TY - JOUR T1 - Genetic variants and associations of 25-hydroxyvitamin D concentrations with major clinical outcomes. JF - JAMA Y1 - 2012 A1 - Levin, Gregory P A1 - Robinson-Cohen, Cassianne A1 - de Boer, Ian H A1 - Houston, Denise K A1 - Lohman, Kurt A1 - Liu, Yongmei A1 - Kritchevsky, Stephen B A1 - Cauley, Jane A A1 - Tanaka, Toshiko A1 - Ferrucci, Luigi A1 - Bandinelli, Stefania A1 - Patel, Kushang V A1 - Hagström, Emil A1 - Michaëlsson, Karl A1 - Melhus, Håkan A1 - Wang, Thomas A1 - Wolf, Myles A1 - Psaty, Bruce M A1 - Siscovick, David A1 - Kestenbaum, Bryan KW - 25-Hydroxyvitamin D3 1-alpha-Hydroxylase KW - Aged KW - Chronic Disease KW - Cohort Studies KW - Female KW - Genetic Variation KW - Genotype KW - Hip Fractures KW - Humans KW - Low Density Lipoprotein Receptor-Related Protein-2 KW - Male KW - Meta-Analysis as Topic KW - Myocardial Infarction KW - Neoplasms KW - Polymorphism, Single Nucleotide KW - Receptors, Calcitriol KW - Receptors, Cell Surface KW - Risk KW - Steroid Hydroxylases KW - Vitamin D KW - Vitamin D3 24-Hydroxylase AB -

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.

VL - 308 IS - 18 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23150009?dopt=Abstract ER -