Abstract

BackgroundMales 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.MethodsData were from the Avon Longitudinal Study of Parents and Children (7727 offspring, 49% male; and 6500 parents, 29% male). Proton nuclear magnetic resonance (1H-NMR) 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-glycaemic factors, and inflammatory glycoprotein acetyls). Metabolites were measured in the same offspring once in childhood (mean age 8 years), twice in adolescence (16 years and 18 years) and once in early adulthood (25 years), and in their parents once in middle adulthood (50 years). Linear regression models estimated differences in metabolites for males versus females on each occasion (serial cross-sectional associations).ResultsAt 8 years, total lipids in very-low-density lipoproteins (VLDL) were lower in males; levels were higher in males at 16 years and higher still by 18 years and 50 years (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 18 years, 0.50 SD (95% CI = 0.42, 0.57) higher at 25 years, and 0.62 SD (95% CI = 0.55, 0.68) higher at 50 years. 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.ConclusionsOur 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.

Highlights

  • Males experience higher rates of coronary heart disease (CHD) than females, but the circulating traits underpinning this difference are poorly understood

  • In this study, we examined sex differences in systemic metabolites at multiple life stages, from childhood to middle adulthood, to help identify circulating traits that may underpin higher age-adjusted CHD rates commonly seen among males

  • From adolescence onwards, lipids in very-low-density lipoproteins (VLDL) are higher among males while levels of other CHD-related traits including low-density lipoprotein (LDL) cholesterol, apolipoprotein-B, and inflammatory glycoprotein acetyls, are higher among females

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Summary

Introduction

Males experience higher rates of coronary heart disease (CHD) than females, but the circulating traits underpinning this difference are poorly understood. Adult females tend to have lower triglyceride levels compared with adult males, potentially due to hormonal mechanisms [14, 15], yet adult females tend to have higher cholesterol in low-density lipoprotein (LDL) particles [12, 16]. Such comparisons have been based mostly on circulating traits measured by conventional clinical assays. Knowledge of sex differences in these more detailed traits at multiple life stages may help reveal more specific circulating pathways that underpin sex differences in age-adjusted rates of CHD, but no such investigation has yet been conducted

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