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Genetic variants and associations of 25-hydroxyvitamin D concentrations with major clinical outcomes

Levin, GP and Robinson-Cohen, C and De Boer, IH and Houston, DK and Lohman, K and Liu, Y and Kritchevsky, SB and Cauley, JA and Tanaka, T and Ferrucci, L and Bandinelli, S and Patel, KV and Hagström, E and Michaëlsson, K and Melhus, H and Wang, T and Wolf, M and Psaty, BM and Siscovick, D and Kestenbaum, B (2012) Genetic variants and associations of 25-hydroxyvitamin D concentrations with major clinical outcomes. JAMA - Journal of the American Medical Association, 308 (18). 1898 - 1905. ISSN 0098-7484

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Context: Lower serum 25-hydroxyvitaminDconcentrations are associatedwith 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 OutcomeMeasure: 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. ©2012 American Medical Association. All rights reserved.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Levin, GP
Robinson-Cohen, C
De Boer, IH
Houston, DK
Lohman, K
Liu, Y
Kritchevsky, SB
Cauley, JAJCauley@edc.pitt.eduJCAULEY
Tanaka, T
Ferrucci, L
Bandinelli, S
Patel, KV
Hagström, E
Michaëlsson, K
Melhus, H
Wang, T
Wolf, M
Psaty, BM
Siscovick, D
Kestenbaum, B
Date: 14 November 2012
Date Type: Publication
Journal or Publication Title: JAMA - Journal of the American Medical Association
Volume: 308
Number: 18
Page Range: 1898 - 1905
DOI or Unique Handle: 10.1001/jama.2012.17304
Schools and Programs: Graduate School of Public Health > Epidemiology
Refereed: Yes
ISSN: 0098-7484
Date Deposited: 03 Apr 2015 00:58
Last Modified: 25 Jan 2019 22:55


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