Research ArticleA vitamin D pathway gene–gene interaction affects low-density lipoprotein cholesterol levels
Introduction
Many studies have associated vitamin D deficiency with an increased risk of developing chronic diseases [1], [2], [3], [4]. Among these diseases, obesity has been investigated extensively, mainly because it has reached epidemic proportions around the world. Studies investigating the relation between obesity and hypovitaminosis D have increased substantially in recent years [5]. Several reports have demonstrated that blood vitamin D levels are decreased in obese individuals [6], [7], [8]. Likewise, plasma levels of this vitamin are inversely correlated to an atherogenic lipid profile [9], [10], [11].
Vitamin D, a soluble steroid hormone, can be obtained from food sources as vitamin D3 (cholecalciferol) or converted from 7-dehydrocholesterol (7DHC) in the skin upon ultraviolet B (UVB) radiation exposure. After being absorbed or synthesized, vitamin D3 binds to the vitamin D-binding protein (DBP) and is transported through the bloodstream to the liver, where it is converted into 25(OH)D (calcidiol), the main circulating form of vitamin D [12], [13]. Calcidiol is biologically inactive and is converted, mainly in the kidneys, into the biologically active form 1,25(OH)2D (calcitriol), which binds to the vitamin D receptor (VDR) [12], [14]. Then, VDR heterodimerizes with the retinoid X receptor gamma (RXRG). This complex binds to DNA at the vitamin D response element, controlling the expression of many genes related to skeletal muscle and calcium metabolism, as well as cell proliferation [12], [15].
Although genetic factors are important in the etiology of obesity and its associated phenotypes, the role of the vitamin D pathway gene variants is poorly investigated, and anthropometric measurements and lipid profile analyses have not been carried out. Most previous studies have focused on the vitamin D receptor gene (VDR) and obesity [16], [17], [18], although there are some reports of associations between the retinoid X receptor gamma gene (RXRG) and lipid and anthropometric parameters [19]. The vitamin D-binding protein gene (GC), which codes for DBP, has been associated with body-fat percentage [20] and obesity [13]. Several other studies, including two genome-wide association studies, have detected associations between GC polymorphisms and circulating levels of vitamin D [13], [21], [22], [23], [24].
Considering the importance of the VDR, RXRG and DBP proteins in the vitamin D pathway, as well as the association of this vitamin with obesity phenotypes, in this study, we sought to (1) investigate the association between polymorphisms in VDR (rs2228570), RXRG (rs2134095) and GC (rs7041) with lipid profile and anthropometric measurements in adult individuals; (2) test the effect of gene–gene interactions on these measurements; and (3) evaluate, in silico, the functionality of these polymorphisms.
Section snippets
Participants
The sample was composed of 542 white Brazilian European-descent individuals (median age=24, minimum=18, maximum=66) recruited at Centro Universitário UNIVATES, an institution located in Southern Brazil. Therefore, this sample group is representative of an academic community (comprised by undergraduate and graduate students, employees and professors). Since this region is characterized by a German and Italian colonization, genetic admixture analyses have shown that the proportion of European
Results
The clinical characteristics and allelic and genotypic frequencies are shown in Table 1. Genotypic frequencies of the rs2228570 (VDR), rs2134095 (RXRG) and rs7041 (GC) polymorphisms are in agreement with Hardy–Weinberg equilibrium.
A comparison of the anthropometric and lipid parameters between the genotypes is shown in Table 2. No significant effect was observed for the analyzed measurements for any of the polymorphisms investigated.
Discussion
The aim of this study was to investigate the association between the rs2228570 (VDR), rs2134095 (RXRG) and rs7041 (GC) polymorphisms with the anthropometric and lipid parameters related to obesity. No significant main effect of the polymorphisms was observed for the evaluated outcomes. On the other hand, gene–gene interaction analyses indicated a significant interaction between the RXRG and GC gene variants and LDL-c levels. Moreover, our in silico analysis suggested a putative functional role
Acknowledgements
The authors would like to thank the Ambulatório de Nutrição from the Centro Universitário UNIVATES, for help with the sample collection, and FAPERGS and FUVATES, for financial support.
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