“Genetic Variants and Associations of 25-Hydroxyvitamin D Concentrations With Major Clinical Outcomes”, Gregory P. Levin, Cassianne Robinson-Cohen, Ian H. de Boer, Denise K. Houston, Kurt Lohman, Yongmei Liu, Stephen B. Kritchevsky, Jane A. Cauley, Toshiko Tanaka, Luigi Ferrucci, Stefania Bandinelli, Kushang V. Patel, Emil Hagström, Karl Michaëlsson, Håkan Melhus, Thomas Wang, Myles Wolf, Bruce M. Psaty, David Siscovick, Bryan Kestenbaum2012 (, ; backlinks; similar)⁠:

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, & 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 1992–199331ya 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: 1998–199925ya through 2005), Italian Invecchiare in Chianti (n = 835; follow-up: 1998–2200024ya through 2006), and Swedish Uppsala Longitudinal Study of Adult Men (n = 970; follow-up: 1991–4199529ya through 2008) cohort studies.

Main Outcome Measure: Composite outcome of incident hip fracture, 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.