Vitamin D receptor gene polymorphism in familial prostate cancer in a Japanese population

AIM: Vitamin D acts as an antiproliferative agent against prostate cells. Epidemiological study has shown that a low level of serum vitamin D concentration is a risk factor for prostate cancer. Vitamin D acts via vitamin D receptor (VDR), and an association of genetic polymorphisms of the VDR gene has been reported. In the current study, we examined the association of VDR gene polymorphisms with familial prostate cancer in a Japanese population. METHODS: We performed a case-control study consisting of 81 familial prostate cancer cases and 105 normal control subjects. Three genetic polymorphisms (BsmI, ApaI and TaqI) in the VDR gene were examined by the restriction fragment restriction length polymorphism method. RESULTS: Overall, there was no significant association of the VDR gene polymorphisms with familial prostate cancer risk in the cases and control subjects. However, a weak association between BsmI or TaqI genotypes and cancer risk was observed in subjects under 70 years of age. Stratification of cases by clinical stage or pathological grade did not show significant association between the VDR gene polymorphisms and prostate cancer risk. CONCLUSION: In the present study, we could not confirm any significant association between VDR gene polymorphisms with familial prostate cancer risk in a Japanese population. Further large-scale case-control studies are warranted to confirm the importance of VDR gene polymorphisms in familial prostate cancer.     

Association of Vitamin D Receptor Genetic Polymorphisms With Nephrolithiasis and End-Stage Renal Disease: A Meta-Analysis

BackgroundOur objective was to evaluate the association between vitamin D receptor (VDR) BsmI, FokI, TaqI, and ApaI gene polymorphisms and the risk of renal disease. A meta?analysis was conducted to determine the correlation between these VDR gene polymorphisms and the renal disease.MethodsMeta-analysis was carried out to clarify the association of BsmI (2467 cases and 2651 controls), FokI (2460 cases and 3085 controls), TaqI (3181cases and 3713 controls), and ApaI (2512 cases and 3091 controls) polymorphisms with nephrolithiasis (NL), diabetic nephropathy (DN), and end-stage renal disease (ESRD).ResultsThe VDR BsmI C allele, under the allele contrast random effect model, was associated with renal diseases calculated for ESRD. Subgroup analysis revealed association of VDR FokI polymorphism with ESRD and no association with NL and DN. The VDR TaqI C allele, under the allele contrast fixed effect model, was associated with renal diseases calculated collectively for DN, ESRD, and NL. Cochran's Q test showed no evidence of heterogeneity for TaqI and ApaI polymorphisms and showed a significant heterogeneity for BsmI and FokI polymorphisms.ConclusionsThis meta-analysis identifies BsmI, FokI, TaqI and ApaI polymorphisms of the VDR gene as risk factors for renal diseases.     

Iron indices and vitamin D receptor polymorphisms in hemodialysis patients

Cardiovascular disease caused by accelerated atherosclerosis is the major determinant of morbidity and mortality in chronic kidney disease patients. Vitamin D and its analogs provide survival benefit for hemodialysis (HD) patients. Vitamin D exerts its effects through the vitamin D receptor (VDR) that is coded for by a gene showing several polymorphisms that, in turn, are associated with a variety of diseases and differential responses to vitamin D. In this study, we evaluated the association between 4 VDR polymorphisms (ie, those identified by the restriction enzymes BsmI, ApaI, TaqI, and FokI) and iron indices (serum iron, transferrin, transferrin saturation, and ferritin) in 88 hemodialysis patients routinely treated with vitamin D. The absence or presence of the BsmI, ApaI, TaqI, and FokI restriction sites were denominated B and b, A and a, T and t, F and f, respectively. Our results show that in HD patients with transferrin saturation <20%, the F allele was more frequent than in HD patients with transferrin saturation >20% (P = .03). This relationship may provide a link between VDR alleles and iron and nutritional markers, which are highly predictive variables of cardiovascular morbidity and mortality in hemodialysis patients.     

