The Association of Vitamin D Receptor Polymorphisms with Multiple Sclerosis in a Case-Control Study from Kuwait

Vitamin D deficiency is associated with several diseases including multiple sclerosis (MS). Several factors influence vitamin D levels and its optimal multi-function maintenance. Our objective was to assess quantifiable variables influencing vitamin D level and metabolism in MS patients from Kuwait. In a case-control study involving 50 MS patients, and 50 healthy control individuals for which plasma vitamin D levels, supplement use, vitamin D receptor (VDR) variants, and skin pigmentation indices were ascertained; we found overall vitamin D levels to be deficient in both groups, and supplement use to be common practice. VDR variants TaqI and BsmI associated with MS risk, and ApaI associated with low disease progression. VDR variant FokI associated with higher vitamin D levels in both groups. We conclude that several quantifiable variables related to vitamin D associate with MS suggesting a possible clinical immuno-modulatory application of vitamin D for MS patients in Kuwait.     

Novel Vitamin D Receptor Mutations in Hereditary Vitamin D Resistant Rickets in Chinese

Hereditary 1, 25-dihydroxyvitamin D-resistant rickets (HVDRR), a rare recessive disease, is caused by mutation in the VDR gene encoding the vitamin D receptor leading to the resistance to vitamin D. We described a female toddler with initial presentation of leg tenderness and clinical features of HVDRR including severe rickets, hypocalcemia and hypophosphatemia without alopecia. Genetic analysis revealed novel compound heterozygous mutations of p.M4I and p.H229Q in patient’s VDR gene. In cis p.M4I with FOKI-F eliminated both translation start sites of the VDR protein. The p.H229Q VDR exhibited significantly reduced VDR transactivation activity with intact dimerization with RXR. Our report expanded the mutation spectrum of HVDRR, and provided the first case of a benign variant p.M4I plus a common p.M1T polymorphism leading to a pathogenic allele.     

Inactivation of the 25-hydroxyvitamin D 1alpha-hydroxylase and vitamin D receptor demonstrates independent and interdependent effects of calcium and vitamin D on skeletal and mineral homeostasis

We employed a genetic approach to determine whether deficiency of 1,25-dihydroxyvitamin D (1,25(OH)2D) and deficiency of the vitamin D receptor (VDR) produce the same alterations in skeletal and calcium homeostasis and whether calcium can subserve the skeletal functions of 1,25(OH)2D and the VDR. Mice with targeted deletion of the 25-hydroxyvitamin D 1alpha-hydroxylase (1alpha(OH)ase-/-) gene, the VDR gene, and both genes were exposed to 1) a high calcium intake, which maintained fertility but left mice hypocalcemic; 2) this intake plus three times weekly injections of 1,25(OH)2D3, which normalized calcium in the 1alpha(OH)ase-/- mice only; or 3) a "rescue" diet, which normalized calcium in all mutants. These regimens induced different phenotypic changes, thereby disclosing selective modulation by calcium and the vitamin D system. Parathyroid gland size and the development of the cartilaginous growth plate were each regulated by calcium and by 1,25(OH)2D3 but independent of the VDR. Parathyroid hormone secretion and mineralization of bone reflected ambient calcium levels rather than the 1,25(OH)2D/VDR system. In contrast, increased calcium absorption and optimal osteoblastogenesis and osteoclastogenesis were modulated by the 1,25(OH)2D/VDR system. These studies indicate that the calcium ion and the 1,25(OH)2D/VDR system exert discrete effects on skeletal and calcium homeostasis, which may occur coordinately or independently.     

