女性青少年特发性脊柱侧凸患者维生素D受体基因多态性与低骨量的相关性研究

目的 检测青少年特发性脊柱侧凸(AIS)女性患者与对照组维生素D受体(VDR)基因型分布情况并比较AIS患者组内不同基因型的骨密度值,探讨VDR基因多态性与AIS患者低骨量之间的关系.方法 对2004年4月至2007年10月门诊就诊的146例AIS女性患者进行人体形态学测量,记录其年龄、身高、体重、Cobb角等指标,应用双能X线骨密度吸收仪测定其腰椎和股骨近端的骨密度,并收集其静脉血标本.经体检收集146名健康女性青少年静脉血标本作为对照.应用聚合酶链反应-限制性片段长度多态性技术(PCR-RFLP)检测分析AIS组及对照组VDR基因型,比较两组间基因型分布情况和AIS组内各基因型间的骨密度差异.结果 AIS组Bb基因型频率明显高于对照组,但AIS组内的各基因型骨密度之间并无差异.结论 VDR基因多态性并不影响VDR介导的骨量吸收与积累.     

Interaction of interleukin-6 and estrogen receptor gene polymorphisms on bone mass accrual in Chinese adolescent girls

We assessed the main and interaction effects of interleukin-6 and estrogen receptor gene polymorphisms on bone mass accrual in Chinese adolescent girls. A total of 228 premenarche Chinese girls (9-11.5 years old) were recruited for a 2-year follow-up study. Bone mineral density (BMD) at the total body, lumbar spine (L1-L4), and total left hip were measured by dual-energy X-ray absorptiometry at baseline and follow-up. The -174G/C and -634C/G polymorphism of IL-6 gene, and PvuII and XbaI polymorphisms of the estrogen receptor (ER)-alpha gene, were determined. The -634C/G polymorphism of the IL-6 gene and PvuII polymorphism of ER-alpha gene were significantly associated with bone mass accrual after adjusting the potential confounding factors. Girls with pp genotype of ER-alpha gene had greater percentage accrual in BMD of total body (P = 0.010) and femoral intertrochanter (P = 0.038) than their PP and Pp counterparts. Girls with CC genotype of IL-6 -634G/C gene had higher percentage accrual in BMD of total body (P = 0.032) and femoral trochanter (P = 0.048) than their CG + GG counterparts. Significant interaction effects of IL-6 -634C/G polymorphism and ER-alpha PvuII polymorphism were observed on percentage change in BMD of total left hip (P = 0.009) and femoral intertrochanter (P = 0.007). The genotype CC (IL-6 -634C/G) x pp (ER-alpha PvuII) was associated with greater BMD accrual than other genotype combination in Chinese adolescent girls. We found that the IL-6 -634C/G and ER-alpha PvuII polymorphism were significantly associated with BMD accrual and that they have an interactional effect on BMD accrual in Chinese adolescent girls.     

Vitamin D receptor gene polymorphisms modulate the skeletal response to vitamin D supplementation in healthy girls

ObjectivesVitamin D receptor (VDR) gene plays an important role in bone mass regulation. We have previously shown a beneficial effect of vitamin D supplementation on bone mass in girls. This study investigated whether the musculo-skeletal response to Vitamin D was modulated by polymorphisms in VDR gene.DesignRandomized placebo-controlled trial.Methods179 girls (10–17 years), were randomly assigned to placebo or Vitamin D3 for one year. VDR genotypes were determined in 167 girls using BsmI, TaqI and ApaI restriction enzymes. Bone mass at the spine, hip, forearm and total body, and lean mass were measured by DXA at baseline and at one year.ResultsAfter one year, VDR gene polymorphisms using Bsm1 and TaqI restriction enzymes were associated with percent changes in bone area, BMC and BMD at multiple skeletal sites in the Vitamin D3 group but not in the placebo group. The least increments were observed in the BB and tt genotypes. No similar effect was observed with ApaI enzyme. This relationship between VDR genotypes and changes in BMD and BMC remained significant after adjustment for puberty, changes in lean mass, height and bone area.ConclusionVDR gene polymorphisms influence the skeletal response to vitamin D supplementation in healthy adolescent girls.     

