Vitamin D Receptor (VDR) mRNA and VDR Protein Levels in Relation to Vitamin D Status, Insulin Secretory Capacity, and VDR Genotype in Bangladeshi Asians

Abstract

Associations have been reported between vitamin D receptor (VDR) gene polymorphisms, type 1 diabetes, insulin secretion, and the insulin resistance syndrome. As VDR polymorphisms have no known functional significance, these findings may implicate a variant of the VDR gene or a locus in linkage disequilibrium with the VDR. We have examined VDR mRNA and VDR protein levels in relation to VDR polymorphisms (41 Bangladeshi subjects) and analyzed insulin secretory capacity (143 Bangladeshi subjects), allowing for other known determinants. Peripheral blood mononuclear cells (PBMCs) from subjects who had been genotyped for BsmI, ApaI, TaqI, and FokI VDR restriction fragment length polymorphisms were used for both total VDR mRNA quantitation (using TaqMan) and measurement of VDR protein levels (using a specific microimmunoassay). Stepwise multiple regression analyses were used (to P < 0.05) to analyze the data. For the insulin secretion index, the best-fit model (n ‫؍‬ 143, P < 0.0001) gave age (P ‫؍‬ 0.002), TaqI (P < 0.0001), and BMI (P ‫؍‬ 0.001) as independent determinants; with the inclusion of VDR mRNA and VDR protein levels, VDR mRNA was the sole independent determinant (n ‫؍‬ 41, P ‫؍‬ 0.024). However, the best-fit model for VDR mRNA (P ‫؍‬ 0.004) gave FokI (P ‫؍‬ 0.044) and TaqI (P ‫؍‬ 0.04) genotypes and insulin secretory capacity (P ‫؍‬ 0.042) as independent determinants. For VDR protein levels, the best-fit model (P ‫؍‬ 0.006) gave TaqI genotype (P ‫؍‬ 0.005) and circulating 1,25-dihydroxyvitamin-D levels (P ‫؍‬ 0.03) as independent determinants. In conclusion, these studies confirm an association between VDR polymorphisms and insulin secretory capacity and demonstrate the VDR genotype to be a significant determinant of VDR mRNA and VDR protein levels in PBMCs, providing functional support to previously described genetic associations with the VDR gene. Furthermore, VDR expression has been shown to be a determinant of insulin secretory capacity. Because the VDR is expressed in a large number of tissues, it is not surprising that ligand-activated VDR modulates the expression of many genes. The VDR gene, located on chromosome 12q, has 14 exons, 6 of which are in the 5Ј untranslated region (1a-1f). At least 22 unique nonfunctional VDR variants have been described, most of which lead to rare syndromes associated with vitamin D-resistant rickets (4). A number of common chronic disorders of inflammatory, infective, and autoimmune etiologies, including both type 1 and type 2 diabetes and colorectal adenoma, have been shown to be associated with specific polymorphisms of the vitamin D receptor gene, although not all such associ-

Vitamin D Deficiency and Insulin Resistance in Normal and Type 2 Diabetes Subjects

“…The calcitriol directly activates the transcription of human Fig. 1 Comparison of the parameters in normal and type 2 diabetes subjects [35,36]. According to Ely prospective study, the baseline 25(OH)D concentration was inversely associated with glucose, IR, metabolic syndrome risk at 10 year follow up [37,38].…”

Association of vitamin D-related gene polymorphisms with manifestation of vitamin D deficiency in children

“…Individuals with VDR minor genotypes are more sensitive to vitamin D administration and exhibit low calcium absorption [31,32]. Moreover, VDR minor alleles have been reported to alter VDR function or expression [33,34]. Otherwise, VDRmediated regulation of 24-hydroxylase may be modified by altered VDR function, thereby influencing the degradation of 25(OH)D and 1,25(OH) 2 D. Taken our results together, we believe that children with VDR minor haplotype may be more influenced by vitamin D insufficiency and more likely to manifest overt rickets or hypocalcemia.…”

The role of T-cells in the pathogenesis of Type 1 diabetes: From cause to cure

“…In this regard, it is of interest that we recently described a genetic polymorphism of the vitamin D receptor with functional consequences that is associated with development of Type 1 diabetes [70]. Intriguingly, this polymorphism was shown to be associated with mRNA and protein levels of the vitamin D receptor, as well as insulin secretory capacity [71]. The active form of vitamin D3 is a potent modulator of differentiation and maturation of dendritic cells, causing redirection in anti-inflammatory dendritic cells that are capable of altering cytokine production profile of proinflammatory Th-1 autoreactive T-cells [72].…”