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Original Contribution
November 14, 2012

Genetic Variants and Associations of 25-Hydroxyvitamin D Concentrations With Major Clinical Outcomes

Author Affiliations

Author Affiliations: Departments of Biostatistics (Dr Levin), Epidemiology (Drs Robinson-Cohen, de Boer, Psaty, Siscovick, and Kestenbaum), Medicine (Drs de Boer, Psaty, Siscovick, and Kestenbaum), and Anasthesiology and Pain Medicine (Dr Patel), Division of Nephrology and Kidney Research Institute (Drs de Boer and Kestenbaum), Center for Pain Research on Impact, Measurement, and Effectiveness (Dr Patel), Cardiovascular Health Research Unit (Drs Psaty and Siscovick), Group Health Research Institute and Cooperative (Dr Psaty), University of Washington, Seattle; Departments of Internal Medicine (Drs Houston and Kritchevsky), Biostatistical Sciences (Mr Lohman), and Epidemiology and Prevention (Dr Liu), Division of Public Health Sciences (Mr Lohman and Dr Liu), School of Medicine (Drs Houston and Kritchevsky and Mr Lohman), Wake Forest University, Winston-Salem, North Carolina; Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania (Dr Cauley); Clinical Research Branch, National Institute on Aging, Baltimore, Maryland (Drs Tanaka and Ferrucci); Geriatric Unit, Azienda Sanitaria Firenze, Florence, Italy (Dr Bandinelli); Departments of Medical Sciences (Drs Hagström and Melhus) and Surgical Sciences (Dr Michaëlsson), Uppsala University, Uppsala, Sweden; Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (Dr Wang); and Miller School of Medicine, University of Miami, Miami, Florida (Dr Wolf).

JAMA. 2012;308(18):1898-1905. doi:10.1001/jama.2012.17304

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.