Vitamin D and the risk of death and diabetes
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2016
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Melbourne Authors
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Melbourne School of Population and Global Health
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PhD thesis
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Description
© 2016 Dr. Alicia Kathryn Heath
Abstract
Background
Uncertainty surrounds the effects of vitamin D on extraskeletal health. Many observational studies have found inverse associations between vitamin D status and several outcomes, including mortality and type 2 diabetes, but these results might be biased by confounding and reverse causality. Evidence from existing randomised controlled trials (RCTs) of vitamin D supplementation is of limited utility due to design limitations. Furthermore, although recent evidence from RCTs suggests that vitamins D2 and D3 might not function equivalently, existing observational studies have generally used total 25-hydroxyvitamin D (25(OH)D) concentrations (the sum of 25-hydroxyvitamin D2 (25(OH)D2) and 25-hydroxyvitamin D3 (25(OH)D3)) to assess vitamin D status without distinguishing between 25(OH)D2 and 25(OH)D3. Thus, any differences in their associations with health outcomes have not been explored.
My principal aims were to investigate associations between vitamin D status and all-cause mortality, cause-specific mortality, and the incidence of type 2 diabetes; investigate the separate associations of 25(OH)D2 and 25(OH)D3 with all-cause mortality; and explore the possibility of reverse causality. Secondary aims were to assess the validity and reliability of measurements of 25(OH)D in dried blood spots (DBS), and investigate correlates of vitamin D status.
Methods
A case-cohort study nested within the Melbourne Collaborative Cohort Study (MCCS) was used. Concentrations of 25(OH)D2 and 25(OH)D3 in archived DBS were measured using liquid chromatography-tandem mass spectrometry. Correlates of vitamin D status were investigated using multiple linear regression. Cox regression was used to estimate hazard ratios (HRs) for mortality with adjustment for confounding variables. Barlow’s method and robust standard errors were used to account for the case-cohort design. Logistic regression was used to estimate odds ratios (ORs) in relation to type 2 diabetes.
Results
Measurements of 25(OH)D from DBS were reliable (within-batch and between-batch intraclass correlations for 493 replicate measurements = 0.82; 95% confidence interval (CI): 0.80, 0.85 and 0.73; 95% CI: 0.68, 0.78, respectively), and were highly correlated with plasma 25(OH)D (R2 from regression of plasma versus DBS 25(OH)D = 0.73). Correlates of vitamin D status were predominantly environmental, behavioural and lifestyle variables, and personal characteristics that influence sun exposure (R2 for predictive model = 0.31). Season was the strongest predictor of vitamin D status (partial R2 = 0.13).
Concentrations of 25(OH)D3 were inversely associated with all-cause mortality (HR per 25 nmol/L increase = 0.85; 95% CI: 0.77, 0.95; P = 0.003), whereas the presence of 25(OH)D2 was positively associated with all-cause mortality (HR = 1.80; 95% CI: 1.09, 2.97; P = 0.02). Higher concentrations of 25(OH)D3 were associated with a reduced risk of death due to cancer (HR per 25 nmol/L increase = 0.86; 95% CI: 0.77, 0.97; P = 0.02), respiratory diseases (HR = 0.59; 95% CI: 0.41, 0.85; P = 0.004), and digestive diseases (HR = 0.45; 95% CI: 0.26, 0.77; P = 0.004), and a reduced risk of type 2 diabetes (HR = 0.76; 95% CI: 0.64, 0.90; P = 0.002). These findings do not appear to be explained by reverse causality.
Conclusion
The results from this study suggest that vitamin D3 might be beneficial for the prevention of type 2 diabetes and premature death, whereas vitamin D2 might have an adverse effect on health. Future observational studies should distinguish between 25(OH)D2 and 25(OH)D3 to explore whether they are dissimilarly associated with extraskeletal outcomes.
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Keywords
vitamin D, vitamin D2, vitamin D3, 25-hydroxyvitamin D, mortality, diabetes, cancer, cardiovascular disease