Persistent Effect of Vitamin D Supplementation on Musculoskeletal Parameters in Adolescents One Year After Trial Completion

We showed a beneficial effect of vitamin D supplementation on musculoskeletal parameters in adolescent girls in a 1‐year, randomized, double‐blinded placebo‐controlled trial (RCT). Our objective for this study was to investigate the residual effect of vitamin D supplementation on bone mineral content (BMC), bone mineral density (BMD), at the lumbar spine and hip, lean mass, and height, 1 year after trial completion. We performed post hoc analyses in 167 adolescents, 86 girls and 81 boys, age 13.9 ± 2 years, who received vitamin D or placebo during the trial, and continued into the follow‐up trial. Musculoskeletal parameters were measured at baseline, 12 months (intervention), and 24 months (follow‐up). ANOVA and t tests were used to compare results between the placebo group and the merged vitamin D arms (200 or 2000 IU/day), by gender. Baseline characteristics were comparable between treatment groups at entry into the extension. Girls who had received vitamin D during the trial, had significantly larger hip BMC increments compared to those assigned to placebo, at 24 months compared to study entry, but not 24 compared to 12 months, which persisted in adjusted analyses. There were no significant differences in bone mass changes between treatment groups in boys, at 24 months compared to 12 months or to baseline. The beneficial effect of vitamin D supplementation on hip bone mass, achieved in girls during the trial, persisted 1 year after trial completion. These net cumulative increments, 1 year after discontinuation of supplementation, may have important implications on optimizing peak bone mass accretion in adolescent girls. © 2016 American Society for Bone and Mineral Research.     

Vitamin D receptor gene polymorphism is related to bone density, circulating osteocalcin, and parathyroid hormone in healthy adolescent girls

Bone mineral density (BMD) in adolescence is under strong genetic control and may influence the risk of future osteoporosis and resulting fracture. We investigated the vitamin D receptor (VDR) gene polymorphisms ApaI, BsmI, FokI, and TaqI, in relation to BMD, circulating calcium, osteocalcin, and parathyroid hormone (PTH) concentrations in healthy Caucasian girls (n = 99; mean (+/- SD) age 16.9 +/- 1.2 years). BMD of the total body, femoral neck, and lumbar spine, and bone area of the femur, lumbar spine, and total body were measured using dual energy X-ray absorptiometry. BMD values were adjusted for age, body height, body weight, and physical activity. Using ANOVA, the ApaI genotype Aa had lower circulating levels of osteocalcin (P < 0.01), higher levels of PTH (P = 0.04), and there was a strong tendency toward a significantly higher lumbar spine BMD (P = 0.08) compared with aa subjects. BMD of the lumbar spine (P = 0.02), but not femoral neck or total body, was higher in Bb subjects compared with their bb counterparts. There was no difference in BMD at any measured site of the FokI alleles. There was a strong tendency for a higher BMD at the lumbar spine of Tt subjects compared with TT subjects (P = 0.05). Neither of the different VDR polymorphisms was related to BMD before adjustment for age, body weight, body height, and physical activity. In conclusion, VDR gene polymorphism, defined by ApaI, is related to differences in circulating osteocalcin and PTH, and BsmI is related to lumbar spine BMD in healthy adolescent girls. The results stress the importance of adjusting BMD for confounding factors, such as body weight and physical activity, in order to be able to find any genotype effect on BMD.     

Vitamin D receptor allele combinations influence genetic susceptibility to type 1 diabetes in Germans

Vitamin D has been shown to exert manifold immunomodulatory effects. Because type 1 diabetes is regarded to be immune-mediated and vitamin D prevents the development of diabetes in the NOD mouse, we investigated the role of the vitamin D receptor (VDR) gene as a candidate for type 1 diabetes susceptibility. A total of 152 Caucasian families with at least one affected offspring were genotyped for four VDR restriction-site polymorphisms (FokI, BsmI, ApaI, and TaqI). Whereas the BsmI, ApaI, and TaqI polymorphisms are in strong linkage disequilibrium with each other, no significant linkage disequilibrium with the FokI site was observed. Extended transmission disequilibrium testing (ETDT) was used to detect preferential transmission of allelic combinations to affected offspring. We found significant haplotype-wise ETDT results for the BsmI/ApaI/TaqI (chi2 = 18.886, df = 7, P = 0.0086), the BsmI/TaqI (chi2 = 8.373, df = 3, P = 0.0389), and theApaI/TaqI (chi2 = 17.182, df = 3, P = 0.0006) haplotypes. The "At" and "Bt" alleles confer an increased risk, whereas "AT" and "at" are protective. The combination with the strongest susceptibility was the "BAt" haplotype (64% transmitted, P = 0.0106). Analysis of the FokI site does not provide more information on susceptibility (FokI/BsmI/ApaI/TaqI [chi2 = 24.702, df = 15, P = 0.0541]). These findings suggest a linkage of VDR itself or a nearby gene with type 1 diabetes susceptibility in Germans, confirming respective observations previously made in Indian Asians.     

