Abstract P288: Sex Differences in Krebs Cycle Metabolites May Explain Differential Predisposition to Cardiovascular Disease

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Introduction: Although there have been numerous observational studies in the literature describing differential predisposition to cardiovascular disease between sexes, there is relatively little in the literature that provides a biochemical account suitable to explain these disparities. We hypothesized that there may be a fundamental biochemical distinction between sexes, productive first of differential metabolic contexts, and thence ultimately of the differential predisposition to disease states described in the epidemiologic literature. Methods: We employed metabolomic analysis together with an unsupervised learning approach to uncover sex-specific alterations in the abundance of several polar metabolites. Blood was collected from healthy volunteers (5 female, 4 male). Polar metabolites were extracted and analyzed using targeted liquid chromatography coupled with tandem mass spectrometry; we then utilized nonnegative matrix factorization (NMF) to search for metabolomic differences. Results: The female and male signatures differ in metabolites related to Krebs Cycle (KC). In males, we observed statistically significant or nearly significant decreases in citrate (P=0.054), isocitrate (P=0.006), and malate (P=0.076); while aconitate, succinate, fumarate, oxaloacetate, and glyoxylate, an intermediate in an alternative KC pathway, were non-significantly decreased. GABA P=0.0008) was also strikingly decreased in males. The KC product GTP (P=0.014) was significantly decreased as well. Conclusion: We observed significant decreases in several KC intermediates in males when compared with female counterparts, in GABA, and in GTP, which plays important roles in protein synthesis, gluconeogenesis, and cellular signal transduction. The status of the KC as the central hub of metabolism confers wide-ranging implications on this data: the reduced KC functionality observed in our study may confer disproportionate exposure to processes requiring efficient energy production in males.