Untargeted Metabolomics Profiling Reveals Perturbations in Arginine-NO Metabolism in Middle Eastern Patients with Coronary Heart Disease.

Coronary heart disease (CHD) is a major cause of death in Middle Eastern (ME) populations, with current studies of the metabolic fingerprints of CHD lacking in diversity. Identification of specific biomarkers to uncover potential mechanisms for developing predictive models and targeted therapies for CHD is urgently needed for the least-studied ME populations. A case-control study was carried out in a cohort of 1001 CHD patients and 2999 controls. Untargeted metabolomics was used, generating 1159 metabolites. Univariate and pathway enrichment analyses were performed to understand functional changes in CHD. A metabolite risk score (MRS) was developed to assess the predictive performance of CHD using multivariate analysis and machine learning. A total of 511 metabolites were significantly different between the CHD patients and the controls (FDR p < 0.05). The enriched pathways (FDR p < 10−300) included D-arginine and D-ornithine metabolism, glycolysis, oxidation and degradation of branched chain fatty acids, and sphingolipid metabolism. MRS showed good discriminative power between the CHD cases and the controls (AUC = 0.99). In this first study in the Middle East, known and novel circulating metabolites and metabolic pathways associated with CHD were identified. A small panel of metabolites can efficiently discriminate CHD cases and controls and therefore can be used as a diagnostic/predictive tool.

Association of vitamin D3 and its metabolites in patients with and without type 2 diabetes and their relationship to diabetes complications.

BACKGROUND: Epidemiological studies have suggested that vitamin D deficiency is associated with the development of type 2 diabetes (T2DM) and is related to diabetes complications. This study was undertaken to determine the relationship between diabetes complications and cardiovascular risk factors with vitamin D3 and its metabolites: 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), 25-hydroxyvitamin D3 (25(OH)D3), 24,25-dihydroxyvitamin D3 (24,25(OH)2D3); and 25-hydroxy-3epi-vitamin D3 (3epi25(OH)D3). METHODS: 750 Qatari subjects, 460 (61.3%) with and 290 (38.7%) without T2DM, who were not taking vitamin D3 supplements, participated in this cross-sectional, observational study. Plasma concentrations of vitamin D3 and its metabolites were measured by liquid chromatography tandem mass spectrometry analysis. RESULTS: T2DM subjects had lower concentrations of all vitamin D3 metabolites (p < 0.001) except 3epi25(OH)D3 (p < 0.071). Males had higher concentrations of all vitamin D3 metabolites (p < 0.001). In the T2DM subjects, lower 25(OH)D3 was associated with retinopathy (p < 0.03) and dyslipidemia (p < 0.04), but not neuropathy or vascular complications; lower 1,25(OH)2D3 was associated with hypertension (p < 0.009), dyslipidemia (p < 0.003) and retinopathy (p < 0.006), and coronary artery disease (p < 0.012), but not neuropathy; lower 24,25(OH)2D3 concentrations were associated with dyslipidemia alone (p < 0.019); 3epi25(OH)D3 associated with diabetic neuropathy alone (p < 0.029). In nondiabetics, 25(OH)D3, 1,25(OH)2D3 and 24,25(OH)2D3 were associated with dyslipidemia (p < 0.001, p < 0.001, p < 0.015, respectively) and lower 1,25(OH)2D3 was associated with hypertension (p < 0.001). Spearman's correlation showed 1,25(OH)2D3 to be negatively correlated to age and diabetes duration. CONCLUSIONS: Different diabetes complications were associated with differing vitamin D parameters, with diabetic retinopathy related to lower 25(OH)D3 and 1,25(OH)2D3 levels, hypertension significantly associated with lower 1,25(OH)2D3, while dyslipidemia was associated with lower 25(OH)D3, 1,25(OH)2D3 and 24,25(OH)2D3. While 25(OH)D metabolites were lower in females, there was not an exaggeration in complications.