Characterization of the metabolic profile associated with serum 25-hydroxyvitamin D: a cross-sectional analysis in population-based data

Abstract

Background: Numerous observational studies have observed associations between vitamin D deficiency and cardiometabolic diseases, but these findings might be confounded by obesity. A characterization of the metabolic profile associated with serum 25-hydroxyvitamin D [25(OH)D] levels, in general and stratified by abdominal obesity, may help to untangle the relationship between vitamin D, obesity and cardiometabolic health.Methods: Serum metabolomics measurements were obtained from a nuclear magnetic resonance spectroscopy (NMR)- and a mass spectrometry (MS)-based platform. The discovery was conducted in 1726 participants of the population-based KORA-F4 study, in which the associations of the concentrations of 415 metabolites with 25(OH)D levels were assessed in linear models. The results were replicated in 6759 participants (NMR) and 609 (MS) participants, respectively, of the population-based FINRISK 1997 study.Results: Mean [standard deviation (SD)] 25(OH)D levels were 15.2 (7.5) ng/ml in KORA F4 and 13.8 (5.9) ng/ml in FINRISK 1997; 37 metabolites were associated with 25(OH)D in KORA F4 at P < 0.05/415. Of these, 30 associations were replicated in FINRISK 1997 at P < 0.05/37. Among these were constituents of (very) large very-low-density lipoprotein and small low-density lipoprotein subclasses and related measures like serum triglycerides as well as fatty acids and measures reflecting the degree of fatty acid saturation. The observed associations were independent of waist circumference and generally similar in abdominally obese and non-obese participants.Conclusions: Independently of abdominal obesity, higher 25(OH)D levels were associated with a metabolite profile characterized by lower concentrations of atherogenic lipids and a higher degree of fatty acid polyunsaturation. These results indicate that the relationship between vitamin D deficiency and cardiometabolic diseases is unlikely to merely reflect obesity-related pathomechanisms.

Metabolic profiling–multitude of technologies with great research potential, but (when) will translation emerge?

“…Thus, in relation to these outcomes, vitamin D sufficiency may be important in delaying onset of or preventing the disease and might thus merit further investigations in long-term randomized controlled trials. These recent applications of the Mendelian randomization framework are interesting examples of causal epidemiology and a welcome reminder that observational association studies, such as those regarding 25-hydroxyvitamin D and circulating lipids and metabolites in this issue, 48 , 49 are often prone to confounding and reverse causation 22 . Furthermore, an important note here is that replication of observational associations does not mean causation, as previously illustrated in the case of sex hormone-binding globulin and systemic metabolism 58 .…”

“…Nevertheless, the results are weakened by the lack of replication. Comparison of the results from Nelson and co-workers 49 with those of Vogt and coauthors 48 illustrates the importance of biologically independent data; for example, the association of 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) with 25-hydroxyvitamin D is similarly positive and strong in all three cohorts; however, eicosapentaenoate (EPA) and docosahexaenoate (DHA), which show strong positive associations in the ATBC study, 49 do not associate with 25-hydroxyvitamin D in KORA F4 48 . Possible explanation for this discrepancy is the finding in the ATBC study that retinol influenced the associations between 25-hydroxyvitamin D and EPA as well as DHA 49 …”

“…Würtz and colleagues 15 corroborated NMR-based cardiovascular biomarker associations with MS in two population cohorts with 671 and 2289 individuals. In this issue, Vogt and coauthors 48 characterize associations between serum 25-hydroxyvitamin D concentrations and those of 415 metabolite and lipid measures, quantified by both NMR- and MS-based platforms in 1726 people from a population-based study, KORA F4. Importantly, they also replicated the majority of their findings in an independent population-based study with 6759 individuals for the NMR-based measures and 609 for the MS-based measures.…”

“…The primary measures can also be used to calculate many derived measures and metabolic ratios with potential biological importance. In addition to the study by Wang and co-workers, 62 three other papers in this issue also apply this methodology, namely the above-mentioned study on serum 25-hydroxyvitamin D by Vogt and co-authors 48 and two by Würtz and co-workers which look at metabolic profiling of alcohol consumption 68 and metabolic signatures of birthweight in adulthood 69 …”

Plasma 25-Hydroxyvitamin D Concentrations are Associated with Polyunsaturated Fatty Acid Metabolites in Young Children: Results from the Vitamin D Antenatal Asthma Reduction Trial

“…Untargeted metabolomics is a high-throughput technology whereby large amounts of small molecules in a biospecimen can be characterized and quantified for their relative abundances [14], which may serve as a useful tool to gain a more comprehensive understanding of the biochemical pathways involved in the multifaceted functions of vitamin D. Previous investigations have examined metabolites associated with vitamin D status predominantly in adults [15,16] and populations with existing health conditions [17][18][19]. There is a need for studies targeting the earliest life course prior to development of diseases, where vitamin D concentrations may influence pathogenesis.…”