, Volume 28, Issue 9, pp 743-752
Date: 04 Sep 2013

Plasma 25-hydroxyvitamin D and its genetic determinants in relation to incident type 2 diabetes: a prospective case-cohort study

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It is unclear whether vitamin D lowers risk of type 2 diabetes (T2D). In an observational study, we assessed the prospective association between plasma 25-hydroxyvitamin D (25(OH)D) and incident T2D, and evaluated whether it holds up for genetically determined elevated 25(OH)D. We used a case-cohort study nested within the German arm of the European Prospective Investigation into Cancer. From a total cohort of 53,088 participants with a mean follow-up of 6.6 years, we identified a random subcohort of 2,121 participants (57 % women) and 1,572 incident cases of T2D. 25(OH)D was measured in baseline plasma samples retrieved from frozen storage. Mean plasma 25(OH)D in the subcohort was 47.1 (5th–95th percentile 19.6–80.7) nmol/L. After controlling for age, sex, center, season of blood draw, education, and lifestyle, the hazard of T2D decreased across increasing plasma concentrations of 25(OH)D (P linear trend <0.0001). The association became non-linear after adjustment for BMI and waist circumference (P non-linearity <0.0001), with the inverse association being restricted to participants with 25(OH)D concentrations below ~45 nmol/L (hazard ratio per 5 nmol/L higher 25(OH)D 0.91, 95 % CI 0.84–0.98). A score predicting genetically determined plasma 25(OH)D by weighting four independent single-nucleotide polymorphisms by their effect on 25(OH)D, explained 3.7 % of the variance in 25(OH)D. The hazard ratio (95 % CI) per 5 nmol/L higher genetically predicted 25(OH)D was 0.98 (0.89–1.08) in the entire study sample and 1.06 (0.93–1.21) in the sub-sample with 25(OH)D <45 nmol/L. This latter finding casts doubt on a strong causal association of 25(OH)D with T2D, but further research in large-scale consortia is needed.

Parts of this work were presented at the third “Statusseminar Ernaehrung” of the German Federal Ministry of Education and Research (BMBF), Berlin, Germany, 19–21 November 2012, and at the annual conference of the European Diabetes Epidemiology Group, Potsdam, Germany, 13–16 April 2013.