Gene polymorphisms,bone mineral density and bone mineral content in young children:the Iowa bone development study

We examined the association of candidate gene polymorphisms with bone mineral density (BMD) and bone mineral content (BMC) in a cohort of 428 healthy non-Hispanic white children participating in the Iowa Bone Development Study, a longitudinal study of determinants of bone accrual in childhood. BMD and BMC measurements of the hip, spine and whole body were made using a Hologic 2000 Plus densitometer in 228 girls and 200 boys ages 4.5–6.5 years. Genotypes at 14 loci representing eight candidate genes [type I collagen genes (COL1A1 and COL1A2), osteocalcin, osteonectin, osteopontin, vitamin D receptor (VDR), estrogen receptor (ER), androgen receptor (AR)] were determined. Gender-specific and gender-combined prediction models for bone measures that included age, weight, height (and gender) were developed using multiple linear regression analysis. COL1A2 and osteocalcin genotypes were identified as having the strongest and most consistent association with BMD/BMC measures. Osteonectin, osteopontin and VDR translation initiation site polymorphisms were associated with some individual bone measures, but none of the associations was as consistent as those identified for the COL1A2 and osteocalcin genes. No association was identified with COL1A1 (RsaI and Sp1), VDR (BsmI) and ER polymorphisms (PvuII, XbaI, TA) and BMD/BMC. However, we identified significant gene-by-gene interaction effects involving the ER and both VDR and osteocalcin, which were associated with BMD/BMC. Our data suggest that genetic variation at multiple genetic loci is important in bone accrual in children. Moreover, the combination of genotypes as several loci may be as important as a single genotype for determining BMD and BMC.     

Association analysis of the polymorphisms of the <Emphasis Type="Italic">VDR</Emphasis> gene with bone mineral density and the occurrence of fractures

Associations of the FokI, BsmI, ApaI, and TaqI polymorphisms of the vitamin D receptor (VDR) gene with the bone mineral density (BMD) of the lumbar part of the spinal column (BMD LS) and the neck of the femur (BMD FN), and with the occurrence of fractures, were studied using the polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis on DNA isolated from peripheral blood of 239 women and 40 men from the region of western Poland. Three polymorphisms of the 3′ end of the VDR gene (BsmI, ApaI, TaqI) indicated a strong linkage disequilibrium. Association analysis of the VDR gene FokI polymorphism with BMD LS showed a dose effect of allele f. The association of the bAT haplotype of the BsmI, ApaI, and TaqI polymorphisms of the VDR gene with BMD FN was statistically significant. The association of the ApaI polymorphism with the occurrence of fractures was observed. Associations were also observed between the occurrence of fractures and the baT haplotypes of the VDR gene.     

Skeletal Effects of Vitamin D Supplementation in Postmenopausal Black Women

Black women have lower serum 25-hydroxyvitamin D (25[OH]D) levels and higher parathyroid hormone (PTH) levels than white peers but lower bone turnover, suggesting skeletal resistance to PTH. Our objective was to determine if vitamin D supplementation (1,000?IU/day) would prevent bone loss and whether vitamin D receptor (VDR) polymorphisms modify the response. We performed a 2-year randomized, controlled, double-blind study of 1,000?IU vitamin D₃ vs. placebo in postmenopausal black women with serum 25(OH)D levels <20?ng/mL (n?=?103). Measurements of 25(OH)D, PTH, and bone turnover were evaluated at baseline and 3, 6, 12, 18, and 24?months. DNA was extracted from peripheral blood leukocytes, and genotyping was conducted using standard techniques. Spine and hip bone mineral density (BMD) was measured at baseline and every 6?months. Serum 25(OH)D increased 11?ng/mL with vitamin D supplementation (p?<?0.001), with no change in the placebo group. Vitamin D supplementation produced a significant decline in PTH at 3?months only, with no differences in bone turnover between placebo and vitamin D at any time point. Two-year changes in BMD were not significantly different between placebo- and vitamin D-treated black women at any skeletal site. Despite similar elevations in 25(OH)D, femoral neck BMD was only responsive to vitamin D supplementation in FF subjects (n?=?47), not Ff/ff subjects (n?=?31). Vitamin D supplementation does not appear to influence bone loss in black women. However, in the FF polymorphism of the VDR gene group, vitamin D supplementation may retard the higher rate of bone loss.     

