Vitamin D Receptor BsmI Research Articles

Vitamin D receptor (VDR) mRNA and VDR protein levels in relation to vitamin D status, insulin secretory capacity, and VDR genotype in Bangladeshi Asians.

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 micro-immunoassay). 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.

Relationship among VDR (BsmI and FokI), COLIA1, and CTR polymorphisms with bone mass, bone turnover markers, and sex hormones in men.

Osteoporosis is a disease characterized by low bone mineral density (BMD) and up to 80% of its variance is under genetic control. Although osteoporosis is more frequent in women, one-third of hip fractures also occur in men. Much information on genetic factors and bone density has been obtained in women, but only a few studies have been performed in osteoporotic men. We have evaluated the relationship between polymorphisms for several candidate genes such as vitamin D receptor (VDR), collagen type Ia1 (COLIA1), and calcitonin receptor (CTR) in a sample of unrelated Italian men (n = 253, mean age 58.41 +/- 15.64 SD). We found no significant differences in BMD when subjects were stratified for their VDR (BsmI and FokI) and COLIA1 genotypes. BMD both at the lumbar spine and at the femoral neck were associated with polymorphism of CTR gene. The CC genotype of CTR gene had the lowest BMD value (P <0.05 and P <0.01 at the spine and hip, respectively) and its prevalence was significantly over-represented in the subgroup of men with prior hip or vertebral fracture as compared with controls (P = 0.004% c2 = 11.10). The men with the CC genotype also showed significantly lower body mass index (BMI), serum sex hormone binding globulin (SHBG), estradiol, total alkaline phosphatase-(total AP) and bone alkaline phosphatase (bone AP) levels and significantly higher free androgen index (FAI). In conclusion, the polymorphism of CTR gene but not VDR and COLIA1 is associated with osteoporosis incidence and the levels of alkaline phosphatase and estradiol. The lower BMD in CC genotype is apparently associated in males with depressed bone formation and lower estradiol levels.

Vitamin D receptor gene polymorphisms, bone mineral density and bone turnover: FokI genotype is related to postmenopausal bone mass

The relationship between vitamin D receptor (VDR) intragenic polymorphisms FokI, BsmI, ApaI and TaqI and bone mineral density (BMD) or biochemical markers of bone remodeling were investigated in 114 Czech postmenopausal women, on the average 62.5±8.9 years of age. Restriction fragment length polymorphisms in the VDR gene were assessed by PCR amplification and digestion with restriction enzymes FokI, BsmI, ApaI, and TaqI recognizing polymorphic sites in the VDR locus. Bone mineral density was measured at the lumbar spine and at the hip by dual-energy X-ray absorptiometry (DEXA, g/cm2). After adjusting for age and the body mass index (BMI), subjects with the ff genotype had 9.4 % lower BMD at the hip than those with the Ff genotype (p=0.0459, Tukey´s test). FF individuals had an intermediate BMD at the hip. A similar pattern of lower lumbar spine BMD was also found in ff individuals, but it did not reach statistical significance. There was no relationship between BsmI, ApaI and TaqI VDR polymorphisms and BMD at any skeletal site. Subjects with Aa (ApaI) genotypes had higher levels of propeptide of type I collagen (PICP) than homozygous AA (p=0.0459, Tukey´s test). In FokI, BsmI and TaqI restriction sites the biochemical markers of bone remodeling did not differ by genotype. In addition, no significant difference was observed in VDR genotypic distribution between osteoporotic women and non-osteoporotic controls in the study group. To conclude, the FokI genotype of the vitamin D receptor gene is related to bone mass at the hip in Czech postmenopausal women, whereas the importance of remaining VDR genotypes was not evident.

