016: 46.4 years) with 779 ASCVD and 784 imputed ASCVD events. After adjusting for sex, cohort, age and HDL-C measurement year, higher HDL-C z-scores in childhood, early childhood and adolescence were associated with lower adult ASCVD risk (HRs: 0.81-0.82), with the lowest risk at HDL-C >1.50mmol/L. Normal-to-low (HR 1.38, 95%CI 1.04-1.82) and consistently low (HR 1.94, 95%CI 1.45-2.63) childhood HDL-C increased adult ASCVD risk compared to consistently normal HDL-C. Adjusting for BMI and triglycerides weakened these associations.

Conclusions: Childhood and adolescent HDL-C were prospectively and inversely associated with adult ASCVD, suggesting that low HDL-C could be a risk maker of adult ASCVD. Future replications, mechanistic studies and Mendelian randomisations on childhood HDL-C may clarify its causal effects on adult ASCVD.

Keywords: Childhood HDL-C; Cox proportional hazards; adult ASCVD; cohort study; risk factors.

Plain language summary

We examined the association between childhood HDL-C measurement and adult ASCVD at follow-up in data from the International Childhood Cardiovascular Cohort (i3C) Consortium. Higher HDL-C levels in childhood were associated with lower risk of a ASCVD event, irrespective of age (early childhood versus adolescence). The lowest risk was observed at HDL-C concentrations of around and above 1.50 mmol/L (58 mg/dL). A decrease in HDL-C from early childhood to adolescence was associated with an increased risk of adult ASCVD. When additionally adjusted for BMI z-score, attenuated associations were noted. Adding triglycerides to models attenuated associations towards null.

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