Impact of vitamin D receptor gene polymorphisms on clinical outcomes of HLA-matched sibling hematopoietic stem cell transplantation

We hypothesized that polymorphisms of the vitamin D receptor (VDR) gene might affect clinical outcomes of allogeneic hematopoietic stem cell transplantation (HSCT). Three VDR gene polymorphisms (BsmI G>A, ApaI G>T, and TaqI T>C) were genotyped in 147 patients who underwent HLA-matched sibling allogeneic HSCT. Frequencies of infection, graft-vs.-host disease (GVHD), overall survival (OS), and disease-free survival (DFS) were compared according to genotypes and haplotypes. Infection and acute GVHD had trends to be less frequent in patients with ApaI TT genotype than non-TT genotypes (p = 0.061 and p = 0.059, respectively). For TaqI genotypes, there were no statistical differences in frequency of infection and acute GVHD (p = 0.84 and p = 0.30, respectively), but TC genotype was associated with longer OS and DFS than TT genotype (p = 0.022 and p = 0.038, respectively). In the ApaI-TaqI haplotype analysis, patients with TC haplotype had significantly longer OS and DFS than those without TC haplotype (p = 0.022 and p = 0.038, respectively). In multivariable analysis, TaqI genotype and ApaI-TaqI haplotype of recipients were independent prognostic factors for both OS and DFS. This study suggests that the genotype and haplotype of VDR in recipient might be associated with clinical outcome of sibling HLA-matched HSCT.     

Polymorphisms in the vitamin D receptor gene and the risk of calcium nephrolithiasis in children

OBJECTIVE: Polymorphism in the Vitamin D Receptor (VDR) gene has recently been reported to be associated with calcium metabolism disorders. This study was conducted to investigate the association of VDR gene polymorphism with the risk of calcium nephrolithiasis. METHODS: We investigated the VDR ApaI, BsmI and TaqI polymorphisms, in relation to serum calcium, phosphate, intact parathyroid hormone and 1.25(OH)(2)D(3) in 64 hypercalciuric stone-forming children and 90 healthy children. DNA was isolated from peripheral blood, and genotyping was performed with PCR-based methods. RESULTS: The frequency of ApaI AA genotype was significantly higher in the children with calcium nephrolithiasis than the controls (chi(2)=9.5; p=0.008). The distribution of BsmI and TaqI genotypes in stone-forming patients was similar to those in the control group. There was a significant association between TaqI TT genotype and the strength of the family history. The patients with TT genotype were observed to have a 8 times more risk than patients with Tt/tt genotype for recurrent stone episodes (OR 8, 95%CI 1.61-39.6). CONCLUSION: VDR genotype determination may provide a tool to identify individuals who are at a risk for calcium nephrolithiasis.     

The role of vitamin D receptor gene polymorphisms in Turkish infants with urolithiasis

Polymorphisms in the vitamin D receptor (VDR) gene have recently been reported to be associated with urinary calculi in pediatric and adult cases, but no studies have looked at the youngest period of life. The purpose of this study was to investigate the role of VDR gene polymorphisms in infantile urolithiasis in a Turkish population. We compared a study group of 104 infants (55 girls and 49 boys, mean age 6.94?±?3.81 months) with a control group of 96 infants (51 girls and 45 boys, mean age 7.51?±?3.23) to evaluate their demographics and metabolic risk factors. PCR-based restriction analysis of the polymorphisms on the VDR gene (BsmI and TaqI) showed statistically significant differences between study and control groups (p?=?0.001 and 0.043, respectively). In addition, the prevalence of the BsmI genotype was significantly different between the hypercalciuric and normocalciuric stone formers (p?=?0.007). Allelic frequencies were similar between the urolithiasis and control groups (p?>?0.05). The B allele of BsmI and the A allele of ApaI were more prevalent in the hypercalciuric stone formers than in the normocalciuric stone formers (p?=?0.018 vs.0.036, respectively). These results suggest that the BsmI and TaqI VDR genotypes could be candidate genes leading to infantile urolithiasis.     