Vitamin D Receptor Gene Polymorphism and Bone Mineral Density in Hypercalciuric Calcium-Stone-Forming Patients

Reduced bone mineral density (BMD) and an increased risk of vertebral fracture have been reported in calcium-stone-forming (CSF) patients presenting with idiopathic hypercalciuria. We investigated the association between BsmI vitamin D receptor (VDR) polymorphism and BMD in 68 hypercalciuric CSF patients (35 males and 33 premenopausal females, mean age ± SD = 39 ± 10 years). BMD was measured at lumbar spine (L₂–L₄) and femur neck sites using dual energy X-ray absorptiometry. A 72-hour dietary record and a 24-hour urine sample were obtained from each patient to determine calcium intake and excretion. The allelic frequency found for the sample as a whole was 16% BB, 44% Bb and 40% bb. Mean BMD values did not significantly differ among BB, Bb and bb patients at L₂–L₄ (1.162 ± 0.10, 1.133 ± 0.11 and 1.194 ± 0.19 g/cm², mean ± SD, respectively) or at neck sites (0.920 ± 0.11, 0.931 ± 0.15 and 0.982 ± 0.15 g/cm², respectively). Calcium intake and excretion were also not significantly different among the three genotypes. Patients were then divided into two groups, normal BMD, T-score ≧–1 (n = 34) and low BMD, T-score <–1 (n = 34), to further evaluate the allele influence on previous bone loss. Despite a trend for a higher mean BMD at spine or neck sites for patients with one or two b alleles when compared to BB patients, the difference did not reach statistical significance. The distribution of BB, Bb and bb genotypes in the low-bone-mass group (15, 47 and 38%, respectively) was similar to that in the normal-bone-mass group (18, 41 and 14%, respectively). These data suggest that BsmI VDR polymorphism does not play an important role in the bone loss seen in hypercalciuric CSF patients.

The BsmI Vitamin D Receptor Gene Polymorphism in Israeli Populations and in Perimenopausal and Osteoporotic Ashkenazi Women

Background: The association between vitamin D receptor (VDR) gene polymorphisms and bone mineral density (BMD) is controversial, and may be effected by ethnic ancestry and age. Aims: To determine the distribution of the BsmI VDR gene polymorphism in healthy Israeli populations, and to study its association with BMD in perimenopausal and osteoporotic Ashkenazi women. Methods: Allele and genotype frequencies of the VDR gene defined by BsmI restriction site were determined in 634 healthy Israelis of seven ethnic groups, 90 Ashkenazi perimenopausal women and in 75 Ashkenazi osteoporotic women. Genotype-related differences in spinal and femoral neck BMD were determined in Ashkenazi perimenopausal women. Allele and genotype frequencies in Ashkenazi osteoporotic women were compared with Ashkenazi controls. Results: The frequency of the BB genotype was higher in Yemenites compared with Ashkenazi and Libyan Jews (23, 11 and 8%, respectively, p < 0.05), and lower in Ashkenazi compared with Iraqi and Persian Jews (11, 20 and 21%, respectively, p = 0.05). BMD did not vary by genotype in perimenopausal women, nor were there differences in the frequencies of the B allele or the BB genotype in osteoporotic women compared with controls. Conclusions: There is ethnic variability in the frequency of the BsmI VDR gene polymorphism. In Ashkenazi perimenopausal and osteoporotic women this polymorphism is not associated with BMD.

Bone mineral metabolism in adults with β‐thalassaemia major and intermedia

Bone disease is an important cause of morbidity in older patients with beta-thalassaemia major and intermedia. We studied 27 women and 23 men with beta-thalassaemia major (37) and intermedia (13) whose mean age was 32.3 +/- 9.7 years. Bone mineral density (BMD) of the lumbar spine, femoral neck and distal radius was determined by dual-energy X-ray absorbiometry (DXA). The longitudinal change in BMD over a mean of 5.6 years was determined in 19 patients. Serum 25-hydroxyvitamin D, insulin growth factor-1 (IGF-1), bone formation markers bone-alkaline phosphatase, osteocalcin and the resorption marker urinary N-telopeptide cross-linked type 1 collagen (NTx) were determined. The BsmI vitamin D receptor (VDR) gene polymorphism was analysed. Reduced BMD (Z-score < -2) was present in 89%, 62% and 73% of patients in the spine, hip and radius respectively. Vitamin D deficiency was found in 62%, decreased IGF-1 in 72% and increased urinary NTx in 84% of patients. Serum IGF-1 correlated with spine and hip BMD (r = 0.4, r = 0.39, P < 0.01 respectively), and NTx correlated with the hip BMD Z-score (r = 0.35 P < 0.05). The mean annual percentage change in spine BMD was -1.36%. Patients with the VDR BB genotype had lower spine BMD than patients with the bb genotype. In conclusion, bone loss continues in adult thalassaemia patients and is associated with increased bone resorption and decreased IGF-1. The BsmI VDR gene polymorphism is associated with osteopenia in thalassaemia.