Genetics and biology of vitamin D receptor polymorphisms

The vitamin D endocrine system is involved in a wide variety of biological processes including bone metabolism, modulation of the immune response, and regulation of cell proliferation and differentiation. Variations in this endocrine system have, thus, been linked to several common diseases, including osteoarthritis (OA), diabetes, cancer, cardiovascular disease, and tuberculosis. Evidence to support this pleiotropic character of vitamin D has included epidemiological studies on circulating vitamin D hormone levels, but also genetic epidemiological studies. Genetic studies provide excellent opportunities to link molecular insights with epidemiological data and have therefore gained much interest. DNA sequence variations, which occur frequently in the population, are referred to as "polymorphisms" and can have modest and subtle but true biological effects. Their abundance in the human genome as well as their high frequencies in the human population have made them targets to explain variation in risk of common diseases. Recent studies have indicated many polymorphisms to exist in the vitamin D receptor (VDR) gene, but the influence of VDR gene polymorphisms on VDR protein function and signaling is largely unknown. So far, three adjacent restriction fragment length polymorphisms for BsmI, ApaI, and TaqI, respectively, at the 3' end of the VDR gene have been the most frequently studied. Because these polymorphisms are probably nonfunctional, linkage disequilibrium with one or more truly functional polymorphisms elsewhere in the VDR gene is assumed to explain the associations observed. Research is therefore focussed on documenting additional polymorphisms across the VDR gene to verify this hypothesis and on trying to understand the functional consequences of the variations. Substantial progress has been made that will deepen our understanding of variability in the vitamin D endocrine system and might find applications in risk assessment of disease and in predicting response-to-treatment.     

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

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.     

Genetic variation in the vitamin D receptor gene and vitamin D serum levels in Egyptian women with polycystic ovary syndrome

Obesity, insulin resistance, and hyperandrogenism are considered crucial parameters of polycystic ovary syndrome (PCOS) which might be related to vitamin D metabolism. The aim of this study was to investigate the associations between polymorphisms (TaqI and ApaI) in the vitamin D receptor gene (VDR) and PCOS among Egyptian women. We aimed also to elucidate the impact of these polymorphisms on vitamin D level, hormonal and metabolic parameters of PCOS. One hundred and fifty Egyptian women with PCOS and 150 unrelated controls were enrolled in this study. Polymorphisms of VDR Taq-I T/C (rs731236) and Apa-I A/C (rs7975232) gene were genotyped using polymerase chain reaction restriction fragment length polymorphism (PCR–RFLP). Serum 25 hydroxy vitamin D [25(OH) D] levels were measured by high-performance liquid chromatography. PCOS women had significantly lower levels of 25(OH) D compared to healthy women. Our results revealed that Taq-I CC genotype and C allele were associated with increased risk of PCOS, while the Apa-I polymorphism was not. Haplotype Taq-I C/ Apa-I C was associated with a higher PCOS risk more than controls. Moreover, there was a significant decrease of 25(OH) D levels in carriers of haplotype Taq-I C/ Apa-I C (with variant alleles) compared to the non-carriers. Results showed also that there was an obesity- VDR Taq-I genotypes interactions. These results suggested that, VDR Taq-I gene polymorphism is associated with increased risk of PCOS in Egyptian women.     

Vitamin D status and vitamin D receptor gene polymorphisms and susceptibility to type 1 diabetes in Egyptian children

Background

Type 1 diabetes mellitus (T1DM) is recognized as a T-cell-mediated autoimmune disease. Vitamin D compounds are known to suppress T-cell activation by binding to vitamin D receptor (VDR); and thus, VDR gene polymorphisms may be related to T-cell-mediated autoimmune diseases. The aim of this study was to investigate the association between vitamin D status and VDR gene polymorphisms and T1DM.

Materials and methods

One hundred and twenty patients with T1DM and one hundred and twenty controls were enrolled in the study. VDR gene BsmI, FokI, ApaI and TaqI polymorphisms were determined using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Serum 25-hydroxyvitamin D (25(OH)D) was determined using ELISA.

Result

Serum 25(OH)D levels revealed a vitamin D deficiency or insufficiency in 75% of the patients. The mean levels of vitamin D were significantly lower in patients as compared to their controls (P = < 0.001). VDR BsmI Bb and bb genotypes and VDR FokI Ff and ff genotypes were associated with increased risk of T1DM (OR = 2.3, 95% CI = 1.3–4.2, P = 0.005; OR = 2.2, 95% CI = 1.1–4.7, P = 0.04; OR = 1.8, 95% CI = 1.03–3.04, P = 0.04; OR = 4.03, 95% CI = 1.2–13.1, P = 0.01 respectively), while the VDR ApaI and TaqI polymorphisms were not.

