Genetic Variations in the Vitamin D Receptor Predict Type 2 Diabetes and Myocardial Infarction in a Community-Based Population: The Tromsø Study

Abstract

BackgroundThough the associations between low serum 25-hydroxyvitamin D (25(OH)D) levels and health outcomes such as type 2 diabetes (T2D), myocardial infarction (MI), cancer, and mortality are well-studied, the effect of supplementation with vitamin D is uncertain. This may be related to genetic differences. Thus, rs7968585, a single nucleotide polymorphism (SNP) of the vitamin D receptor (VDR), has recently been reported as a predictor of composite health outcome. We therefore aimed to evaluate whether rs7968585 predicts separate clinical outcomes such as T2D, MI, cancer, and mortality in a community-based Norwegian population.Methods and FindingsMeasurements and DNA were obtained from the participants in the Tromsø Study in 1994–1995, registered with the outcomes of interest and a randomly selected control group. The impact of the rs7968585 genotypes was evaluated with Cox proportional hazards. A total of 8,461 subjects were included among whom 1,054 subjects were registered with T2D, 2,287 with MI, 3,166 with cancer, and 4,336 with death. Mean follow-up time from birth was 60.8 years for T2D and MI, 61.2 years for cancer, while mean follow-up time from examination date was 16.5 years for survival. Mean serum 25(OH)D levels did not differ across the rs7968585 genotypes. With the major homozygote genotype as reference, the minor homozygote subjects had hazard ratios of 1.25 (95% CI 1.05–1.49) for T2D and 1.14 (1.02–1.28) for MI (P = 0.011 and 0.023, respectively, without the Bonferroni correction). No significant interaction between serum 25(OH)D status and the rs7968585 genotype was found for any of the endpoints.ConclusionsThe VDR-related SNP rs7968585 minor allele is a significant and positive predictor for T2D and possibly for MI. Since the functional mechanism of this SNP is not yet understood, and the association with T2D is reported for the first time, confirmatory studies are needed.

Vitamin D pathway-related gene polymorphisms and their association with metabolic diseases: A literature review

“…Only two studies have examined the association between the VDR Cdx2 SNP and T2D (Table 2 ); one in the Italian population (n = 1,788) where individuals with ‘AA’ genotype of the SNP had 1.43 times increased risk of T2D compared to those with ‘GG + GA’ genotypes (P = .002) [ 105 ] and the other one in the Norwegian populations (n = 4,563), which failed to show an association [ 93 ]. More studies in different ethnic groups are required to understand the role of the VDR Cdx2 SNP in T2D.…”

Role of Vitamin D in Cardiovascular Diseases

“…rs7968585) could be a positive predictor for MI [58]. Further, the upregulation of endogenous VDR expression in the mouse heart after the myocardial ischemia/reperfusion by natural and synthetic agonists and reduction in the myocardial infarct size with improved cardiac function suggest the protective role of upregulated VDR.…”

Effect of Calcium‑Vitamin D Co‑Supplementation on Insulin, Insulin Sensitivity, and Glycemia: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

“…The hypothesis of the possible association between diabetes and hypovitaminosis D was supported by detection of the nuclear receptor of vitamin D (VDR) in β-cells of the pancreas [11]. Polymorphism of VDR was associated with changes in insulin sensitivity and secretion, indicating vitamin D involvement in the pathogenesis of both types of diabetes [12,13]. Since then, numerous randomized clinical trials (RCTs) have been conducted to confirm or reject the beneficial effects of vitamin D supplementation in patients with diabetes, however, the results were controversial [14,15].…”