Vitamin D receptor gene polymorphisms influence susceptibility to type 1 diabetes mellitus in the Taiwanese population.

Vitamin D and its receptor have been suggested to play a role in the pathogenesis of type 1 diabetes mellitus. We have therefore studied the influence of vitamin D receptor (VDR) gene polymorphisms on susceptibility to type 1 diabetes, and rates of glutamic acid decarboxylase (GAD65) autoantibody and islet cell autoantibody (ICA512) positivity. AND MEASUREMENTS One hundred and fifty-seven type 1 diabetic patients and 248 unrelated normal controls were recruited for this study. Genomic DNA was extracted from peripheral blood leucocytes. All type 1 diabetic patients and controls were genotyped using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP), for three restriction sites in the VDR gene, BsmI, ApaI and TaqI. The chi2 test was used to compare the frequency of the VDR gene polymorphisms in patients and normal controls. The association of VDR gene polymorphisms in type 1 diabetes with the presence of GAD65 and ICA512 autoantibodies were also examined using the chi2 test. The allele frequency of the BsmI and ApaI polymorphisms, but not TaqI polymorphism, differed between patients and controls (BsmI P = 0.015; ApaI P = 0.018; TaqI P = 0.266). However, after correction for the three different polymorphisms tested, only the BsmI was significant (pc = 0.045). Vitamin D receptor gene polymorphisms were associated with type 1 diabetes in a Taiwanese population. However, functional studies are needed to establish the role of the vitamin D receptor in the pathogenesis of type 1 diabetes mellitus.

Consequences of vitamin D receptor gene polymorphisms for growth inhibition of cultured human peripheral blood mononuclear cells by 1, 25-dihydroxyvitamin D3.

In the vitamin D receptor (VDR) gene a BsmI restriction fragment length polymorphism (RFLP) in intron 8 and a translational start-site polymorphism, identified as a FokI RFLP, have been described. Crucial for a proper interpretation of these polymorphisms in association studies is the knowledge whether they have direct consequences for 1,25-(OH)2D3 action at cellular level. The present study was designed to assess functional significance of the FokI and BsmI VDR gene polymorphisms in peripheral blood mononuclear cells (PBMC) with a natural occurring VDR genotype for cell growth inhibition by 1,25-(OH)2D3. PBMC of women were isolated, VDR genotyped and in vitro inhibition by 1,25-(OH)2D3 of Phytohemagglutinin (PHA)-stimulated growth of PBMC was examined in relation to VDR genotype. PHA-stimulated growth and maximal growth inhibition were independent of VDR genotype. However, the FF genotype had a significant lower ED50 than the Ff genotype corresponding to an allele dose effect of 0.32 nM per f allele copy (P = 0.0036). For BsmI genotypes no differences in ED50 were observed. The present study demonstrates for the first time in cells with a natural VDR genotype a direct functional consequence of the VDR gene translational start-site polymorphism for the action of 1,25-(OH)2D3. Especially under conditions of vitamin D insufficiency these findings might have clinical implications.

Vitamin D receptor genotype and bone mineral density in Caucasian children with congenital hypothyroidism.

Recent studies in adults suggest that some of the genetic effects on bone mineral density (BMD) and bone turnover are related to allelic variation in the vitamin D receptor (VDR) genes. It has also been suggested in patients with hyperthyroidism that the VDR genotype might influence the risk of low BMD. We examined allelic influences of the VDR gene on BMD and metabolism in 42 children with congenital hypothyroidism (CH) aged 8.5 +/- 3.4 yr treated from the neonatal period and in whom we have previously demonstrated no detrimental effects to the skeleton of prolonged L-thyroxine therapy. The prevalence of the different VDR BsmI polymorphism in this population was as expected for Caucasian children (Bb heterozygote 52%, bb homozygote 31% and BB homozygote 17%). No relationship was found between VDR genotypes and BMD (SDS), nor between VDR genotypes and serum osteocalcin levels as markers of bone formation. However, urinary D-pyridinoline levels, as markers of bone resorption, were related to VDR genotypes (p<0.04). These data indicate that the VRD genotype does have some effect on bone metabolism in children with CH but the present results give no clear indication of a detrimental effect for any given VDR genotype, at least at the BsmI restriction site, on the bone mineralization of children with CH when adequately treated with thyroxine.