维生素D受体基因TaqⅠ和ApaⅠ位点单核苷酸多态性与特发性低枸橼酸尿症关系的研究

目的：探讨维生素D受体（VDR）基因TaqⅠ和ApaⅠ位点单核苷酸多态性与特发性低枸橼酸尿症的关系及其临床意义。方法：实验筛选出无特发性低枸橼酸尿症者50名及特发性低枸橼酸尿症患者21名．通过PCR—RFLP技术检测VDR基因TaqⅠ及ApaⅠ位点单核苷酸多态性，并分析其与特发性低枸橼酸尿症之间的相关性。结果：两组间VDR基因ApaⅠ位点各基因型频率差异无统计学意义（P〉0．05）；而TaqⅠ各基因型频牢差异有统计学意义（P〈0．05）．在特发性低枸橼酸尿症患者组中TT型较为多见。且两组人群中基因型为TT者21h尿枸橼酸含量明显低于同组的其他基因型（P〈0．05）。结论1特发性低枸橼酸尿症与VDR—TaqⅠ单核降酸多态性间存在遗传相关性，而与VDR ApaⅠ单核苷酸多态性关系不明显。VDR基因TaqⅠ位点的TT型基因有望成为特发性低枸橼酸尿症的遗传标志基因。     

Vitamin D,Vitamin D Receptor (VDR) Gene Polymorphisms (ApaI and FokI), and Bone Mineral Density in Patients With Inflammatory Bowel Disease

In the etiology of inflammatory bowel disease (IBD) and osteoporosis, the connecting element is the involvement of environmental and genetic factors. Vitamin D receptor (VDR) gene polymorphisms may be associated with the pathogenesis of IBD and bone mineral density (BMD). The study aimed to analyze the relationship between ApaI and FokI polymorphisms of the VDR gene, serum vitamin D concentration, and BMD in patients with IBD. The studied group consisted of 172 patients (85 with Crohn's disease [CD], 87 with ulcerative colitis [UC], and 39 healthy subjects – control group [CG]) were examined. Lumbar spine densitometry (L1-L4) and the femoral neck (FN) measurements were performed using dual-energy X-ray absorptiometry (DXA). Serum concentrations of 25-hydroxyvitamin D were determined using electrochemiluminescence binding assay (ECLIA). Polymorphisms were determined with polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). . We found no statistically significant differences in vitamin D concentration between the 3 studied groups. CD patients who were FF homozygotes had significantly lower FN BMD than FF homozygous from CG (p-value < 0.05). CD patients who were Aa heterozygotes had significantly lower lumbar spine (L2-L4) BMD than Aa heterozygotes from CG (p-value < 0.05). Among patients with the same polymorphic variants, but belonging to different studied groups, statistically significant differences in bone mineral density in the lumbar spine and the closer end of the femoral neck were observed. We consider that it is the disease entity, not the polymorphism variant, may have a decisive impact on BMD.     

Vitamin D Receptor Gene Polymorphisms, Bone Mass, Bone Loss and Prevalence of Vertebral Fracture: Differences in Postmenopausal Women and Men

Bone mineral density (BMD), the major determinant of fracture risk, is under strong genetic control. Although polymorphisms of the vitamin D receptor (VDR) gene have been suggested to account for some of the genetic variation in bone mass, the influence of VDR genotypes on osteoporosis remains controversial. Previous published studies have focused mainly on women, but the pattern of response in men has not been determined. Using the BsmI restriction enzyme, we studied the influence of the different VDR genotypes on bone mass, bone loss and the prevalence of vertebral fractures in a population-based sample of both sexes (n = 326). BMD was measured at the lumbar spine and femoral neck, with a 4-year interval, using dual-energy X-ray absorptiometry. Vertebral fractures were assessed by two lateral radiographs at the beginning and end of the study. The prevalence of the three possible VDR genotypes was similar to those in other Caucasian populations and no differences were found between men and women. Women with the favorable bb genotype showed significantly higher BMD values at the lumbar spine and femoral neck, and a positive rate of BMD change at the femoral neck compared with women with the BB and Bb genotypes. Moreover, women with the bb genotype showed a trend toward a lower prevalence and incidence of vertebral fractures (p= 0.07). We have not found any differences between VDR genotypes in men. In conclusion, VDR gene polymorphisms are related to bone mass and bone loss in women; also a trend in the prevalence of vertebral fractures was observed in postmenopausal women but not in men. Received: 8 June 1998 / Accepted: 7 December 1998     

