Genetic markers, bone mineral density, and serum osteocalcin levels.

We evaluated five genetic markers for products that contribute to skeletal mineralization including the Sp1 polymorphism for type I collagen Ai (COLIA1), the vitamin D receptor (VDR) translation initiation site polymorphism, the promoter of the osteocalcin gene containing a C/T polymorphism, the estrogen receptor (ER) gene containing a TA repeat, and the polymorphic (AGC)n site in the androgen receptor. These markers were evaluated for their potential relationship with bone mineral density (BMD), measured by dual-energy X-ray densitometry, or its 3-year change. Additionally, potential associations of these genotypes and with baseline osteocalcin concentration or its 3-year change (assessed using radioimmunoassay) were evaluated. The study was conducted in 261 pre- and perimenopausal women of the Michigan Bone Health Study, a population-based longitudinal study of musculoskeletal characteristics and diseases. The polymorphic (AGC)n site in the androgen receptor showed a strong association with BMD of the femoral neck (FN) and lumbar spine and remained highly significant after adjusting for body mass index (BMI), oophorectomy/hysterectomy, oral contraceptive (OC) use and hormone replacement use (p < 0.001). The TA repeat at the 5' end of the ER gene was associated with total body calcium (p < 0.05) after adjusting for BMI, oophorectomy and hysterectomy, and OC use. The frequency of oophorectomy and hysterectomy within selected genotypes explained much of the statistically significant association of the ER genotypes with BMD of the FN and spine. There was no association of measures of BMD or bone turnover with the Sp1 polymorphism for COLIA1, the VDR translation initiation site polymorphism, or the C/T promoter polymorphism of the osteocalcin gene. These findings suggest that sex hormone genes may be important contributors to the variation in BMD among pre- and perimenopausal women.     

Genetic control of bone density and turnover: role of the collagen 1alpha1, estrogen receptor, and vitamin D receptor genes.

Genetic factors are known to influence both the peak bone mass and probably the rate of change in bone density. A range of regulatory and structural genes has been proposed to be involved including collagen 1alpha (COL1A1), the estrogen receptor (ER), and the vitamin D receptor (VDR), but the actual genes involved are uncertain. We therefore studied the role of the COL1A1 and VDR loci in control of bone density by linkage in 45 dizygotic twin pairs and 29 nuclear families comprising 120 individuals. The influences on bone density of polymorphisms of COL1A1, VDR, and ER were studied by association both cross-sectionally and longitudinally in 193 elderly postmenopausal women (average age, 69 years) over a mean follow-up time of 6.3 years. Weak linkage of the COL1A1 locus with bone density was observed in both twins and families (p = 0.02 in both data sets), confirming previous observations of linkage of this locus with bone density. Association between the MscI polymorphism of COL1A1 and rate of lumbar spine bone loss was observed with significant gene-environment interaction related to dietary calcium intake (p = 0.0006). In the lowest tertile of dietary calcium intake, carriers of "s" alleles lost more bone than "SS" homozygotes (p = 0.01), whereas the opposite was observed in the highest dietary calcium intake (p = 0.003). Association also was observed between rate of bone loss at both the femoral neck and the lumbar spine and the TaqI VDR polymorphism (p = 0.03). This association was strongest in those in the lowest tertile of calcium intake, also suggesting the presence of gene-environment interaction involving dietary calcium and VDR, influencing bone turnover. No significant association was observed between the PvuII ER polymorphism alone or in combination with VDR or COL1A1 genotypes, with either bone density or its rate of change. These data support the involvement of COL1A1 in determination of bone density and the interaction of both COL1A1 and VDR with calcium intake in regulation of change of bone density over time.     

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。     

老年男性维生素D受体基因多态性与骨密度关系的研究

目的研究维生素D受体(vitamin D receptor,VDR)基因多态性在老年男性中的分布, 并进一步研究其与骨密度的关系。方法采用聚合酶链反应-限制性片段长度多态性(PCR- RFLP)方法,分析145例老年男性的VDR基因型,同时用双能X线吸收法测定腰椎及髋部骨密度。结果 VDR基因型分别为BB,0．014;Bb,0．117;bb,0．869。骨质疏松组与非骨质疏松组之间VDR基因型分布频率的差异无显著性(P>0．05)。比较各基因型组的骨密度,bb组及 Bb组只有在股骨颈处显示出BMD均低于BB组,差异有显著性(P<0．05),其它部位,三个基因型组的BMD均差异无显著性(P>0．05)。结论老年男性VDR基因型分布频率与某些西方国家人群分布不同,其VDR基因型与骨密度无明显相关性。VDR基因可能不是我们所研究群体 BMD的主要遗传基因。     

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 *5.8% spine BMD variation. Both ERX and ERP genotypes are significantly (p = 0.02) associated with *3.5% femoral neck BMD variation. ERX genotypes are significantly (p = 0.03) associated with *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. Received: 4 August 1998 / Accepted: 2 November 1998     

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.     