Lack of relationship between BsmI vitamin D receptor polymorphism and primary hyperparathyroidism in a Spanish female population.

The role of vitamin D receptor (VDR) gene polymorphisms in the pathogenesis of hyperparathyroidism is uncertain. Controversial results have been reported. The aim of this study was to explore the relevance of BsmI VDR gene polymorphism in patients with primary hyperparathyroidism (PHPT) due to adenomas. For this purpose, 36 postmenopausal patients with PHPT, mean age 64 years, were compared with a normal age-matched female population (n = 81). BsmI polymorphism distribution in PHPT group was as follows: Bb 50% (18/36); BB 22% (8/36); bb 28% (10/36). In the control group, the distribution was Bb 49% (40/81); BB 16% (13/81); bb 35% (28/81). No statistical differences were found between the two groups. In the PHPT group, no statistical associations were found between different allelic distribution and age, creatinine, hematocrit, phosphorus, alkaline phosphatase (ALP), total calcium, serum parathyroid hormone (PTH), or gland weight. By contrast, levels of serum calcium and iPTH values positively correlated with the PT weight (r = 0.421 and 0.599, respectively, P = 0.0001). Our data suggest that at least in this group, BsmI VDR gene polymorphism appears to be of minor relevance in clinical presentation and possibly, tumorigenesis in PHPT due to adenomas.

Association of VDR and estrogen receptor genotypes with bone mass in postmenopausal Caucasian women: different conclusions with different analyses and the implications.

Much work has been done on the association between vitamin D receptor (VDR) genotypes and bone mineral density (BMD). Despite considerable effort, the results are inconsistent. While the VDR association remains unresolved, studies have expanded to other candidate genes (i.e., estrogen receptor (ER) genotypes), also yielding inconsistent results. A few studies have suggested that interaction effects between VDR and ER genotypes significantly affect BMD. We assessed associations of BMD with VDR BsmI genotypes, and ER XbaI and PvuII polymorphisms (denoted as ERX and ERP respectively) with spine, femoral neck, distal radius BMD, and with total body bone mineral content (tbBMC) in 108 US Mid-western postmenopausal Caucasian women. We statistically controlled for confounding factors such as height, weight, etc., in the analysis. No significant association was detected for ER genotypes with spine and radius BMD, or for VDR genotypes with femoral neck and radius BMD and tbBMC. No significant interaction between VDR and ER genotypes was detected in our sample. However, the VDR genotypes are significantly (p = 0.004) associated with approximately 5.8% spine BMD variation. Both ERX and ERP genotypes are significantly (p = 0.02) associated with approximately 3.5% femoral neck BMD variation. ERX genotypes are significantly (p = 0.03) associated with approximately 2.4% tbBMC variation. However, if the data were analyzed by simple ANOVA as in some previous studies, without adjusting statistically for confounding factors, all the significant results we found here would have gone undetected. Our findings suggest that: (1) VDR and ER genotypes may have different effects on BMD at different sites and on tbBMC; and (2) if significant factors influencing bone are not appropriately controlled, true significant associations can easily be missed. These findings may offer a partial explanation for some of the earlier inconsistent results of association studies on BMD with VDR and ER genotypes.

Early and late postmenopausal bone loss is associated with BsmI vitamin D receptor gene polymorphism in Japanese women.

To determine whether vitamin D receptor (VDR) gene polymorphisms are associated with bone mineral density (BMD) and bone loss in the Japanese population, VDR BsmI RFLPs were analyzed in 191 postmenopausal Japanese women by comparing B allele and b allele DNA sequences, and a point mutation was confirmed. We examined VDR BsmI restriction fragment length polymorphism (RFLP) with an amplification refractory mutation system (ARMS) using this point of mutation. The frequency of VDR BsmI alleles in the Japanese population was significantly different from that in whites. The bb genotype was identified in 79.6%, of the subjects, the Bb genotype in 19.3%, and the BB genotype was in only 1.1%. We find no significant differences in lumbar spine baseline BMD between the bb genotype and the Bb genotype. In both early and late postmenopausal periods, serial measurements of vertebral BMD revealed that subjects with the Bb genotype lost BMD faster than those with the bb genotype (P = 0.001). We conclude that there is a significant relationship between RFLPs of BsmI VDR and the annual rates of bone loss during early and late postmenopausal periods in the Japanese population.

