Metabolomics analysis of serum 25-hydroxy-vitamin D in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study

Background: Vitamin D has been discussed in the context of cardiovascular disease, cancer, bone health and other outcomes. Epidemiological studies have reported on the importance of vitamin D in cancer prevention and treatment. The discovery of vitamin D-associated metabolites through agnostic metabolomics analyses offers a new approach for elucidating disease aetiology and health-related pathway identification. Methods: Baseline serum 25-hydroxy-vitamin D [25(OH) D] and 940 serum metabolites were measured in 392 men from eight nested cancer case-control studies in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish male smokers (aged 50-69 years). The metabolomic profiling was conducted using mass spectrometry. We used linear regression to estimate the standardized beta-coefficient as the effect metric for the associations between metabolites and 25(OH) D levels. Results: A majority of the metabolites associated with 25(OH) D were of lipid origin, including 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) [beta-estimate 0.38 per 1 standard deviation (SD) increment], stearoyl-arachidonoyl-glycerophosphoethanolamine (GPPE) (-0.38 per SD) and two essential fatty acids: eicosapentaenoate (EPA; 0.17 per SD) and docosahexaenoate (DHA; 0.13 per SD). Each of these lipid metabolites was associated with 25(OH) D at the principal components corrected P-value of 3.09 x 10(-4). Conclusions: The large number of metabolites, particularly lipid compounds, found to be associated with serum 25(OH) D provide new biological clues relevant to the role of vitamin D status and human health outcomes. The present findings should be re-examined in other metabolomics studies of diverse populations.