%0 Journal Article %J JAMA %D 2012 %T Genetic variants and associations of 25-hydroxyvitamin D concentrations with major clinical outcomes. %A Levin, Gregory P %A Robinson-Cohen, Cassianne %A de Boer, Ian H %A Houston, Denise K %A Lohman, Kurt %A Liu, Yongmei %A Kritchevsky, Stephen B %A Cauley, Jane A %A Tanaka, Toshiko %A Ferrucci, Luigi %A Bandinelli, Stefania %A Patel, Kushang V %A Hagström, Emil %A Michaëlsson, Karl %A Melhus, Håkan %A Wang, Thomas %A Wolf, Myles %A Psaty, Bruce M %A Siscovick, David %A Kestenbaum, Bryan %K 25-Hydroxyvitamin D3 1-alpha-Hydroxylase %K Aged %K Chronic Disease %K Cohort Studies %K Female %K Genetic Variation %K Genotype %K Hip Fractures %K Humans %K Low Density Lipoprotein Receptor-Related Protein-2 %K Male %K Meta-Analysis as Topic %K Myocardial Infarction %K Neoplasms %K Polymorphism, Single Nucleotide %K Receptors, Calcitriol %K Receptors, Cell Surface %K Risk %K Steroid Hydroxylases %K Vitamin D %K Vitamin D3 24-Hydroxylase %X

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.

%B JAMA %V 308 %P 1898-905 %8 2012 Nov 14 %G eng %N 18 %1 http://www.ncbi.nlm.nih.gov/pubmed/23150009?dopt=Abstract %R 10.1001/jama.2012.17304