Conclusion

Our study indicated that vitamin D deficiency and VDR BsmI and FokI polymorphisms were associated with T1DM in Egyptian children.     

Vitamin D Receptor Gene Expression and Function in a South African Population: Ethnicity,Vitamin D and FokI

Polymorphisms of the vitamin D receptor gene (VDR) have been associated inconsistently with various diseases, across populations of diverse origin. The T(f) allele of the functional SNP FokI, in exon 2 of VDR, results in a longer vitamin D receptor protein (VDR) isoform, proposed to be less active. Genetic association of VDR with disease is likely confounded by ethnicity and environmental factors such as plasma 25(OH)D₃ status. We hypothesized that VDR expression, VDR level and transactivation of target genes, CAMP and CYP24A1, depend on vitamin D, ethnicity and FokI genotype. Healthy volunteers participated in the study (African, n = 40 and White, n = 20). Plasma 25(OH)D₃ levels were quantified by LC-MS and monocytes cultured, with or without 1,25(OH)₂D₃. Gene expression and protein level was quantified using qRT-PCR and flow cytometry, respectively. Mean plasma 25(OH)D₃ status was normal and not significantly different between ethnicities. Neither 25(OH)D₃ status nor 1,25(OH)₂D₃ supplementation significantly influenced expression or level of VDR. Africans had significantly higher mean VDR protein levels (P<0.050), nonetheless transactivated less CAMP expression than Whites. Genotyping the FokI polymorphism by pyrosequencing together with HapMap data, showed a significantly higher (P<0.050) frequency of the CC genotype in Africans than in Whites. FokI genotype, however, did not influence VDR expression or VDR level, but influenced overall transactivation of CAMP and 1,25(OH)₂D₃-elicited CYP24A1 induction; the latter, interacting with ethnicity. In conclusion, differential VDR expression relates to ethnicity, rather than 25(OH)D₃ status and FokI genotype. Instead, VDR transactivation of CAMP is influenced by FokI genotype and, together with ethnicity, influence 1,25(OH)₂D₃-elicited CYP24A1 expression. Thus, the expression and role of VDR to transactivate target genes is determined not only by genetics, but also by ethnicity and environment involving complex interactions which may confound disease association.     

Genetic variations in VDR associated with prostate cancer risk and progression in a Korean population

Low levels of vitamin D are implicated as a potential risk factor for prostate cancer, and the vitamin D receptor (VDR) gene may be important in the onset and progression of prostate cancer. In this study, sequence variants in the VDR gene were investigated in a Korean study cohort to determine whether they are associated with prostate cancer risk. We evaluated the association between 47 single nucleotide polymorphisms (SNPs) in the VDR gene and prostate cancer risk as well as clinical characteristics (prostate-specific antigen level, clinical stage, pathological stage and Gleason score) in Korean men (272 prostate cancer patients and 173 benign prostatic hyperplasia patient who underwent a prostate biopsy, which was negative for malignancy) using unconditional logistic regression. The statistical analysis suggested that two VDR sequence variants (rs2408876 and rs2239182) had a significant association with prostate cancer risk (odds ratio [OR]. 1.41; p = 0.03; OR, 0.73; p = 0.05, respectively). Logistic analyses of the VDR polymorphisms with several prostate cancer related factors showed that several SNPs were significant; nine SNPs to PSA level, three to clinical stage, two to pathological stage, and three SNPs to the Gleason score. The results suggest that some VDR gene polymorphisms in Korean men might not only be associated with prostate cancer risk but also significantly related to prostate cancer-related risk factors such as PSA level, tumor stage, and Gleason score. However, current limitation for small cohort with not-healthy control group might have false positive effects; therefore it should be overcome via further large-scale validating studies.