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 polymorphisms in patients with urolithiasis

Urolithiasis is a multifactorial disease, the onset and severity of which is influenced by both genetic and environmental factors. This study represents an investigation of the role of vitamin D receptor (VDR) gene polymorphisms (ApaI, BsmI, and TaqI) and combined genotypes in urolithiasis in a Turkish population. We studied 110 patients with urinary stones and 150 control subjects. The polymorphic regions were amplified using polymerase chain reaction, followed by digestion with restriction enzymes BsmI, ApaI, and TaqI, and analyzed electrophoretically. Genotype and allele frequencies were calculated, and the association with urolithiasis, family history, and recurrence of stone was investigated. Our data provide no evidence for an association between urolithiasis and VDR ApaI, BsmI, and TaqI genotypes. We also analyzed the effects of VDR ApaI, BsmI, and TaqI genotypes in combination; the “GTT” VDR haplotype, constructed from three adjacent restriction fragment length polymorphisms was overrepresented among the urolithiasis patients. However, no significant differences between heterozygous carriers (OR 1.302; 95% CI 0.527–3.215) and homozygous carriers (OR 3.39; 95% CI 0.719–15.985) were observed in our study population. A significant association was found only between the ApaI polymorphism and family history (P=0.017; χ ²=5.657). Our data indicate that the VDR ApaI, BsmI, and TaqI polymorphisms do not confer a significant risk for urolithiasis.     

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.     

Vitamin D receptor gene polymorphism,bone mass,body size,and vitamin D receptor density

We determined vitamin D receptor (VDR) gene alleles (based on the BsmI restriction site polymorphism), duodenal mucosal receptor density, bone mass at spine and total body, and body size in 32 healthy premenopausal females. While we found no relationship between allele and receptor density in duodenal mucosa, bone mineral content (BMC) at both spine and total body was significantly associated with VDR gene alleles. BMC was highest for the bb allele, lowest for BB, and intermediate for Bb. A similar association was noted between allele and body size variables, particularly weight. When BMC was adjusted for body weight, the association with VDR polymorphism disappeared. The VDR gene polymorphism may be affecting bone mass not through classical nutritional mechanisms (e.g., intestinal calcium absorption), but through an influence on body size.     

VDR基因型分布及其与骨矿含量的关系

近年来，在骨质疏松研究领域，维生素Ｄ受体基因（ＶＤＲ）与骨量及骨代谢的研究受到许多国外学者的重视。我们利用国际合作的机会，对９６名沈阳妇女ＶＤＲ基因进行了分析。研究对象来自于一项正在进行的骨代谢影响因素研究课题。采用标准方法（Ｎｕｃｌｅｏｎｋｉｔ，ｓｃｏｔｌａｂ，ＵＫ）从白细胞中提取ＤＮＡ，以聚合酶链反应（ＰＣＲ）来扩增特定基因段。用ＢｓａＭＩ限制性内切酶消化ＰＣＲ产物，以２％琼脂糖电泳分离判定ＶＤＲ基因型。使用ＤＰＸ－Ｌ（ＬｕｎａｒＵＳＡ）骨矿测定仪测定研究对象的腰椎（Ｌ２～４）及髋部骨矿含量（ＢＭＣ）。结果：与其他国家人群相比，该人群ＶＤＲ基因的分布状态不同。ＶＤＲ基因的ｂｂ型占总数的９１．７％；Ｂｂ型仅占８．３％，而且ＢＢ基因型完全不存在。在青年妇女中发现ｂｂ基因型组股骨颈ＢＭＣ高于Ｂｂ型组股骨颈ＢＭＣ（Ｐ＝０．０２７）。老年妇女ｂｂ基因型组股骨颈ＢＭＣ也高于Ｂｂ型组，但差异无统计学意义，没有发现其他部位ＢＭＣ与ＶＤＲ基因型有关。     

School-based calcium-vitamin D with micronutrient supplementation enhances bone mass in underprivileged Indian premenarchal girls