Vitamin D receptor gene allelic variants,bone density,and bone turnover in community-dwelling men

The role of vitamin D receptor (VDR) gene polymorphisms in the determination of bone mass and bone turnover is controversial in women. The aim of the study was to determine whether VDR polymorphisms are associated with indices of bone mineral density (BMD) (by dual-energy X-ray absorptiometry and by ultrasound) and/or with bone turnover and muscle strength, factors related to both BMD and fracture risk. For this purpose, we investigated a cohort of community-dwelling men >70 years (n = 271) and a group of healthy control subjects between the ages of 20 and 50 years (n = 137). VDR TaqI, ApaI, and FokI genotypes were determined using enzymatic restriction digestion of polymerase chain reaction (PCR) fragments. In the elderly group, the lowest BMD value at the femoral neck and at the calcaneus was observed in subjects with the "At-At" haplotype genotype, with differences between extreme haplotype groups ("At-At" vs. noncarriers of the "At" allele) ranging from 5.8% to 34.3% (p < or = 0.05). Moreover, at the different subregions of the distal forearm and the tibia, the lowest BMD estimates were consistently associated in both elderly and younger men with the "At" haplotype allele, although this did not approach statistical significance. Elderly subjects with the "At-At" genotype had a significantly higher serum osteocalcin level. BMD was not significantly related to the FokI VDR polymorphism at any of the assessed skeletal sites, nor were any of the biochemical markers associated with the FokI VDR genotype. There were no differences between genotype groups for any of the indices of muscle strength. The present study indicates that the VDR genotype is associated with BMD in healthy community-dwelling elderly men and tends to be associated with biochemical markers, particularly of bone formation, in elderly men.     

Association of vitamin D receptor gene polymorphism with urolithiasis

PURPOSE: Recent studies suggest that allelic variations of the vitamin D receptor (VDR) gene can influence calcium absorption and excretion. Therefore, we studied the association of VDR gene polymorphism with urolithiasis. SUBJECTS AND METHODS: We studied 83 patients with urinary stones and 83 controls. Patients were scored for certain clinical characteristics, including long axis diameter of the largest stone (1 point-less than 10 mm. and 2-10 mm. or greater), number of stones (1 point-1 and 2-multiple) and history of calcium stone disease (1 point-absent and 2-present). They were classified into 3 groups according to the total score, including low-3, intermediate-4 or 5 and high-6 points. The 2 VDR gene polymorphisms TaqI and ApaI were detected by polymerase chain reaction-restriction fragment length polymorphism and their relationships with the urinary calcium level were examined. RESULTS: The incidence of TaqI Tt and tt genotypes was significantly higher in the high score group than in controls. The TaqI t allele was associated with a 5.2-fold increase in the risk of severe stone disease. The urinary calcium level in patients with the Tt and tt genotypes was also higher than in those with the TT genotype. The rate of the ApaI genotype was not different in the high score group and controls. CONCLUSIONS: The TaqI t allele of the VDR gene may be a risk factor for severe stone disease and recurrent stones.     

Vitamin D receptor gene polymorphisms and the risk of fractures in older women. For the Study of Osteoporotic Fractures Research Group.

