Sex differences in the association of phospholipids with components of the metabolic syndrome in young adults

Background: There are differences in the prevalence and severity of diseases between males, females not taking hormonal contraceptives (non-HC females) and females taking hormonal contraceptives (HC females). The aim of this study was to identify sex-specific differences in the metabolome and its relation to components of the metabolic syndrome in a young adult population. Methods: The subjects analysed are from the 20-year follow-up of the Western Australian Pregnancy Cohort (Raine) Study. Two hundred fifteen plasma metabolites were analysed in 1021 fasted plasma samples by a targeted liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) metabolomics approach. Principal component analysis between males (n = 550), non-HC females (n = 199) and HC females (n = 269) was applied. Regression analysis with a sex x metabolite concentration interaction was performed on components of the MetS, namely waist circumference, systolic blood pressure, and plasma HDL-C, triglycerides and glucose concentration, as outcome to select the significant metabolites of the interaction. Those selected metabolites were used as predictors in a sex group stratified analysis to compare the different beta coefficients and therefore the sex group-dependent associations. Results: Principal component analysis between males, non-HC females, and HC females showed a general discriminating trend between males and HC females. One hundred twenty-seven metabolites were significantly different between males and non-HC females, whereas 97 differed between non-HC females and HC females. Males and non-HC females mainly differed in sphingomyelin, lyso-phosphatidylcholine, acyl-carnitine and amino acid species, whilst non-HC females and HC females mainly differed in phosphatidylcholine, lyso-phosphatidylcholine and acyl-carnitine concentrations. Forty-one metabolites (phosphatidylcholines, sphingomyelines, lysophosphatidylcholine) were significantly differently associated with the MetS factors in the different groups. Conclusions: We have shown clear differences between plasma metabolite concentrations in males, and HC or non-HC females, especially in lyso-phosphatidylcholine, sphingomyelin and phosphatidylcholine, which have been shown to associate with obesity in other studies. The association of these metabolites differed between sexes with components of the metabolic syndrome, which means that development of diseases like obesity and diabetes may differ between the sexes. Our findings highlight the importance of considering sex differences when conducting a metabolomics study and the need to account for the effect of HC usage in females in future studies.