Document Detail


Genetic variants and associations of 25-hydroxyvitamin D concentrations with major clinical outcomes.
MedLine Citation:
PMID:  23150009     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
CONTEXT: 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.
DESIGN, SETTING, AND PARTICIPANTS: 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.
MAIN OUTCOME MEASURE: 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.
CONCLUSION: Known associations of low 25-hydroxyvitamin D with major health outcomes may vary according to common genetic differences in the vitamin D receptor.
Authors:
Gregory P Levin; Cassianne Robinson-Cohen; Ian H de Boer; Denise K Houston; Kurt Lohman; Yongmei Liu; Stephen B Kritchevsky; Jane A Cauley; Toshiko Tanaka; Luigi Ferrucci; Stefania Bandinelli; Kushang V Patel; Emil Hagström; Karl Michaëlsson; Håkan Melhus; Thomas Wang; Myles Wolf; Bruce M Psaty; David Siscovick; Bryan Kestenbaum
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  JAMA     Volume:  308     ISSN:  1538-3598     ISO Abbreviation:  JAMA     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-15     Completed Date:  2012-11-20     Revised Date:  2014-09-17    
Medline Journal Info:
Nlm Unique ID:  7501160     Medline TA:  JAMA     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1898-905     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
25-Hydroxyvitamin D3 1-alpha-Hydroxylase / genetics
Aged
Chronic Disease / mortality*
Cohort Studies
Female
Genetic Variation*
Genotype
Hip Fractures / mortality
Humans
Low Density Lipoprotein Receptor-Related Protein-2 / genetics
Male
Meta-Analysis as Topic
Myocardial Infarction / mortality
Neoplasms / mortality
Polymorphism, Single Nucleotide
Receptors, Calcitriol / genetics*
Receptors, Cell Surface / genetics
Risk
Steroid Hydroxylases / genetics
Vitamin D / analogs & derivatives*,  blood,  metabolism
Grant Support
ID/Acronym/Agency:
263 MD 821336/MD/NIMHD NIH HHS; 263 MD9164/MD/NIMHD NIH HHS; DK063491/DK/NIDDK NIH HHS; HHSN268200782096C//PHS HHS; HHSN268201200036C//PHS HHS; HL087652/HL/NHLBI NIH HHS; HL096875/HL/NHLBI NIH HHS; K01 AG030506/AG/NIA NIH HHS; KL2 TR000421/TR/NCATS NIH HHS; M01RR00069/RR/NCRR NIH HHS; N.1-AG-1-1/AG/NIA NIH HHS; N.1-AG-1-2111/AG/NIA NIH HHS; N01 HC-15103/HC/NHLBI NIH HHS; N01 HC-55222/HC/NHLBI NIH HHS; N01-AG-5-0002/AG/NIA NIH HHS; N01-HC-35129/HC/NHLBI NIH HHS; N01-HC-45133/HC/NHLBI NIH HHS; N01-HC-75150/HC/NHLBI NIH HHS; N01-HC-85079/HC/NHLBI NIH HHS; N01-HC-85086/HC/NHLBI NIH HHS; N01AG62101/AG/NIA NIH HHS; N01AG62103/AG/NIA NIH HHS; N01AG62106/AG/NIA NIH HHS; R01 AG029364/AG/NIA NIH HHS; R01 HL084443/HL/NHLBI NIH HHS; R01 HL096875/HL/NHLBI NIH HHS; R01 HL105756/HL/NHLBI NIH HHS; R01-AG029364/AG/NIA NIH HHS; R01-AG032098/AG/NIA NIH HHS; R01AG027002/AG/NIA NIH HHS; U01 HL080295/HL/NHLBI NIH HHS; UL1 TR000423/TR/NCATS NIH HHS
Chemical
Reg. No./Substance:
0/Low Density Lipoprotein Receptor-Related Protein-2; 0/Receptors, Calcitriol; 0/Receptors, Cell Surface; 0/intrinsic factor-cobalamin receptor; 1406-16-2/Vitamin D; 64719-49-9/25-hydroxyvitamin D; EC 1.14.-/25-Hydroxyvitamin D3 1-alpha-Hydroxylase; EC 1.14.-/Steroid Hydroxylases; EC 1.14.13.126/vitamin D 24-hydroxylase
Comments/Corrections
Comment In:
JAMA. 2013 Mar 6;309(9):873   [PMID:  23462777 ]
JAMA. 2013 Mar 6;309(9):872-3   [PMID:  23462776 ]

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