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

Abstract

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.

Vitamin D and Cardiovascular Disease

“…162,163 The importance of this confounding has been highlighted in gene association studies. Although a large study suggested that a variant within the VDR gene (rs7968585) increased the composite risk of outcomes, which included myocardial infarction, 164 a recent Mendelian randomization study failed to demonstrate any consistent relationship between various genetic variants associated 25(OH)D metabolism and cardiovascular outcomes. 16 This raises important questions concerning the role of vitamin D deficiency in the causal pathway of CVD, although the role of variants in VDR and other components of vitamin D signaling has not been extensively investigated.…”

Vitamin D Deficiency and Cardiovascular Disease: Potential Mechanisms and Novel Perspectives

“…Although Jorde et al (77) found no association between their investigated SNPs and myocardial infarction (among other outcomes), Levin et al (78) found that variations in the VDR gene may alter the association of 25(OH)D with major clinical outcomes, including myocardial infarction. While results of both studies were heavily supported by a large cohort size, their applicability to other populations is questionable on the basis that one study was confined to elderly white adults (78), whereas the other took place in Norway (77), the population of which does not possess a significantly lower 25(OH)D level compared to the rest of west Europe despite its latitude, and thus does not represent a vitamin D-depleted population. Nevertheless, it is abundantly clear that large-scale studies investigating different populations are warranted since SNPs in CYP2R1, CYP27B1 and DHCR7 have been associated with type 1 diabetes (79), warranting further investigations on diseases not covered by the previously conducted studies.…”

MANAGEMENT OF ENDOCRINE DISEASE: Value and limitations of assessing vitamin D nutritional status and advised levels of vitamin D supplementation

“…In this context, it is important to note that a recent study has demonstrated the association between bone mineral density (BMD) and levels of free 25(OH)D but not total circulating values of the vitamin (46). Along these lines, a recent longitudinal study showed that the known associations of low 25(OH)D concentrations with clinical outcome are related to common genetic differences in the vitamin D receptor (47).…”