04322nas a2200625 4500008004100000022001400041245010600055210006900161260001600230300001300246490000800259520250400267653004502771653000902816653002002825653001902845653001102864653002202875653001302897653001802910653001102928653005502939653000902994653002703003653002603030653001403056653003603070653002603106653002803132653000903160653002503169653001403194653003003208100002203238700003003260700002003290700002303310700001703333700001703350700002803367700002003395700002003415700002003435700002503455700002203480700002003502700002303522700001903545700001703564700001603581700002003597700002103617700002203638856003603660 2012 eng d a1538-359800aGenetic variants and associations of 25-hydroxyvitamin D concentrations with major clinical outcomes.0 aGenetic variants and associations of 25hydroxyvitamin D concentr c2012 Nov 14 a1898-9050 v3083 a
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.
10a25-Hydroxyvitamin D3 1-alpha-Hydroxylase10aAged10aChronic Disease10aCohort Studies10aFemale10aGenetic Variation10aGenotype10aHip Fractures10aHumans10aLow Density Lipoprotein Receptor-Related Protein-210aMale10aMeta-Analysis as Topic10aMyocardial Infarction10aNeoplasms10aPolymorphism, Single Nucleotide10aReceptors, Calcitriol10aReceptors, Cell Surface10aRisk10aSteroid Hydroxylases10aVitamin D10aVitamin D3 24-Hydroxylase1 aLevin, Gregory, P1 aRobinson-Cohen, Cassianne1 ade Boer, Ian, H1 aHouston, Denise, K1 aLohman, Kurt1 aLiu, Yongmei1 aKritchevsky, Stephen, B1 aCauley, Jane, A1 aTanaka, Toshiko1 aFerrucci, Luigi1 aBandinelli, Stefania1 aPatel, Kushang, V1 aHagström, Emil1 aMichaëlsson, Karl1 aMelhus, Håkan1 aWang, Thomas1 aWolf, Myles1 aPsaty, Bruce, M1 aSiscovick, David1 aKestenbaum, Bryan uhttps://chs-nhlbi.org/node/1554