Sex differences in systemic metabolites at four life stages: cohort study with repeated metabolomics

Joshua A Bell*, Diana L Dos Santos Ferreira, Abigail Fraser, Ana Luiza Goncalves Soares, Laura D Howe, Debbie A Lawlor, David J Carslake, George Davey Smith, Linda M O'Keeffe

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Background: Males experience higher rates of coronary heart disease (CHD) than females, but the circulating traits underpinning this difference are poorly understood. We examined sex differences in systemic metabolites measured at four life stages, spanning childhood to middle-adulthood.

Methods: Data were from the Avon Longitudinal Study of Parents and Children (7,727 offspring, 49% male; and 6,500 parents, 29% male). Proton nuclear magnetic resonance (1HNMR) spectroscopy from a targeted metabolomics platform was performed on EDTA-plasma or serum samples to quantify 229 systemic metabolites (including lipoprotein-subclass specific lipids, pre-glycemic factors, and inflammatory glycoprotein acetyls). Metabolites were measured in the same offspring once in childhood (mean age 8y), twice in adolescence (16y and 18y) and once in early-adulthood (25y), and in their parents once in middle adulthood (50y). Linear regression models estimated differences in metabolites for males versus females on each occasion (serial cross-sectional associations).

Results: At 8y, total lipids in very-low-density lipoproteins (VLDL) were lower in males; levels were higher in males at 16y and higher still by 18y and 50y (among parents) for medium-or-larger subclasses. Larger sex differences at older ages were most pronounced for VLDL triglycerides – males had 0.19 standard deviations (SD) (95% CI=0.12, 0.26) higher at 18y, 0.50 SD (95% CI=0.42, 0.57) higher at 25y, and 0.62 SD (95% CI=0.55, 0.68) higher at 50y. Low-density lipoprotein (LDL) cholesterol, apolipoprotein-B, and glycoprotein acetyls were generally lower in males across ages. The direction and magnitude of effects were largely unchanged when adjusting for body mass index measured at the time of metabolite assessment on each occasion.

Conclusions: Our results suggest that males begin to have higher VLDL triglyceride levels in adolescence, with larger sex differences at older ages. Sex differences in other CHD-relevant metabolites, including LDL cholesterol, show the opposite pattern with age, with higher levels among females. Such life course trends may inform causal analyses with clinical endpoints in specifying traits which underpin higher age-adjusted CHD rates commonly seen among males.
Original languageEnglish
Article number58 (2021)
Number of pages13
JournalBMC Medicine
Publication statusPublished - 24 Feb 2021


  • Sex differences
  • Metabolites
  • Coronary heart disease
  • NMR metabolomics
  • Epidemiology


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