Low adult bone mass is linked to osteoporosis and fractures and is dependent on the extent of childhood and adolescent bone mineralization. The aim of the study was to investigate the effect of 1-year supplementation of calcium, multivitamin with zinc along with vitamin-D on bone mass accrual of school-going premenarchal girls from low income groups in Pune, India. Double-blind, matched-pair, cluster, randomization study was carried out in 214 premenarchal girls (8-12 years) from 2 schools in Pune, India. The two schools together formed 3 classes with 3 clusters each of age-matched girls of which one cluster was allocated to either one of the intervention groups (Ca-group:500 mg/d calcium, Ca+MZ-group:500 mg/d calcium+multivitamin tablet containing 15 mg/d zinc) or control group (C-group: multivitamin tablet without any minerals); all subjects received vitamin-D supplementation. Anthropometry, biochemical parameters, total body bone mineral content (TBBMC) and bone mineral density (TBBMD) (Dual energy X-ray absorptiometry) were assessed at baseline and endline. Post supplementation, mean percent increase in TBBMC was significantly higher in Ca-group (22.3%) and Ca+MZ-group (20.8%) compared to C-group (17.6%) (p<0.05) with no significant differences observed between Ca+MZ and Ca groups (p>0.1). Improvement in TBBMC-for-age Z-scores was higher in the two calcium supplemented groups (13.6%-22%) compared to the C-group (no improvement). Calcium supplementation, with or without multivitamins and zinc, showed a promising improvement in bone health especially with regards to improvement in bone related Z-scores in our population of underprivileged premenarchal girls.     

Vitamin D receptor gene polymorphisms and disease free survival after radical prostatectomy

BACKGROUND: Vitamin D has been linked with prostate cancer risk in epidemiologic studies and has antiproliferative, prodifferentiation, and antimetastatic properties in experimental systems. Its hormonal activity is mediated by the vitamin D receptor. We investigated whether germ-line genetic variation in the vitamin D receptor impacts progression of prostate cancer after radical prostatectomy. METHODS: We analyzed BsmI and TaqI polymorphisms using archived specimens from a large series of radical prostatectomy patients at a single institution. Our series included 428 white men (WM) and 310 African-American men (AAM) who were carefully and uniformly staged and followed for 5-10 years. RESULTS: The distribution of polymorphisms varied between WM and AAM. There was little association between genotype and extent of disease at diagnosis, Gleason score, preoperative PSA, or recurrence overall. Among WM with locally advanced disease, however, the BsmI B allele protected against recurrence in models examining gene dose (P = 0.04) and dominant effects (P = 0.05). CONCLUSIONS: Overall vitamin D receptor polymorphisms did not predict pathologic features of prostate cancer but may impact on risk of recurrence among men in certain risk groups. Analysis of polymorphisms may provide clues about the mechanisms through which vitamin D exerts its inhibitory effects on prostate cancer in vivo in men.     

Vitamin D receptor gene start codon polymorphism (FokI) is associated with forearm bone mineral density and calcaneal ultrasound in Finnish adolescent boys but not in girls

We examined the association between vitamin D receptor (VDR) gene FokI polymorphism and bone mineral density and quantitative ultrasound parameters in Finnish adolescents. We assessed bone mineral density at the distal sites of radius and ulna, quantitative ultrasound of the calcaneus, serum concentration of 25-hydroxyvitamin D (25-OHD), calcium intake, physical activity, and BsmI and FokI polymorphisms of the vitamin D receptor gene in 86 girls and 38 boys aged 14 to 16 years. In girls, FokI polymorphism was not significantly associated with bone mineral density or quantitative ultrasound parameters. In adolescent boys, the Ff genotype was associated with higher forearm BMD and calcaneal ultrasound values, when adjusted for body and bone size, BsmI polymorphism, calcium intake, vitamin D status, smoking, and physical activity.     

Association of gene polymorphisms and bone density in Japanese girls

Although some studies have reported a relationship between several candidate polymorphic genes and bone mineral density (BMD), little is known concerning the genetic factors influencing BMD in children. This study examined this relationship in healthy Japanese girls (n = 125; age, 13.4 ± 0.89 years; range, 12–15 years). We investigated allelic variants of the vitamin D receptor (VDR) gene, the estrogen receptor (ER) gene, the parathyroid hormone (PTH) gene, the Ca-sensing receptor (CaSR) gene, and the β3-adrenergic receptor (β3-AR) gene. The genotype of the VDR gene (Fok I) correlated with lumbar spine, and femoral neck BMD. The PTH polymorphisms (BstB I, Dra II) were also associated with lumbar spine BMD. No relationship was found between genotypes of the ER gene, CaSR gene, or β3-AR gene and BMD. The age, height, weight, and body mass index did not differ significantly among girls with different VDR and PTH genotypes. These results suggest that the Fok I polymorphism of the VDR gene and the Dra II polymorphism of the PTH gene are risk factors for low bone density in Japanese girls. Received: September 18, 2001 / Accepted: November 16, 2001     

