title: Circulating 25-hydroxyvitamin D concentration and the risk of type 2 diabetes: results from the European Prospective Investigation into Cancer (EPIC)-Norfolk cohort and updated meta-analysis of prospective studies.
abstract: OBJECTIVE
  Epidemiological evidence is suggestive, but limited, for an association between circulating 25-hydroxyvitamin D (25[OH]D) and risk of type 2 diabetes. We conducted a systematic review and meta-analysis that included new data from previously unpublished studies.
  
  
  METHODS
  Using a nested case-cohort design in the European Prospective Investigation into Cancer (EPIC)-Norfolk study, we identified a random subcohort and incident type 2 diabetes cases occurring between baseline (1993-1997) and 2006. In the Ely prospective study we identified incident type 2 diabetes cases between 1990 and 2003. We conducted a systematic review of prospective studies on 25(OH)D and type 2 diabetes published in MEDLINE or EMBASE until 31 January 2012, and performed a random-effects meta-analysis combining available evidence with results from the EPIC-Norfolk and Ely studies.
  
  
  RESULTS
  In EPIC-Norfolk, baseline 25(OH)D was lower among incident type 2 diabetes cases (mean [SD] 61.6 [22.4] nmol/l; n=621) vs non-case subcohort participants (mean 65.3 [23.9] nmol/l; n=826). There was an inverse association between baseline 25(OH)D and incident type 2 diabetes in multivariable-adjusted analyses: HR (95% CI) 0.66 (0.45, 0.97), 0.53 (0.34, 0.82), 0.50 (0.32, 0.76), p trend <0.001, comparing consecutive increasing 25(OH)D quartiles with the lowest. In Ely, 37 incident type 2 diabetes cases were identified among 777 participants. In meta-analysis, the combined RR of type 2 diabetes comparing the highest with lowest quartile of 25(OH)D was 0.59 (0.52, 0.67), with little heterogeneity (I (2) =2.7%, p=0.42) between the 11 studies included (3,612 cases and 55,713 non-cases).
  
  
  CONCLUSIONS
  These findings demonstrate an inverse association between circulating 25(OH)D and incident type 2 diabetes. However, causal inference should be addressed through adequately dosed randomised trials of vitamin D supplementation or genetic Mendelian randomisation experiments.
authors.affiliation: Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Box 285, Hills Road, Cambridge, CB2 0QQ, UK. nita.forouhi@mrc-epid.cam.ac.uk
authors.forename: N G
authors.initials: NG
authors.lastname: Forouhi
authors.forename: Z
authors.initials: Z
authors.lastname: Ye
authors.forename: A P
authors.initials: AP
authors.lastname: Rickard
authors.forename: K T
authors.initials: KT
authors.lastname: Khaw
authors.forename: R
authors.initials: R
authors.lastname: Luben
authors.forename: C
authors.initials: C
authors.lastname: Langenberg
authors.forename: N J
authors.initials: NJ
authors.lastname: Wareham
mesh_terms: D000328:Adult; D000368:Aged; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000453:epidemiology; D004739:England / Q000453:epidemiology; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012307:Risk Factors; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000097:blood; D044465:White People
chemical_list: D014807:Vitamin D; C104450:25-hydroxyvitamin D