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.     

Association between vitamin D receptor genetic polymorphisms and acute cellular rejection in liver-transplanted patients

Vitamin D receptor (VDR) polymorphisms may confer susceptibility to immunologically mediated liver diseases. We aimed to verify whether recipient VDR polymorphisms might affect the incidence of acute cellular rejection (ACR) of the graft after liver transplantation (LT). Two hundred and fifty-one liver-transplanted patients surviving at least 1month were studied. ACR in the first post-LT year was graded according to the Banff score. Recipients genotyping for VDR polymorphic sites (FokI C>T, BsmI G>A, ApaI T>G, TaqI T>C) was performed. A significant difference was found between patients with and without ACR episodes in allele frequencies of BsmI (G: 0.660 vs. 0.545, P=0.017) and TaqI (T: 0.667 vs. 0.543, P=0.010). Patients carrying the G-*-T/G-*-T diplotypes of the BsmI G>A, ApaI T>G and TaqI T>C experienced more frequently ACR: 33/79 Vs 42/172, P=0.005. Carriage of G-*-T/G-*-T diplotypes was an independent predictor of ACR (OR 2.41, P=0.006), with CMV reactivation (OR 2.34, P=0.033) and HCV aetiology (OR 1.86, P=0.036). In conclusion, recipient VDR polymorphic loci are strongly associated with ACR occurrence during the first year after LT. The knowledge of VDR genetic polymorphisms may be helpful in identifying recipients at higher risk of ACR and in selecting them for a more aggressive immunosuppressive therapy.     

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.     

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.     

Polymorphisms in the Vitamin D Receptor Gene and Parathyroid Hormone Gene in the Development and Progression of Diabetes Mellitus and its Chronic Complications, Diabetic Nephropathy and Non-Diabetic Renal Disease

Background : We chose to study polymorphisms of vitamin D receptor gene (VDR) and parathyroid hormone genes (PTH), whose protein products significantly affect calcium-phosphate metabolism in kidneys and are implicated in the pathogenesis of diabetes, which may also involve kidney damage. Methods : Distribution of genotypes of four polymorphisms in VDR gene i.e TaqI (rs731236), BsmI (rs1544410) ApaI (rs7975232), FokI (rs2228570) and two polymorphisms of PTH gene, i.e. DraII (rs6256), BstBI (rs6264), were studied using PCR-RFLP. Examined groups consisted of 147 patients with diabetes (DM), 47 patients with nondiabetic renal disease (NDRD), 132 patients with diabetic nephropathy (DN) and 118 healthy subjects. Conclusion : Comparison of DN group and healthy subjects identified statistically significant difference for the FokI polymorphism in VDR gene (P<10-4) and also for the BstBI polymorphism in PTH gene (P=0,023). Differences in DraII polymorphism distribution in PTH gene were statistically significant in each group of patients compared to healthy subjects. In DN patients, the BBFFAATt combination of VDR gene was more frequent than in healthy subjects (P=0,046), and the BbFFAaTt variant was more frequent than in DM2 patients (P=0,018). The BBDD haplotype of PTH gene seems to be a predisposing factor for diabetes itself (P=0,019).     

The relationship of 3' vitamin D receptor haplotypes to urinary supersaturation of calcium oxalate salts and to age at onset and familial prevalence of nephrolithiasis.

BACKGROUND: Idiopathic hypercalciuria (IHc) and idiopathic hypocitraturia are frequently associated with calcium nephrolithiasis. We investigated the relationship of vitamin D receptor (VDR) polymorphisms (BsmI, TaqI and FokI) to urinary supersaturation of calcium oxalate salts in recurrent calcium oxalate stone formers with IHc and the clinical relevance of this relationship. METHODS: The study included 110 Caucasian stone formers with IHc and 127 unrelated healthy controls without history of nephrolithiasis. Age at onset of nephrolithiasis, familial history score (FHS) and the ion activity product of calcium oxalate salts in urine (AP(CaOx)) were tabulated. BsmI, TaqI and FokI VDR polymorphisms were evaluated in all participants. RESULTS: Patients and controls were classified as homozygous (bbTT and BBtt) or heterozygous in relation to BsmI and TaqI polymorphisms. Compared with BBtt patients, bbTT homozygous stone formers showed lower citrate excretion (1.91+/-0.89 vs 3.46+/-1.39 mmol/24 h, P = 0.004) and higher AP(CaOx) (2.02+/-0.51 vs 1.53+/-0.53, P = 0.006). Among controls, there were similar differences in citrate excretion and AP(CaOx) between the two groups, but they were not statistically significant. Compared with BBtt, bbTT patients showed lower mean age at onset of nephrolithiasis (29.7+/-12.1 vs 38.1+/-12.7 years, P = 0.008) and higher values of FHS (2.45+/-1.9 vs 0.83+/-0.7, P = 0.006). Similar results were obtained for individual BsmI and TaqI alleles. The analysis of FokI alleles was not informative. CONCLUSIONS: Recurrent calcium oxalate stone formers with IHc and the bT VDR haplotype have more aggressive kidney stone diseases as indicated by a higher familial incidence and lower mean age at onset. This clinical severity is associated with the higher urinary supersaturation of calcium oxalate salts and abnormalities of renal citrate handling.     