Change of bone mass in postmenopausal Caucasian women with and without hormone replacement therapy is associated with vitamin D receptor and estrogen receptor genotypes.

Our purpose is to assess whether genotypes of the vitamin D receptor (VDR) and estrogen receptor (ER) and their interaction influence changes in bone mass in postmenopausal Caucasian women with and without hormone replacement therapy (HRT). A population of 108 US Mid-West women who participated in a study of low-dose continuous estrogen/progestin was genotyped at the VDR BsmI site and the ER XbaI and PvuII sites. Adequate vitamin D and calcium nutritional intakes were assured in all the study subjects. For the 3.5-year duration of the study, we analyzed changes in bone mineral density (BMD) at the spine, femoral neck, distal radius, and the total body (total body bone mineral content, tbBMC). We adjusted for confounding factors, such as age and weight, in the analysis. We found that VDR and/or ER genotypes and/or their interaction generally had significant effects on the changes in the bone mass measurements in both the placebo and HRT groups. When a significant gene-by-gene interaction exists between VDR and ER genotypes, failure to account for them in analyses may yield nonsignificant results, even if significant genotypic effects exist. The amount of variation in changes in bone mass measurements explained by the total genotypic effects of the VDR and ER loci varies from approximately 1.0% (for the tbBMC changes in combined placebo and HRT groups) to approximately 18.7% (for the spine BMD changes in the HRT group). These results suggest that individual genotypes are important factors in determining changes in bone mass in the elderly with and without HRT and thus may need to be considered with respect to the treatment to preserve bone mass in elderly Caucasian women.

Vitamin D receptor gene start codon polymorphisms (FokI) and bone mineral density: interaction with age, dietary calcium, and 3'-end region polymorphisms.

Osteoporosis is a polygenic disease, whose determining loci have not yet been identified. Vitamin D receptor (VDR) gene polymorphisms in the 3'-end region (as determined by the enzymes BsmI and ApaI) have been inconsistently associated with bone mineral mass. More recently, VDR start codon polymorphisms (as determined by the enzyme FokI) have been found to be related to adult bone mineral density (BMD) in pre- and postmenopausal American women. We investigated the association between BMD and FokI genotypes in premenopausal European-Caucasian women as well as in prepubertal girls from the same genetic background and examined the interaction with VDR 3'-end region polymorphisms and with dietary calcium intake. Areal BMD (g/cm2) was measured by dual-energy X-ray absorptiometry at the level of the lumbar spine, femoral neck, and femoral shaft in 177 healthy premenopausal women (age range, 18.7-56.0 years) as well as in 155 prepubertal girls (age range, 6.6-11.4 years). Genotyping for FokI, BsmI, and ApaI VDR polymorphisms was performed using polymerase chain reaction methods. FokI genotype-dietary calcium interaction was cross-sectionally analyzed in all subjects and longitudinally in 103 prepubertal girls enrolled in a calcium intervention trial. The prevalence of FokI VDR gene polymorphisms in this cohort was 15% for ff, 50% for Ff, and 35% for FF. In the whole cohort of premenopausal women or prepubertal girls, no significant association was found between FokI VDR gene polymorphisms and BMD, even adjusted for age (Z score), weight, height, and calcium intake. Further analysis of FokI VDR gene polymorphisms and dietary calcium intake suggested a possible interaction in BMD determination, since a trend for an association with FokI genotypes was more evident at high than low calcium intake in both cross-sectional and longitudinal studies. Furthermore, cross-genotyping FokI and either BsmI or ApaI VDR polymorphisms suggested that the ff genotype was associated with a significantly lower lumbar spine BMD in bb and aa prepubertal girls. FokI VDR gene polymorphisms were not significantly associated with BMD in healthy European-Caucasian females. However, cross-genotyping of the VDR 3'-end and start codon polymorphic regions may provide a further insight into the complex determination of BMD.

