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

Study Questions:

Are associations of between vitamin D concentrations and outcomes affected by gene variants affecting vitamin D metabolism?

Methods:

A total of 141 single nucleotide polymorphisms (SNPs) were analyzed in a cohort of 1,514 white participants from the community-based Cardiovascular Health Study. Participants had serum 25-hydroxyvitamin D measurements in 1992 and were followed up for a median of 11 years. Replication meta-analyses were conducted across the independent, community-based US Health, Aging, and Body Composition (n = 922; follow-up: 1998-2005), Italian Invecchiare in Chianti (n = 835; follow-up: 1998-2006), and Swedish Uppsala Longitudinal Study of Adult Men (n = 970; follow-up: 1991-2008) cohort studies. Composite outcome of incident hip fracture, myocardial infarction, cancer, and mortality over long-term follow-up was determined.

Results:

Interactions between five SNPs and low 25-hydroxyvitamin D concentration were identified in the discovery phase and one 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 for those who had one minor allele at rs7968585 and 1.82 for those with two minor alleles at rs7968585. In contrast, there was no evidence of an association (hazard ratio, 0.93) among participants who had 0 minor alleles at this SNP.

Conclusions:

Known associations of low 25-hydroxyvitamin D with major health outcomes may vary according to common genetic differences in the vitamin D receptor.

Perspective:

The relationship between low 25-hydroxyvitamin D serum concentrations and a variety of adverse clinical outcomes is controversial. It may be that the relationship is complex and affected by other factors. This study suggests that patients might be stratified, on the basis of genetic testing, for susceptibility to low vitamin D-related complications. In addition to confirming these intriguing findings, it will be helpful to understand how genetic variation in the vitamin D receptor affects susceptibility to vitamin D deficiency.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Genetic Variation, Risk, Myocardial Infarction, Neoplasms, Follow-Up Studies, European Continental Ancestry Group, Genetic Testing, Heart Diseases, Vitamin D Deficiency, Polymorphism, Genetic, Biological Markers, Heart Failure, Vitamin D


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