绝经后骨质疏松人群雌激素受体基因Xba I多态性和年龄对骨密度的影响

目的 分析绝经后骨质疏松人群雌激素受体(ER)基因XbaⅠ多态性与骨密度的相关性以及在基因多态性下年龄、绝经年限及体重指数(BMI)对骨密度的影响。方法 用双能X线骨密度仪检测患者151例，以PCR-RFLP的方法检测ER基因XbaⅠ多态性，SPSS软件进行相关回归分析。结果 ER基因型的频率分布为XX型16．6％，Xx型67．5％，xx型15．9％，XX型的骨密度在腰椎、股骨颈和Ward’s三角要高于Xs型和xx型。但ER多态性与骨密度无相关性。在Xx型和XX型人群中年龄越大，绝经年限越长，腰椎和股骨上端骨密度则越低。在XX型中，BMI是影响股骨颈和Ward’s三角骨密度的主要因素。而在xx型中，腰椎和ward’s三角骨密度与年龄、BMI和绝经年限无相关性，绝经年限与股骨颈骨密度相关，大转子与BMI相关。结论 福州地区绝经后骨质疏松人群ER基因XbaⅠ基因型与骨密度无明显相关性，但在不同基因型人群中，其骨密度的丢失趋势和影响因素也各异，临床上应采用不同的防治措施。     

维生素D受体基因型与骨密度

目的考察维生素D受体(VDR)基因多态性在我国汉族人群中的分布频率,分析VDR基因型与骨密度的关系.方法采用聚合酶链反应和限制性酶切技术检测100例绝经前健康妇女VDR基因多态性.应用双能X线骨密度仪检测受试者腰椎及髋部骨密度.结果VDR基因型分布频率为BB型4.0%,Bb型10.0%,bb型86.0%;而三种基因型受试者髋部及腰椎骨密度均表现出Bb＞bb＞BB,经F检验腰椎骨密度3基因型比较,P＜0.05,具有显著差异.结论绝经前妇女VDR基因型分布频率与西方及国内的一些报道不尽相同,且骨密度显示出Bb＞bb＞BB,亦与国内外一些研究结果不同.     

上海地区汉人维生素D受体基因多态性与骨密度关系的初步分析

目的：了解维生素D受体（VDR）基因多态性在中国人群中的分布，并进一步研究其与骨密度的关系。方法：通过聚合酶链反应－限制性片段长度多态性（PCR－RFLP）方法分析了348例无亲缘关系的上海地区男女居民的VDR基因型，并用双能X线吸收仪测定了其中202例骨密度。结果：348例研究对象中bb型占81．9％，Bb型占18．1％，未见到BB型。b等位基因在本组人群中分布 高达90．0％。男女性之间VDR基因型分布频率无明显区别（P＞0．5）。比较这两组各部位的骨密度值，只有女性在华氏三角区部位显示出Bb型比bb型有较高的BMD，在其余部位，不管男性还是女性，两组基因型的BMD均差异无显性（P＞0．05）。结论：VDR基因多态性与骨密度无相关关系。     

No major effect of estrogen receptor gene polymorphisms on bone mineral density or bone loss in postmenopausal Danish women

