Short reportInteraction between vitamin D receptor gene polymorphisms and 25-hydroxyvitamin D concentrations on metabolic and cardiovascular disease outcomes
Introduction
Vitamin D is a hormone precursor. Low vitamin D status, measured by 25-hydroxyvitamin D [25OHD], has been shown to be associated with various metabolic traits such as obesity, diabetes, cardiovascular disease (CVD) risk factors and inflammatory diseases [1], [2], [3]. Metabolic actions related to vitamin D are mediated via binding of the active hormonal form, 1,25-dihydroxyvitamin D, to its nuclear receptor. Vitamin D receptor (VDR) is ubiquitously expressed in a variety of body tissues, and hence, single nucleotide polymorphisms (SNPs) in the VDR gene may affect the risk of vitamin D-related metabolic traits, and could modify the efficacy of the receptor depending on the state of vitamin D deficiency or repletion [4].
Recently, a study in 1514 white individuals examined a range of vitamin D related variants and showed that two SNPs [rs7968585 (T→G) and rs2239179 (T→C)] in the VDR gene were able to modify the association between 25OHD concentrations and major clinical outcomes, a finding that was further replicated in a meta-analysis of three independent cohorts (n = 2727) [5]. The main outcome measure used in this previous study [5] was a composite outcome including incident hip fracture, myocardial infarction, cancer and mortality over long-term follow-up, hence providing limited insight as to the metabolic drivers of this association. In this paper, we use data from a large population-based study (n up to 5160) to examine interactions between these two VDR SNPs and 25OHD concentrations in relation to multiple metabolic traits, to evaluate whether evidence can be obtained for influences operating through an array of outcomes including obesity, blood pressure, lipids, inflammatory and diabetes related markers.
Section snippets
Study population
Study participants are from the 1958 British birth cohort (1958BC), which initially included all births in England, Scotland, and Wales during 1 week in March 1958 (n = 16,751) [6]. The main analyses were conducted in up to 5160 participants of European Ancestry with information on the two VDR SNPs, 25OHD and metabolic outcomes such as body mass index, waist circumference (WC), waist-hip ratio (WHR), high- (HDL) and low-density (LDL) lipoproteins, serum triglycerides, total cholesterol, c-reactive
Results
None of the VDR polymorphisms were associated with any of the metabolic outcomes (Table 1). After correction for multiple testing, none of the VDR SNPs showed a significant interaction with 25OHD except for the borderline interaction between the SNP rs2239179 and 25OHD concentrations on WHR (corrected P = 0.03) (Table 1). For every 1 nmol/L higher 25OHD concentrations, the association with WHR appeared stronger among those with two major ‘T’ alleles of the SNP rs2239179 (4.0% lower WHR, P = 6.26e−24
Discussion
Our study on British adults did not provide evidence for genetic variations in the VDR gene acting as major modifiers of the association between 25OHD concentrations and cardio-metabolic risk. This suggests, that the previous observations of VDR-25OHD interaction observed using a composite outcome (including incident hip fracture, myocardial infarction, cancer, and all-cause mortality), may have been driven by factors more closely related to longevity, bone metabolism/strength or cancer risk,
Disclosure of interest
The authors declare that they have no conflicts of interest concerning this article.
Acknowledgements and Funding
We thank Alana Cavadino (UCL-ICH) for assistance in preparing the dataset. We are grateful to all the participants in the 1958BC. Professor Ian Gibb, Dr Steve Turner, and Marie-Claude Fawcett (Royal Victoria Infirmary, Newcastle-upon-Tyne, UK) are acknowledged for carrying out the laboratory assays; and the Centre for Longitudinal studies, Institute of Education (original data producers) for providing the data. Research at the University College London, Institute of Child Health and Great
References (15)
- et al.
Genetics and biology of vitamin D receptor polymorphisms
Gene
(2004) - et al.
Physical (in)activity over 20 y in adulthood: associations with adult lipid levels in the 1958 British birth cohort
Atherosclerosis
(2011) - et al.
Vitamin D status and body fat measured by dual-energy X-ray absorptiometry in a general population of Japanese children
Nutrition
(2013) - et al.
Calcium and vitamin D supplementation is associated with decreased abdominal visceral adipose tissue in overweight and obese adults
Am J Clin Nutr
(2012) - et al.
Causal relationship between obesity and vitamin d status: bi-directional Mendelian randomization analysis of multiple cohorts
PLoS Med
(2013) - et al.
Decreased serum concentrations of 25-hydroxycholecalciferol are associated with increased risk of progression to impaired fasting glucose and diabetes
Diabetes Care
(2013) - et al.
Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: a meta-analysis of prospective studies
Circ Cardiovasc Qual Outcomes
(2012)
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