Abstract
Vitamin D plays an important role in bone metabolism and pathology. Although the VDR gene is one of the most studied determinants of bone mineral density (BMD) and osteoporosis (OP), its exact effects have yet to be established. Prediction of OP and/or fracture risk, based on individual genetic profile, is of high importance. The aim of our study was to develop prognostic model for postmenopausal OP individual risk evaluation in Belarusian women, based on the analysis of VDR gene variants. Case group included women with postmenopausal OP (n = 350), the control group comprised of women with normal BMD and without previous fragility fractures (n = 243). VDR gene ApaI rs7975232, BsmI rs1544410, TaqI rs731236, FokI rs2228570 and Cdx2 rs11568820 variants were determined using TaqMan genotyping assays. We revealed a significant association of single ApaI A/A (p = 0.045), BsmI T/T (p = 0.015) and TaqI G/G (p = 0.005) variants and their A-T-G-haplotype (OR = 4.6, p = 0.003) with increased OP risk. Together with Cdx2 rs11568820, these variants correlated with BMD (p <0.05 in all cases). For the bearers of non-favorable alleles of VDR gene variants, the serum 25(OH)D level was significantly increased. The constructed from informative VDR gene variants model of individual OP risk evaluation possessed a good prognostic value (AUC = 0.79) with high sensitivity level (82.9 %) and average specificity (69.4 %). Our findings highlight the importance of analyzed VDR gene variants for personalized OP risk prediction.
Highlights
Vitamin D is a secosteroid hormone that implements its numerous cellular effects by initiating transcription of vitamin D-dependent genes
Studies of the last two decades have established that diverse biological effects of the active metabolite of vitamin D-1.25-dihydroxyvitamin D are carried out by modulating the expression of genes that are mediated by interaction with the intracellular vitamin D receptor (VDR) [1]
By binding to VDR, which is present in all types of bone cells – osteoblasts, osteocytes and osteoclasts, calcitriol has a direct effect on bone metabolism [1]
Summary
Vitamin D is a secosteroid hormone that implements its numerous cellular effects by initiating transcription of vitamin D-dependent genes. Activation of VDR through direct interaction with 1.25(OH)2D causes fast binding of the receptor to the regulatory regions of target genes, which initiates the transcription and synthesis of new mRNA molecules, translation of mRNA, synthesis of new proteins and the implementation of specific biological reactions. These reactions are specific to various tissues and range from very complex mechanisms necessary for homeostatic control of mineral metabolism to focal effects that regulate growth, differentiation, proliferation, apoptosis, adaptive and innate immune responses, and the functional activity of many types of cells [2]. By binding to VDR, which is present in all types of bone cells – osteoblasts, osteocytes and osteoclasts, calcitriol has a direct effect on bone metabolism [1]
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