Genetic Variants and Associations of 25-Hydroxyvitamin D Concentrations With Major Clinical Outcomes
JAMA. 2012;308(18):1898-1905. doi:10.1001/jama.2012.17304.
Gregory P. Levin, PhD; Cassianne Robinson-Cohen, PhD; Ian H. de Boer, MD, MS; Denise K. Houston, PhD; Kurt Lohman, MS; Yongmei Liu, PhD; Stephen B. Kritchevsky, PhD; Jane A. Cauley, DrPh; Toshiko Tanaka, PhD; Luigi Ferrucci, MD, PhD; Stefania Bandinelli, MD; Kushang V. Patel, PhD, MPH; Emil Hagström, MD, PhD; Karl Michaëlsson, MD, PhD; Håkan Melhus, MD, PhD; Thomas Wang, MD; Myles Wolf, MD, MMSc; Bruce M. Psaty, MD, PhD; David Siscovick, MD, MPH; Bryan Kestenbaum, MD, MS
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,
- 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.
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