The polymorphisms of the estrogen receptor (ER) gene defined by the restriction enodonucleases PvuII and XbaI have recently been reported to be associated with bone mineral density (BMD) in postmenopausal women. To investigate the possible relation of the PvuII and XbaI restriction fragment-length polymorphisms of the ER gene with BMD in Danish postmenopausal women, two studies were undertaken: 1) a cross-sectional study of 499 postmenopausal women, where the ER genotypes and alleles were related to BMD of the hip, spine, and lower forearm; and 2) a longitudinal study of 101 postmenopausal women followed up for 18 years. In the latter study, late postmenopausal bone loss in the hip and spine was determined over a period of 6 years in women (mean age of 63 to 69 years), and long-term postmenopausal bone loss in the lower forearm was determined over a period of 18 years in women (mean age of 51 to 69 years). Genotyping was performed through the restriction cleavage of polymerase chain reaction-amplified genomic DNA with the two restriction enzymes, PvuII and XbaI. Restriction fragment-length polymorphisms were represented as P or p (PvuII) and X or x (XbaI), with the lower case letters signifying the presence of the restriction site. The frequencies of the ER genotypes were similar to previously published genotype frequencies in Caucasian and Asian populations. No significant effect of the ER genotypes or alleles on BMD was found at any site, nor was there a relation between ER genotypes and the rate of bone loss either in the hip and spine over 6 years, or in the lower forearm over 18 years. In conclusion, we could not demonstrate any major effect of the ER gene polymorphisms on BMD or rate of bone loss in healthy postmenopausal Danish women.     

The genetic background of osteoporosis in cystic fibrosis: Association analysis with polymorphic markers in four candidate genes

BACKGROUND: Reduced Bone Mass Density (BMD) is frequent in Cystic Fibrosis (CF). Potentially, other genes than the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene may contribute to the bone phenotype variability in CF patients. METHODS: Four candidate genes likely associated with BMD variability were studied: the vitamin D receptor (VDR) gene, the estrogen receptor alpha (ESR1), the calcitonin receptor (CALCR) and the type I alpha 1 collagen (COL1A1) gene. A complete bone and CF evaluation was obtained for 82 subjects (39 m, 43 f): 15 had normal BMD (group 1), 46 were osteopenic (group 2), and 21 were osteoporotic (group 3). RESULTS: No statistical difference was found among the three groups for age, sex, pancreatic status, and vertebral fractures, nor for any of the biochemical markers. Weight, Body Mass Index (BMI), and FEV1, scored significantly worse in the two groups with the lowest T score. The CFTR mutations R1162X and F508del were more frequent in patients with lower BMD (p=0.044 and p=0.071). There was no significant difference in the distribution of the five marker genotypes among the 3 groups defined according to the unadjusted or adjusted (BMI and FEV1) BMD T score. No significant correlation was found between the VDR, CALCR, or COL1A1 gene polymorphisms and reduced BMD values. The individual ESR1 PvuII-XbaI haplotype C-A is associated to elevated u-calcium levels whereas the haplotype T-A is associated to lower values (p=0.00251). CONCLUSIONS: There was no evidence that the genes under study, with the possible exception of ESR1 gene variants, may modulate bone phenotype in CF.     

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.     

广西壮、汉族绝经后妇女维生素D受体基因型与骨密度的关系

目的 探讨维生素D受体基因(VDR)型在广西壮、汉族绝经后妇女中的分布及其与骨密度(BMD)的关系。方法 在广西居住20年以上、无血缘关系的健康绝经后妇女198名,其中三代均为壮族的116名,均为壮族的82名。记录他们的年龄、绝经年龄,测量他们的身高、体重。用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法测定受试者的VDR基因型;用双能X线吸收法测定髋部、腰椎和前臂的骨密度。结果 壮、汉两组妇女VDR基因型和VDR等位基因频率分布均无显著性差异(P>0.05);198名妇女BB、Bb、bb基因型检出率分别为6.57％、66.16％和27.27％;B、b等位基因分别为39.65％和60.35％。BB基因型组第二腰椎(L2)BMD较bb基因型组低10.03％(P=0.047),第四腰椎(L4)BMD分别较bb、Bb基因型组低9.63％(P=0.043)和12.44％(P=0.005)。BB基因型组骨质疏松发生率最高(46.15％),Bb基因型组次之(19.86％),bb基因型组最低(14.81％),差异有显著性(P=0.04)。结论 VDR基因型与广西壮、汉族绝经后妇女BMD有关联,BB基因型可能可作为预测广西壮、汉族绝经后妇女骨质疏松危险性的遗传学标志之一。     

Gene Expression for Extracellular Matrix Proteins in Shockwave-Induced Osteogenesis in Rats

