Elsevier

Diabetes & Metabolism

Volume 40, Issue 5, November 2014, Pages 386-389
Diabetes & Metabolism

Short report
Interaction between vitamin D receptor gene polymorphisms and 25-hydroxyvitamin D concentrations on metabolic and cardiovascular disease outcomes

https://doi.org/10.1016/j.diabet.2014.01.003Get rights and content

Abstract

Aim

25-hydroxyvitamin D (25OHD) concentrations have been shown to be associated with major clinical outcomes, with a suggestion that individual risk may vary according to common genetic differences in the vitamin D receptor (VDR) gene. Hence, we tested for the interactions between two previously studied VDR polymorphisms and 25OHD on metabolic and cardiovascular disease-related outcomes in a large population-based study.

Methods

Interactions between two previously studied VDR polymorphisms (rs7968585 and rs2239179) and 25OHD concentrations on metabolic and cardiovascular disease-related outcomes such as obesity- (body mass index, waist circumference, waist-hip ratio (WHR)), cardiovascular- (systolic and diastolic blood pressure), lipid- (high- and low-density lipoprotein, triglycerides, total cholesterol), inflammatory- (C-reactive protein, fibrinogen, insulin growth factor-1, tissue plasminogen activator) and diabetes- (glycated haemoglobin) related markers were examined in the 1958 British Birth cohort (n up to 5160). Interactions between each SNP and 25OHD concentrations were assessed using linear regression and the likelihood ratio test.

Results

After Bonferroni correction, none of the interactions reached statistical significance except for the interaction between the VDR SNP rs2239179 and 25OHD concentrations on waist-hip ratio (WHR) (P = 0.03). For every 1 nmol/L higher 25OHD concentrations, the association with WHR was stronger among those with two major alleles (−4.0%, P = 6.26e−24) compared to those with either one or no major alleles (−2.3%, P  8.201e−07, for both) of the VDR SNP rs2239179.

Conclusion

We found no evidence for VDR polymorphisms acting as major modifiers of the association between 25OHD concentrations and cardio-metabolic risk. Interaction between VDR SNP rs2239179 and 25OHD on WHR warrants further confirmation.

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)

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