青少年特发性脊柱侧凸患者雌激素受体基因多态性与骨密度的关系

目的探讨青少年特发性脊柱侧凸患者雌激素受体基因多态性与骨密度的关系。方法取青少年特发性脊柱侧凸女性患者92例,年龄10～19岁,Cobb角25°～134°,应用聚合酶链反应限制性片段长度多态(PCRRFLPs)的方法分析雌激素受体基因型,同时用双能X线骨密度吸收仪分别对其腰椎(L24)和股骨近端(股骨颈、大转子、Wards三角)的骨密度进行测量。结果特发性脊柱侧凸患者雌激素受体基因型PvuⅡ多态性PP,Pp,pp型分别为19.6%,46.7%,33.7%,XbaⅠ多态性XX,Xx,xx型分别为22.8%,33.7%,43.5%;XX型的腰椎、股骨大转子和Wards三角的骨密度明显低于xx型(P<0.05),而PvuⅡ基因的各基因型与骨密度无关;联合分析PvuⅡ和XbaⅠ位点,PPXX基因型的腰椎、股骨大转子和Wards三角的骨密度明显低于Ppxx和ppxx型(P<0.05)。结论雌激素受体XbaⅠ基因多态性与特发性脊柱侧凸患者的骨密度有关,PPXX基因型的骨密度较低,有助于较早发现特发性脊柱侧凸的低骨量者。     

Collagen gene polymorphisms influence fracture risk and bone mass acquisition during childhood and adolescent growth

Fractures are common in childhood with incidence maximal during puberty, around the time of peak height velocity. The relationships between single nucleotide polymorphisms (SNPs) in COL1A1 and COL1A2, bone mass acquisition, and childhood fractures are unclear.We recruited 394 children and adolescents aged 4 to 16 years into a noninterventional case control study. All had suffered an episode of trauma leading to hospital presentation; 205 had sustained a fracture. We determined the frequency of COL1A1 Sp1 and COL1A2 PvuII SNPs. Lumbar spine dual-energy X-ray absorptiometry (DXA) measurements were compared between fracture and control groups according to genotype. Subgroup analyses were performed according to sex, pubertal status, and site of injury.We found that the COL1A2 ‘PP’ genotype approximately halved the odds of fracture in the study group as a whole (OR = 0.45 [95% CI = 0.24–0.82], p = 0.01). In particular, possession of the same genotype by subjects who had not yet progressed beyond midpuberty was associated with reduced odds of fracture (OR = 0.38 [95% CI = 0.19–0.79], p = 0.01) and significantly increased lumbar spine bone mineral content (p = 0.03) and areal bone mineral density (p = 0.007). The COL1A1 Sp1 binding site ‘s’ allele was associated with a trebling of the odds of fracture in prepubertal children (OR = 3.1 [95% CI = 1.43–6.61], p = 0.004), but there was no association with any DXA measures.This is the first paediatric study to our knowledge that shows an association of the COL1A2 PvuII restriction site ‘PP’ genotype with a reduced risk of fracture and of the COL1A1 Sp1 binding site ‘s’ allele with an increased risk. The association of these variants with fracture risk is greatest during periods of predominantly appendicular bone growth.     

Vitamin D receptor gene BsmI and TaqI polymorphisms and fracture risk: a meta-analysis

INTRODUCTION: Fracture is the major clinical outcome of osteoporosis. The vitamin D receptor (VDR) gene is thought to be a candidate gene for osteoporosis. Many genetic studies have suggested an association of VDR polymorphisms and osteoporosis, but evidence remains conflicting. MATERIALS AND METHODS: We searched published studies from 1996 to September 2005 through PubMed and evaluated the genetic effect of the BsmI and TaqI polymorphism of VDR on fracture risk in a meta-analysis. Thirteen studies with a total of 20 eligible comparisons (1632 fracture cases and 5203 controls) were analyzed with fixed and random effects models. RESULT: No evidence of relationship between the VDR BsmI or TaqI polymorphism and fracture risk was observed with any genetic model. The odds ratio (95% confidence interval) of b-allele versus B-allele was 0.98 (0.86-1.12) with random effects calculations. There was significant between-study heterogeneity. Small studies did not differ significantly from larger ones. CONCLUSION: No relationship of the VDR BsmI or TaqI polymorphism and fracture risk was found in the meta-analysis of published data.     

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.