To clarify the mechanisms underlying shockwave-induced osteogenesis, we applied shockwave to rat femoral shafts from the ventral side. We assessed bone mineral content (BMC) and bone mineral density (BMD), and analyzed the spatial and temporal gene expression for pro-1 (I) collagen (COL1A1), pro-1 (II) collagen (COL2A1), pro-1 (X) collagen (COL10A1), osteocalcin (OC) and osteopontin (OPN) using in situ hybridization. On the 21st day post-exposure, BMC and BMD in the exposed femur were elevated by 8.46% and 5.80%, respectively, relative to the unexposed femur. Immediately following exposure, there was evidence of scraping of the cortex and periosteal separation with hemorrhage. On day 4, new periosteal bone formation could be seen on the ventral and dorsal side of the femur. In the newly formed bone, COL1A1, OC and OPN were expressed in osteoblastic cells underlying the periosteum. On day 7, there was progression of periosteal bone and trabeculae formation. COL1A1 and OC were expressed in mature osteoblasts lining the trabeculae, whereas OPN was expressed in immature osteoblastic cells, osteocytes and osteoclasts. On day 14, bone remodeling commenced in the periosteal bone. COL1A1, OC and OPN were still expressed at this stage, however, signals were much weaker. Between 4–7 days, chondrocyte clusters were distributed multi-focally near the exposed site, and there was expression of COL2A1 but not of COL10A1. The results demonstrate that gene expression patterns of shockwave-induced osteogenesis are similar to those of periosteal hard callus formation during fracture healing. Shockwaves can yield dramatic activation of cells in normal long bones, and drive the cells to express genes for osteogenesis.     

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.     

The relation of the Xbal and Pvull polymorphisms of the estrogen receptor gene and the CAG repeat polymorphism of the androgen receptor gene to peak bone mass and bone turnover rate among young healthy men

The genes coding for estrogen receptor- (ER-) and androgen receptors (AR) are potential candidates for the regulation of bone mass and turnover, which may contribute to both the achievement of peak bone mass and bone loss after completion of growth. The present study was aimed at elucidating the role of two restriction fragment lengths (XbaI and PvuII) polymorphisms of the ER gene and the CAG repeat polymorphism of the AR gene as determinants of peak bone mass in men; special attention was paid to the interaction between serum free estradiol (E₂) levels and the XbaI and PvuII genotypes. A cross-sectional study, with data on lifestyle factors collected retrospectively, was performed in 234 young men, aged 18.3 to 20.6 years. Of the men, 184 were recruits of the Finnish Army and 50 were men of similar age who had postponed their military service for reasons not related to health. Bone mineral content (BMC), density (BMD) and scan area were measured in the lumbar spine and upper femur by dual-energy X-ray absorptiometry (DXA). The bone turnover rate was assessed by measuring serum type I procollagen aminoterminal propeptide (PINP) and tartrate-resistant acid phosphatase 5b (TRACP5b) as well as urinary excretion of type I collagen aminoterminal telopeptide (NTX). After adjusting for age, height, weight, exercise, smoking, calcium and alcohol intake, BMC, scan area and BMD at all measurement sites were similar for the different XbaI and PvuII genotypes of the ER and independent of the number of the CAG repeats of the AR gene. No association was found between free E₂ levels and bone parameters among any genotype group of the XbaI and PvuII polymorphisms. Except for urinary NTX, which showed a tendency to higher values for the xx ( P =0.08) and pp ( P =0.10) genotypes of the ER, bone turnover markers were not related to the genotypes studied. Our study does not support the view that the XbaI and PvuII polymorphisms of the ER gene and the CAG polymorphism of the AR gene would have a substantial impact on the development of peak bone mass in young Finnish men.     

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.     

甲状旁腺素和维生素D受体基因多态对糖尿病患者骨密度的影响

目的探讨甲状旁腺素(PTH)基因多态性与中国北方汉族人糖尿病患者骨密度的关系,联合分析维生素D受体(VDR)基因和PTH基因多态性与骨密度的相关性。方法选自青岛市内分泌糖尿病医院1998年1月~2002年1月住院的糖尿病患者,运用聚合酶链反应限制性片段长度多态性(PCR-RFLP)技术检测了1型糖尿病(T1DM)组54例,2型糖尿病(T2DM)组104例,健康对照(CON)组102例,260例中国北方汉族人PTH基因多态性;采用双能X线吸收法骨密度仪(DEXA)测量骨密度。结果校正年龄和BMI后,1型糖尿病组腰椎、股骨颈骨密度低于对照组(P0.05);2型糖尿病组与对照组相比,骨密度差异无显著性(P0.05);甲状旁腺素(BSTB1位点)基因型和等位基因分布频率在1型糖尿病组、2型糖尿病组与对照组间差异无显著性(P0.05);在对照组及2型糖尿病组,BB基因型者腰椎(L2-4)和股骨颈部位骨密度显著高于Bb/bb基因型(P0.05);在1型糖尿病组,BB基因型仅腰椎L2-4部位骨密度高于Bb/bb基因型(P0.05);联合VDR基因多态(Apa I酶切位点)分析结果表明,Bbaa基因型在腰椎和股骨颈骨密度低于其他基因型(P0.05)。结论糖尿病患者PTH基因多态性(BSTB1位点)可能是预测骨量减少、骨质疏松易感性的遗传标志。联合VDR基因多态(Apa I酶切位点)有助于识别糖尿病患者发生骨质疏松的高危人群。     

