TY - JOUR
T1 - Genetic variants and associations of 25-hydroxyvitamin D concentrations with major clinical outcomes
AU - Levin, Gregory P.
AU - Robinson-Cohen, Cassianne
AU - De Boer, Ian H.
AU - Houston, Denise K.
AU - Lohman, Kurt
AU - Liu, Yongmei
AU - Kritchevsky, Stephen B.
AU - Cauley, Jane A.
AU - Tanaka, Toshiko
AU - Ferrucci, Luigi
AU - Bandinelli, Stefania
AU - Patel, Kushang V.
AU - Hagström, Emil
AU - Michaëlsson, Karl
AU - Melhus, Håkan
AU - Wang, Thomas
AU - Wolf, Myles
AU - Psaty, Bruce M.
AU - Siscovick, David
AU - Kestenbaum, Bryan
PY - 2012/11/14
Y1 - 2012/11/14
N2 - 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.
AB - 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.
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U2 - 10.1001/jama.2012.17304
DO - 10.1001/jama.2012.17304
M3 - Article
C2 - 23150009
AN - SCOPUS:84868658828
SN - 0098-7484
VL - 308
SP - 1898
EP - 1905
JO - Journal of the American Medical Association
JF - Journal of the American Medical Association
IS - 18
ER -