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 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.     

BsmI,TaqI, ApaI and FokI polymorphisms in the vitamin D receptor (VDR) gene and risk of fracture in Caucasians: A meta-analysis

ContextVitamin D receptor (VDR) gene polymorphisms have been strongly associated with bone mineral density in some studies. However, in a recent meta-analysis, no relationship of the VDR BsmI or TaqI polymorphism and fracture risk was found in the meta-analysis of published data.Objective and designOur meta-analysis studied whether a relationship exists between BsmI, TaqI, ApaI and FokI polymorphisms in the VDR gene and risk of fracture.Data sourcesRelevant studies were identified from the following electronic databases: MEDLINE, EMBASE and Current Contents before January 2010.Data synthesisThis meta-analysis included 17 studies with a total of 21 eligible comparisons, which included 2112 fracture cases and 4521 controls. All of these studies reported on Caucasians. The combined results based on all studies showed that fracture cases had a significantly lower frequency of bb genotype of BsmI [odds ratio (OR) = 0.87, 95% confidence interval (CI) = 0.76, 0.98]. When stratifying by fracture type, we found that (1) hip fracture cases had a significantly lower frequency of bb genotype of BsmI (OR = 0.82, 95% CI = 0.70, 0.97); (2) hip fracture cases had a significantly lower frequency of Tt genotype of TaqI (OR = 0.65, 95% CI = 0.43, 0.97); (3) hip fracture cases had a significantly higher frequency of tt genotype of TaqI (OR = 1.74, 95% CI = 1.05, 2.91); (4) vertebral fracture cases had a significantly higher frequency of Aa genotype of ApaI (OR = 1.63, 95% CI = 1.03, 2.59). No significant difference was found in any genotype of FokI.ConclusionOur meta-analysis suggests that there is a modest but statistically significant association between the BsmI bb genotypes and fracture.     

Vitamin D receptor gene polymorphisms are associated with increased risk and progression of renal cell carcinoma in a Japanese population

AIM: Biological and epidemiologic data suggest that 1 alpha, 25 dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) levels may influence development of renal cell carcinoma. The vitamin D receptor (VDR) is a crucial mediator for the cellular effects of 1,25(OH)(2)D(3) and additionally interacts with other cell signaling pathways that influence cancer progression. VDR gene polymorphisms may play an important role in risk of incidence for various malignant tumors. This study investigated whether VDR gene polymorphisms were associated with increased risk and prognosis of renal cell carcinoma (RCC) in a Japanese population. METHODS: To analyze risk of RCC depending on VDR polymorphism, a case-control association study was performed. The VDR gene polymorphisms at three locations, BsmI, ApaI and TaqI, were genotyped in 135 RCC patients and 150 controls in a Japanese population. Logistic regression models were used to assess the genetic effects on prognosis. RESULTS: Significant differences in the ApaI genotype were observed between RCC patients and controls (chi(2) = 6.90, P = 0.032). No statistical significant difference was found in the BsmI and TaqI polymorphisms. The frequency of the AA genotype in the ApaI polymorphism was significantly higher in the RCC patients than in the controls (odds ratio, 2.59; 95% confidence intervals, 1.21-5.55; P = 0.012). Multivariate regression analysis showed that the AA genotype was an independent prognostic factor for cause-specific survival (relative risk 3.3; P = 0.038). CONCLUSION: The AA genotype at the ApaI site of the VDR gene may be a risk of incidence and poor prognosis factor for RCC in the Japanese population. Additional studies with a large sample size and investigation of the functional significance of the ApaI polymorphism in RCC cells are warranted.     