The association between vitamin D receptor gene polypmorphisms and bone mineral density is controversial. The relationship between vitamin D receptor genotype and risk of fracture is uncertain. To determine whether vitamin D receptor polymorphisms were associated with the risk of hip, vertebral, and other (nonhip, nonvertebral) fractures in elderly women, we conducted a case-cohort study within a prospective study of 9704 community-dwelling women aged 65 years and older. Vitamin D receptor allele and genotype frequencies in women who experienced first incident hip (n = 181), vertebral (n = 127), and other (n = 223) fractures were compared with those of control women selected randomly from the cohort. Average length of follow-up was 6.5, 3.7, and 5.4 years for women in hip, vertebral, and other fracture analyses, respectively. Vitamin D receptor polymorphisms were determined by polymerase chain reaction amplification of genomic DNA using TaqI and ApaI restriction site endonuclease digestion. All nonvertebral fractures were confirmed by X-ray reports; hip fractures were validated by review of X-ray films. Vertebral fractures were defined by morphometry using lateral spine radiography at baseline and an average of 3.7 years later. Allele or genotype frequencies did not differ between fracture cases and their respective controls. Vitamin D receptor genotype (defined by TaqI, ApaI, or the combination of TaqI and ApaI) was not significantly associated with the risk of hip, vertebral, or other fractures. For example, compared with the referent group of women with TT genotype, those with Tt and tt genotypes had similar age- and weight-adjusted risks of fracture at the hip (hazard ratios 0.9, 95% confidence interval [CI] 0.6-1.3, and 0.8, 95% CI 0.5-1.2, respectively), spine (odds ratios 1.1, 95% CI 0.7-1.8, and 0.7, 95% CI 0.4-1.3, respectively), or other skeletal site (hazard ratios 1.0, 95% CI 0. 7-1.4, and 1.0, 95% CI 0.7-1.5, respectively). These findings were not altered in additional analyses including those adjusted for and stratified by age, ethnic ancestry, calcaneal bone density, dietary calcium intake, use of calcium supplements, use of vitamin D supplements, and oral estrogen use. We conclude that Vitamin D receptor polymorphisms defined by TaqI and ApaI are not associated with the risk of fracture in older women. Our results suggest that determination of these vitamin D receptor polymorphisms is not a clinically useful test for the prediction of fracture risk in elderly women.     

Haplotype analysis of VDR gene polymorphisms: a meta-analysis

Introduction: Although many studies have addressed the relationship between multiple individual polymorphisms in the vitamin D receptor (VDR) gene and bone health, few have analyzed this data in terms of haplotypes. We performed a meta-analysis of studies with data on the BsmI, ApaI, and TaqI polymorphisms in order to (a) estimate haplotype frequencies, (b) determine linkage disequilibrium (LD), and (c) estimate the magnitude of the association between haplotypes and osteoporosis/bone mineral density (BMD). Methods: Haplotypes were inferred using the expectation-maximization algorithm (EM); log-linear models were used to determine association with osteoporosis; and regression analysis with variance components was used to determine association with BMD. Results: Our results indicate that the most common haplotype for the VDR gene, regardless of ethnicity, is baT, followed by BAt and bAT in Caucasians, and bAT and BaT in Asians. This indicates strong LD between the BsmI and TaqI polymorphisms. We demonstrate a gain in power when considering the haplotypes rather than the individual polymorphisms separately, i.e., although BsmI, ApaI, and TaqI were not significantly associated with osteoporosis on their own, the haplotypes Bat and BAt were significantly associated, with an OR of approximately 4. Conclusion: We have applied haplotype analysis to the VDR polymorphisms and bone measures. We also highlight a number of methodologic issues, including linkage disequilibrium, the robustness of the EM algorithm in this context, and the potential for exploring effect modification.     

Vitamin D and estrogen receptor-α genotype and indices of bone mass and bone turnover in Danish girls

Peak bone mass is a major determinant of osteoporosis risk in later life. It is under strong genetic control; however, little is known about the identity of the genes involved. In the present study, we investigated the relationship between polymorphisms in the genes encoding the vitamin D receptor (VDR) (FokI, TaqI) and estrogen receptor-α (ERα) (PvuII, XbaI), and bone mineral density (BMD), bone mineral content (BMC), and markers of bone turnover in 224 Danish girls aged 11–12 years. BMD and BMC were measured by dual-energy X-ray absorptiometry. Serum osteocalcin, 25(OH)D, and parathyroid hormone (PTH) were measured by ELISA assays and urinary pyridinium cross-links by HPLC. Physical activity, dietary calcium, and Tanner stage were assessed by questionnaire. In general, there were no significant differences in anthropometrical variables, physical activity, dietary calcium, serum 25(OH)D, or PTH among genotype groups. BMD or BMC of lumbar spine or whole body (adjusted for body and bone size and pubertal status) were not associated with VDR or ERα genotypes or the combination of these genotypes. This lack of association remained even after adjustment for dietary and environmental factors. VDR genotypes had no effect on bone turnover markers. XX and PP ERα genotypes were associated (P < 0.05) with reduced levels of urinary pyridinium cross-links, whereas serum osteocalcin was similar among genotypes. These findings suggest that the rate of bone resorption was influenced by ERα genotypes, even though these biochemical differences were not evident in bone mass indices.