title: Plasma 25-hydroxyvitamin D and its genetic determinants in relation to incident type 2 diabetes: a prospective case-cohort study.
abstract: 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.
authors.affiliation: Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany, brian.buijsse@dife.de.
authors.forename: Brian
authors.initials: B
authors.lastname: Buijsse
authors.forename: Heiner
authors.initials: H
authors.lastname: Boeing
authors.forename: Frank
authors.initials: F
authors.lastname: Hirche
authors.forename: Cornelia
authors.initials: C
authors.lastname: Weikert
authors.forename: Matthias B
authors.initials: MB
authors.lastname: Schulze
authors.forename: Marion
authors.initials: M
authors.lastname: Gottschald
authors.forename: Tilman
authors.initials: T
authors.lastname: Kühn
authors.forename: Verena A
authors.initials: VA
authors.lastname: Katzke
authors.forename: Birgit
authors.initials: B
authors.lastname: Teucher
authors.forename: Jutta
authors.initials: J
authors.lastname: Dierkes
authors.forename: Gabriele I
authors.initials: GI
authors.lastname: Stangl
authors.forename: Rudolf
authors.initials: R
authors.lastname: Kaaks
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000453:epidemiology* / Q000235:genetics; D005260:Female; D005838:Genotype; D005858:Germany / Q000453:epidemiology; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012307:Risk Factors; D011795:Surveys and Questionnaires; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000097:blood / Q000235:genetics; D044465:White People / Q000235:genetics / Q000706:statistics & numerical data
chemical_list: D014807:Vitamin D; C104450:25-hydroxyvitamin D