Effect of VDR gene polymorphisms on osteocalcin secretion in calcitriol-stimulated human osteoblasts

BACKGROUND: The impact of vitamin D receptor (VDR) gene polymorphisms in bone metabolism remains controversial. Some authors have found a beneficial effect of some VDR gene polymorphisms, while others found no differences, or even a lower bone mass in subjects with the same type of polymorphisms. The aim of this study was to assess if the VDR gene polymorphisms could have an effect on the calcitriol-stimulated osteocalcin in human osteoblasts. METHODS: Osteoblasts were obtained from human femoral necks replaced because of osteoarthritis. Bones were cut into pieces of 1 to 2 mm and placed in a nylon mesh. After the migration of osteoblasts, the pieces were collected and cultured with different concentrations of calcitriol (10(-8), 10(-9), and 10(-1)0 mol/L). After 48 hours of incubation with calcitriol, the osteocalcin secreted into the medium (corrected by either total proteins or total DNA content) was measured. The DNA was extracted from the osteoblasts, amplified by polymerase chain reaction (PCR), and analyzed for target sequences sites of the BsmI, ApaI, TaqI, and FokI restriction enzymes. RESULTS: The response observed in osteocalcin secretion in the bb or TT genotypes doubled the response observed in the BB or tt genotypes (calcitriol 10(-8) and 10(-9) mol/L). A slight trend was also observed with the aa genotype. Men showed higher levels of osteocalcin secretion than women. Age did not show any influence in osteocalcin secretion. CONCLUSION: VDR alleles and gender demonstrated an effect on the osteocalcin secretion. BB or tt genotypes, and also the "A" allele, showed the lowest calcitriol-stimulated osteocalcin secretion.     

Clinical and genetic risk factors for posttransplant diabetes mellitus in adult renal transplant recipients treated with tacrolimus

BACKGROUND: The present study investigated the incidence of posttransplant diabetes mellitus (PTDM) and calculated the risk of developing PTDM under a tacrolimus-based immunosuppression based on clinical characteristics, tacrolimus pharmacokinetics, and genetic polymorphisms related to tacrolimus pharmacokinetics or diabetes mellitus. METHODS: Seventy nondiabetic adult kidney recipients were studied. Patients with continuous high plasma glucose levels, over 6.5 mg/dl of hemoglobin A1c, or requiring insulin and/or oral antidiabetic agents for more than 3 months after transplantation 6 months postoperatively were diagnosed as having PTDM. Twelve genomic polymorphisms were assessed. RESULTS: Six months after transplantation, 10 recipients (14.3%) developed PTDM. Positive risk factors were age (P=0.019) and body mass index (P=0.038). There were no significant differences in acute rejection rate, total steroid doses, tacrolimus pharmacokinetics or its related to genetic polymorphisms between the two groups. The frequency of PTDM was significantly higher in patients with the vitamin D receptor (VDR) TaqI t allele than in those with the TT genotype (P=0.013). On multivariate analysis, age over 50 years (odds ratio 9.28, P=0.003) and the presence of the VDR TaqI t allele (odds ratio 7.05, P=0.048) were correlated with the development of PTDM. CONCLUSION: The incidence of PTDM was 14.3% in our cohort. Age over 50 years was a risk factor. The presence of the VDR TaqI t allele may also be a risk factor for PTDM, suggesting that genotyping of diabetes-related polymorphisms is a possible method of predicting a patient's risk for developing PTDM and would be a valuable asset in selecting appropriate immunosuppressive regimens for individuals.     

Improved renal allograft survival with vitamin D receptor polymorphism

BACKGROUND: Polymorphisms in genes, coding for proteins involved in immune response, or the pathogenesis of atherosclerosis may influence immunological and non-immunological mechanisms that lead to allograft loss. Vitamin D receptor (VDR) agonists reduce allograft rejection in animal models, and there are a number of functional polymorphisms in VDR. METHODS: In all, 379 renal transplant recipients were genotyped for VDR (FokI & ApaI) polymorphisms, and the association of each genotype with renal allograft survival and acute rejection was determined. RESULTS: There was significantly improved allograft survival for patients who were homozygous or heterozygous for the VDR FokI T allele (Hazard Ratio [HR] = 0.488, p < 0.001). CONCLUSION: The association of VDR FokI T allele with improved renal allograft survival is a unique observation. The finding is in keeping with data showing the prevention of chronic allograft rejection with the use of Vitamin D receptor agonists.     

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.     