Genetic and environmental determinants of peak bone mass in young men and women.

Peak bone mass is an important risk factor for the development of osteoporosis in later life. Previous work has suggested that genetic, intrauterine, and environmental factors all contribute to the regulation of bone mass, but the ways in which they interact with each other to do so remain poorly understood. In this study, we investigated the relationship between peak bone mass and polymorphisms of the vitamin D receptor (VDR), estrogen receptor (ER) a, and collagen type Ialpha1 (COLIA1) genes in relation to other factors such as birth weight, lifestyle diet, and exercise in a population-based cohort of 216 women and 244 men in their early 20s. Stepwise multiple regression analysis showed that body weight was the strongest predictor of bone mineral density (BMD) in women, accounting for 16.4% of the variance in spine BMD and 8.4% of the variance in femoral neck BMD. Other significant predictors were VDR genotype (3.8%) and carbohydrate intake (1.6%) at the spine and vitamin D intake (3.4%) and ER genotype (3.4%) at the femoral neck. Physical activity was the strongest predictor of BMD in men, accounting for 6.7% of the variance at the spine and 5.1% at the hip. Other significant predictors were body weight (5%) and ER PvuII genotype (2.8%) at the spine and weight (3.4%) and alcohol intake (2%) at the femoral neck. Birth weight was not a significant predictor of BMD at either site but COLIA1 genotype significantly predicted birth weight in women, accounting for 4.3% of the variance. We conclude that peak bone mass is regulated by an overlapping but distinct set of environmental and genetic influences that differ in men and women. However, much of the variance in BMD was unexplained by the variables studied here, which suggests that either most of the genes that regulate BMD remain to be discovered or major environmental influences on BMD exist that have not yet been identified.     

Association of the vitamin D receptor genotype BB with low bone density in hyperthyroidism.

Bone mineral density (BMD) is modulated by genetic and environmental factors or certain diseases. In several conditions such as low calcium intake, an influence of vitamin D receptor (VDR) polymorphisms on BMD has been suggested. In the present study, we investigated the relationship of Bsm I and Fok I polymorphisms of the VDR gene and BMD in patients with hyperthyroidism, a disease that often results in low BMD. Bsm I and Fok I genotypes were determined in 76 postmenopausal hyperthyroid patients and 62 healthy postmenopausal women as controls. Patients and controls were matched for age, time since menopause, and lifestyle factors and were free of estrogen medication. BMD evaluation included axial dual X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (PQCT). Low BMD was defined as -2.5 STD below the young adult mean value. Biochemical parameters investigated were thyroid hormones, osteocalcin, and 25-(OH)-vitamin D3 as well as routine laboratory data. Low BMD was found in 61% of hyperthyroid patients and in only 23% of euthyroid controls. In the group of hyperthyroid patients with low bone density, the BB genotype (VDR Bsm I polymorphisms) was significantly more frequent (39%) than in controls (13%; p = 0.003) and hyperthyroid patients with normal BMD (6%; p = 0.013). The odds ratio (OR) for low BMD in patients with BB genotype was 5.7 (95% CI, 1.7-19.1; p < 0.005) as compared with the Bb and bb genotypes and 5.5 (95% CI, 2.3-13.2; p < 0.0001) for hyperthyroidism alone. The cumulative risk for low BMD in patients with hyperthyroidism and BB genotype was 31.4 (95% CI, 3.9-256; p < 0.0003). VDR Fok I genotypes showed no significant relationship with BMD or other general or bone-specific parameters. Thus, hyperthyroidism and the genetic background of a BB genotype may promote synergistically the development of low BMD in hyperthyroid patients. Screening for the BB genotype in these patients therefore could help to identify those with particularly high risk for the development of low BMD and allow early treatment.