Vitamin D Receptor Alleles Do Not Predict Bone Mineral Density or Bone Loss in Danish Perimenopausal Women

A BsmI restriction enzyme polymorphism in the vitamin D receptor (VDR) gene has been reported to be associated with bone mineral density (BMD) and bone turnover. However, findings in other studies suggest the presence of considerable interaction by race, body size, and environmental factors. Therefore, we VDR BsmI genotyped 200 healthy perimenopausal Danish white women (mean age 50.8 years, mean calcium intake 900 mg/day) in a comprehensive, longitudinal, community-based population study. Bone loss was assessed by dual-energy X-ray absorptiometry (DXA) using cross-calibrated Hologic QDR-1000W and QDR-2000 densitometers, with a mean follow-up period of 4 years (range 1–5 years). Despite a distribution of genotypes similar to that of other white populations (28% bb, 49% Bb, 23% BB), VDR genotypes were not associated with lumbar or femoral baseline BMD, subsequent bone loss rates, or biochemical markers of bone metabolism (bone-specific alkaline phosphatase, urinary hydroxyproline, and serum osteocalcin). Controlling for body size, calcium intake, and serum levels of 25-hydroxyvitamin D 3 [25(OH)D 3] did not alter this finding. The possible existence of a threshold effect was subsequently investigated by restricting analysis to women with low serum 25(OH)D 3 levels or low calcium intake. VDR BsmI genotypes showed no significant impact on bone density or bone loss in healthy Danish early postmenopausal women, even when allowance was made for calcium intake, serum 25(OH)D 3, and body size.

Bone mineral density and its change in white women: estrogen and vitamin D receptor genotypes and their interaction.

Low bone mineral density (BMD) is a major risk factor for development of osteoporosis; increasing evidence suggests that attainment and maintenance of peak bone mass as well as bone turnover and bone loss have strong genetic determinants. We examined the association of BMD levels and their change over a 3-year period, and polymorphisms of the estrogen receptor (ER), vitamin D receptor (VDR), type I collagen, osteonectin, osteopontin, and osteocalcin genes in pre- and perimenopausal women who were part of the Michigan Bone Health Study, a population-based longitudinal study of BMD. Body composition measurements, reproductive hormone profiles, bone-related serum protein measurements, and life-style characteristics were also available on each woman. Based on evaluation of women, ER genotypes (identified by PvuII [n = 253] and XbaI [n = 248]) were significantly predictive of both lumbar spine (p < 0.05) and total body BMD level, but not their change over the 3-year period examined. The VDR BsmI restriction fragment length polymorphism was not associated with baseline BMD, change in BMD over time, or any of the bone-related serum and body composition measurements in the 372 women in whom it was evaluated. Likewise, none of the other polymorphic markers was associated with BMD measurements. However, we identified a significant gene x gene interaction effect (p < 0.05) for the VDR locus and PvuII (p < 0.005) and XbaI (p < 0.05) polymorphisms, which impacted BMD levels. Women who had the (-/-) PvuII ER and bb VDR genotype combination had a very high average BMD, while individuals with the (-/-) PvuII ER and BB VDR genotype had significantly lower BMD levels. This contrast was not explained by differences in serum levels of osteocalcin, parathyroid hormone, 1,25-dihydroxyvitamin D, or 25-dihydroxyvitamin D. These data suggest that genetic variation at the ER locus, singly and in relation to the vitamin D receptor gene, influences attainment and maintenance of peak bone mass in younger women, which in turn may render some individuals more susceptible to osteoporosis than others.

Lack of correlation between start codon polymorphism of the vitamin D receptor gene and bone mineral density in premenopausal French women: the OFELY study.

