title: Genetic variants and associations of 25-hydroxyvitamin D concentrations with major clinical outcomes.
abstract: BACKGROUND
  Lower serum 25-hydroxyvitamin D concentrations are associated with greater risks of many chronic diseases across large, prospective community-based studies. Substrate 25-hydroxyvitamin D must be converted to 1,25-dihydroxyvitamin D for full biological activity, and complex metabolic pathways suggest that interindividual variability in vitamin D metabolism may alter the clinical consequences of measured serum 25-hydroxyvitamin D.
  
  
  OBJECTIVE
  To investigate whether common variation within genes encoding the vitamin D-binding protein, megalin, cubilin, CYP27B1, CYP24A1, and the vitamin D receptor (VDR) modify associations of low 25-hydroxyvitamin D with major clinical outcomes.
  
  
  METHODS
  Examination of 141 single-nucleotide polymorphisms in a discovery cohort of 1514 white participants (who were recruited from 4 US regions) from the community-based Cardiovascular Health Study. Participants had serum 25-hydroxyvitamin D measurements in 1992-1993 and were followed up for a median of 11 years (through 2006). Replication meta-analyses were conducted across the independent, community-based US Health, Aging, and Body Composition (n = 922; follow-up: 1998-1999 through 2005), Italian Invecchiare in Chianti (n = 835; follow-up: 1998-2000 through 2006), and Swedish Uppsala Longitudinal Study of Adult Men (n = 970; follow-up: 1991-1995 through 2008) cohort studies.
  
  
  METHODS
  Composite outcome of incident hip facture, myocardial infarction, cancer, and mortality over long-term follow-up.
  
  
  RESULTS
  Interactions between 5 single-nucleotide polymorphisms and low 25-hydroxyvitamin D concentration were identified in the discovery phase and 1 involving a variant in the VDR gene replicated in independent meta-analysis. Among Cardiovascular Health Study participants, low 25-hydroxyvitamin D concentration was associated with hazard ratios for risk of the composite outcome of 1.40 (95% CI, 1.12-1.74) for those who had 1 minor allele at rs7968585 and 1.82 (95% CI, 1.31-2.54) for those with 2 minor alleles at rs7968585. In contrast, there was no evidence of an association (estimated hazard ratio, 0.93 [95% CI, 0.70-1.24]) among participants who had 0 minor alleles at this single-nucleotide polymorphism.
  
  
  CONCLUSIONS
  Known associations of low 25-hydroxyvitamin D with major health outcomes may vary according to common genetic differences in the vitamin D receptor.
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, USA.
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Levin
authors.forename: Cassianne
authors.initials: C
authors.lastname: Robinson-Cohen
authors.forename: Ian H
authors.initials: IH
authors.lastname: de Boer
authors.forename: Denise K
authors.initials: DK
authors.lastname: Houston
authors.forename: Kurt
authors.initials: K
authors.lastname: Lohman
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Liu
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Kritchevsky
authors.forename: Jane A
authors.initials: JA
authors.lastname: Cauley
authors.forename: Toshiko
authors.initials: T
authors.lastname: Tanaka
authors.forename: Luigi
authors.initials: L
authors.lastname: Ferrucci
authors.forename: Stefania
authors.initials: S
authors.lastname: Bandinelli
authors.forename: Kushang V
authors.initials: KV
authors.lastname: Patel
authors.forename: Emil
authors.initials: E
authors.lastname: Hagström
authors.forename: Karl
authors.initials: K
authors.lastname: Michaëlsson
authors.forename: Håkan
authors.initials: H
authors.lastname: Melhus
authors.forename: Thomas
authors.initials: T
authors.lastname: Wang
authors.forename: Myles
authors.initials: M
authors.lastname: Wolf
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
authors.forename: David
authors.initials: D
authors.lastname: Siscovick
authors.forename: Bryan
authors.initials: B
authors.lastname: Kestenbaum
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics; D000368:Aged; D002908:Chronic Disease / Q000401:mortality*; D015331:Cohort Studies; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006620:Hip Fractures / Q000401:mortality; D006801:Humans; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000235:genetics; D008297:Male; D015201:Meta-Analysis as Topic; D009203:Myocardial Infarction / Q000401:mortality; D009369:Neoplasms / Q000401:mortality; D020641:Polymorphism, Single Nucleotide; D018167:Receptors, Calcitriol / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics; D012306:Risk; D013250:Steroid Hydroxylases / Q000235:genetics; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D026561:Low Density Lipoprotein Receptor-Related Protein-2; D018167:Receptors, Calcitriol; D011956:Receptors, Cell Surface; C029486:intrinsic factor-cobalamin receptor; D014807:Vitamin D; C104450:25-hydroxyvitamin D; D013250:Steroid Hydroxylases; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase