Association of VDR-gene variants with factors related to the metabolic syndrome, type 2 diabetes and vitamin D deficiency

Highlights

• Association was observed between MetS components and VDR gene BsmI.

• Contradictory results from FokI and BsmI in relation to T2DM

• ApaI gene related with low prevalence of Vitamin D deficiency

Abstract

The prevalence of metabolic syndrome (MetS) is rising alarmingly in the Saudi Arabian population. This study was conducted to assess the association between vitamin D receptor (VDR) polymorphisms and genetic susceptibility to components of the metabolic syndrome, type 2 diabetes mellitus (T2DM), and vitamin D deficiency in the Saudi Arabian population. Five-hundred-seventy Saudi individuals (285 MetS and 285 controls) were enrolled in this cross-sectional study. TaqI, BsmI, ApaI and FokI single nucleotide polymorphisms (SNPs) of the VDR gene were genotyped. The CT genotype and allele T of BsmI were associated with lower HDL-C levels [OR 0.60 (0.37, 0.96), p = 0.03] and obesity [OR 1.4 (1.0, 1.90), p = 0.04], respectively. The CT genotype and the dominant model CT + TT of BsmI were associated with increased risk of diabetes [OR 1.7 (1.2, 2.4), p = 0.007], and [OR 1.5 (1.1, 2.2), p = 0.01], respectively. On the contrary, the CT and CT + CC genotypes of FokI exhibited an association with a reduced risk of diabetes [OR 0.70 (0.49, 0.99), p = 0.05] and [OR 0.67 (0.48, 0.94), p = 0.02], respectively. The allele C of FokI was associated with lower risk of developing T2DM [OR 0.73 (0.56, 0.95), p = 0.02]. The prevalence of vitamin D deficiency was lower in subjects with the AC genotype of ApaI [OR, 0.34 (0.14, 0.80), p = 0.01]. Components of the MetS such as obesity, low HDL and T2DM were associated with the VDR gene. FokI and BsmI have protective and facilitative effects on the risk for T2DM, while the ApaI genotype was associated with reduced vitamin D deficiency.

Introduction

The components of metabolic syndrome (MetS) (dyslipidemia, hyperglycemia, hypertension and obesity), individually and cumulatively, increase the risk of developing T2DM and cardiovascular diseases (CVD) (Alkharfy et al., 2012). Moreover, the involvement of vitamin D in the prevalence of metabolic syndrome has also been suggested (Ford et al., 2005). The mechanism of action regarding the effect of vitamin D either includes binding of the active metabolite 1,25 (OH)₂D₃ with the cytosolic/nuclear VDR or via non-genomic pathways (Lips, 2006). Cytosolic/Nuclear VDR is a member of the steroid/thyroid hormone receptor family that functions as a transcriptional activator of many genes (Uitterlinden et al., 2004b). Polymorphisms in the VDR gene that produce variation in the activity of the VDR have been described in various populations (Valdivielso and Fernandez, 2006). Polymorphisms in the VDR gene have also been shown to be associated with the components of MetS, obesity and T2DM in different populations (Bid et al., 2009, Filus et al., 2008). In addition, increased susceptibility to type 1 diabetes has also been associated with allelic variations of the VDR gene (McDermott et al., 1997, Pani et al., 2000). Most VDR gene polymorphisms, including the BsmI, ApaI and TaqI restriction fragment length polymorphisms, are located at the 3′ untranslated region (3′ UTR) of the gene (Panierakis et al., 2009), while the FokI polymorphism, is localized within the 5′ end of the gene, near the promoter region (Uitterlinden et al., 2004b). Recently, we demonstrated co-segregation between VDR and HLA alleles in T2DM patients in the Saudi Arabian population (Al-Daghri et al., 2012a). Numerous cross-sectional studies have noted significant negative associations among circulating levels of 25-hydroxyvitamin D and cardiometabolic risk factors, highlighting potential extra skeletal functions of this sterol hormone (Al-Daghri et al., 2012b). However, there are still very limited studies that combine VDR gene polymorphisms with the components of the MetS, T2DM, and vitamin D deficiency in this part of the world.

Therefore, the aim of this study was to examine the association of four single nucleotide polymorphisms (SNPs) in intron 8 (BsmI, ApaI) exon 9 (TaqI) and exon 2 (FokI) of the VDR gene with components of MetS, T2DM, and vitamin D deficiency in the Saudi Arabian population.