Previous studies have demonstrated an association between bone mineral density (BMD) and a start codon polymorphism (SCP) of the vitamin D receptor (VDR) gene in pre- and postmenopausal Caucasian and Japanese women. The SCP can be determined by a restriction fragment length polymorphism defined by the FokI restriction endonuclease. VDR alleles containing the FokI site are denoted by f and alleles lacking the site by F. In this study, the association between BMD and the SCP was examined in a group of 174 premenopausal French women who previously had been studied for a relationship between BMD and the VDR BsmI polymorphism. The SCP genotypes of the French women were FF 40%, Ff 44%, and ff 16% and they were independent of the BsmI genotype. BMD was measured by dual-energy X-ray absorptiometry at the lumbar spine, proximal femur, forearm, and total body. In contrast to previous reports, there was no association of BMD with SCP genotype in this group of Caucasian women at any site. We also measured several biochemical indices of calcium homeostasis and bone turnover. We found no statistically significant associations between SCP genotype and calcium, parathyroid hormone, or vitamin D levels. There was a 33.5% higher level of the skeletal resorption marker N-telopeptides of type I collagen in the women with the ff genotype when compared with women with the FF genotype (p = 0.004). Other bone turnover markers failed to show an association with SCP genotype. In summary, the SCP genotype may not be associated with reduced BMD in all geographical or ethnic populations.

Quadriceps and grip strength are related to vitamin D receptor genotype in elderly nonobese women.

Osteoporotic fragility fractures are related to bone density and injury, which are both related to muscle strength. The influence of genetic factors, such as the vitamin D receptor (VDR) polymorphism on bone mineral density (BMD), is documented but still controversial, and is not known for muscle strength. In the present study, we investigated the association between the VDR BsmI polymorphism and BMD (femoral neck [FN], lumbar spine [LS], and proximal forearm [FA]) and muscle strength (quadriceps and grip strength) in 501 healthy women older than 70 years. No association was found between the VDR genotypes and BMD in elderly women. However, in nonobese women (body mass index <30 kg/cm2), the BMD in the FN was 5% higher in women with the bb BsmI genotype than in women with the BB genotype (p < 0.05). After correction for muscle strength, no association was found. A significant association between the VDR genotypes and quadriceps and grip strength was observed. In nonobese women, a 23% difference in quadriceps strength (p < 0.01) and 7% in grip strength (NS) was observed between the bb and BB genotype of the VDR. After correction for confounding factors and BMD, this association was significant for quadriceps and grip strength. These results indicate a major association of an allelic variant at the VDR locus with muscle strength in elderly nonobese women, which could explain a small association between VDR polymorphism with BMD in the femoral neck in nonobese women. No such associations were found in obese women, suggesting that factors related to obesity obscure such an association.

Vitamin D receptor alleles and bone mineral density in a normal premenopausal Brazilian female population.

Studies on the association between vitamin D receptor (VDR) polymorphism and bone mineral density (BMD) in different populations have produced conflicting results probably due to ethnic differences in the populations studied. The Brazilian population is characterized by a very broad genetic background and a high degree of miscegenation. Of an initial group of 164, we studied 127 women from the city of São Paulo, aged 20 to 47 years (median, 31 years), with normal menses, a normal diet and no history of diseases or use of any medication that could alter BMD. VDR genotype was assessed by PCR amplification followed by BsmI digestion of DNA isolated from peripheral leukocytes. BMD was measured using dual energy X-ray absorptiometry (Lunar DPX) at the lumbar site (L2-L4) and femoral neck. Most of the women (77.6%) were considered to be of predominantly European ancestry (20.6% of them reported also native American ancestry), 12.8% were of African-Brazilian ancestry and 9.6% of Asian ancestry, 41.0% (52) were classified as bb, 48.8% (62) as Bb and 10.2% (13) as BB. The BB, Bb and bb groups did not differ in age, height, weight, body mass index or age at menarche. Lumbar spine BMD was significantly higher in the bb group (1.22 +/- 0.16 g/cm2) than in the BB group (1.08 +/- 0.14; P < 0.05), and the Bb group presented an intermediate value (1.17 +/- 0.15). Femoral neck BMD was higher in the bb group (0.99 +/- 0.11 g/cm2) compared to Bb (0.93 +/- 0.12) and BB (0.90 +/- 0.09) (P < 0.05). These data indicate that there is a significant correlation between the VDR BsmI genotype and BMD in healthy Brazilian premenopausal females.

The BsmI vitamin D-receptor polymorphism and secondary hyperparathyroidism

The BsmI vitamin D-receptor polymorphism and secondary hyperparathyroidism