血清25-(OH)D水平及VDR基因多态性与类风湿性关节炎骨侵蚀的关系探讨

目的探讨血清25-羟维生素D[25-(OH) D]及维生素D受体(vitamin D receptor,VDR)基因多态性与类风湿性关节炎骨侵蚀的关系。方法将94例类风湿性关节炎患者设为研究组,另将85名健康体检者设为健康组。2组均检测血清25-(OH) D水平,且提取基因组DNA,采用MassARRAY分子量阵列技术平台检测VDR基因多态性,分析其与类风湿性关节炎骨侵蚀度之间的关系。结果研究组血清25-(OH) D水平低于健康组(P0.05),且骨侵蚀患者血清25-(OH) D水平低于无骨侵蚀者(P0.05);研究组Fok I位点基因型FF、Ff及等位基因F和Apa I位点基因型AA、Aa及等位基因A频率均高于健康组(P0.05);研究组ff、aa出现频率均低于健康组(P0.05);血清25-(OH) D30 ng/m L、Fok I位点基因型FF及Ff、Apa I位点基因型AA及Aa均是类风湿性关节炎发病的危险因素(P0.05),血清25-(OH) D20 ng/m L是类风湿性关节炎骨侵蚀的危险因素(P0.05)。结论血清25-(OH) D水平缺乏可增加类风湿性关节炎骨侵蚀发生风险,VDR基因Fok I位点等位基因F及Apa I位点等位基因A可增加类风湿性关节炎发病风险,但与骨侵蚀无关。     

Vitamin D receptor gene polymorphisms and prostate cancer risk

BACKGROUND: Vitamin D is a steroid hormone that is thought to play a role in the etiology and progression of prostate cancer. Hormone activity requires binding to the vitamin D receptor (VDR), which contains several genetic polymorphisms that have been associated with risk of prostate cancer. To further evaluate this relationship, we conducted a population-based case-control study of the VDR BsmI, FokI, and Poly-A polymorphisms, and prostate cancer. METHODS: Germline DNA samples and survey data from incident prostate cancer cases (n = 559) and controls (n = 523) of similar age (40-64 years) without a history of the disease who resided in King County, Washington were analyzed. RESULTS: The frequency of the BsmI, FokI, and Poly-A genotypes were similar in cases and controls, and no overall association between any variants and prostate cancer risk were noted. Stratification by clinical features of disease revealed that among men with localized stage disease, the BsmI bb genotype was associated with a modest increase in risk (OR, 1.49; 95% CI, 1.02-2.17; P = 0.04) compared to the BB genotype. CONCLUSIONS: These results suggest that polymorphisms in the VDR gene are not strong predictors of prostate cancer risk among Caucasian men in the U.S.     

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.     

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.     

Incidence and risk factors of clinical characteristics, tacrolimus pharmacokinetics, and related genomic polymorphisms for posttransplant diabetes mellitus in the early stage of renal transplant recipients

PURPOSE: Posttransplant diabetes mellitus (PTDM) is an important complication in a tacrolimus (TAC)-based immunosuppressive regimen. The present study investigated the incidence, clinical risk factors, TAC pharmacokinetics (PK), and genomic polymorphisms related to TAC-PK or diabetes mellitus (DM) under the TAC-based immunosuppressive protocol. PATIENTS AND METHODS: Seventy-one nondiabetic renal allograft recipients transplanted from February 1998 to March 2004 were studied. Patients with over 6.5 mg/dL of hemoglobin A1c on sequential blood samples or requiring insulin or oral antidiabetic agents around 6 months after transplantation were diagnosed as having PTDM. RESULTS: Six months after transplantation, 10 recipients (14.1%) developed PTDM. The positive risk factors were age (P = .003) and body mass index (P = .035). There were no significant differences in gender distribution, pretransplant dialysis period, dialysis modality, acute rejection rate, total steroid doses, TAC-PK, or its related genomic polymorphisms between the two groups. In the DM-related polymorphisms, the frequency of PTDM was significant higher in patients with the VDR TaqI tt or Tt genotype than in those with the TT genotype (P = .013). After a multivariate analysis, age over 50 years (P = .007, odds ratio 8.92) and the presence of VDR TaqI t allele (P = .043, odds ratio 6.71) were correlated with the development of PTDM. CONCLUSION: The incidence of PTDM in our series was 14.1%. Age over 50 years was a risk factor. The presence of VDR TaqI t allele might be a risk for PTDM. An association between TAC-PK and development of PTDM was not observed.