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Genetic variants and associations of 25-hydroxyvitamin D concentrations with major clinical outcomes
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2012 (English)In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 308, no 18, 1898-1905 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2012. Vol. 308, no 18, 1898-1905 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-186192DOI: 10.1001/jama.2012.17304ISI: 000310952700026OAI: oai:DiVA.org:uu-186192DiVA: diva2:572847
Available from: 2012-11-29 Created: 2012-11-28 Last updated: 2014-10-15Bibliographically approved

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Hagström, EmilMichaëlsson, KarlMelhus, Håkan
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