Estrogen receptor alpha gene polymorphisms and peak bone density in Chinese nuclear families.

PBD is an important determinant of osteoporotic fractures. Few studies were performed to search for genes underlying PBD variation in Chinese populations. We tested linkage and/or association of the estrogen receptor alpha gene polymorphism with PBD in 401 Chinese nuclear families. This study suggests the ER-alpha gene may have some minor effects on PBM variation in the Chinese population. Low peak bone density (PBD) in adulthood is an important determinant of osteoporotic fractures in the elderly. PBD variation is mainly regulated by genetic factors. Extensive molecular genetics studies have been performed to search for genes underlying PBD variation, largely in whites. Few studies were performed in Chinese populations. In this study, we simultaneously test linkage and/or association of the estrogen receptor alpha (ER-alpha) gene polymorphism with PBD in 401 Chinese nuclear families (both parents plus their female children) of 1260 subjects, with the 458 children generally between 20 and 40 years of age. All the subjects were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) at polymorphic PvuII and XbaI sites inside the ER-alpha gene. Bone mineral density was measured at the lumbar spine (L1-L4) and hip (femoral neck, trochanter, and intertrochanteric region). Raw bone mineral density values were adjusted by age, height, and weight as covariates. We detected marginally significant results for within-family association (transmission disequilibrium; p = 0.054) between the spine bone mineral density variation and the ER-alpha XbaI genotypes. For the hip bone mineral density variation, significant (p < 0.05) linkage results were generally found for the two intragenic markers. Analyses of the haplotypes defined by the two markers confer further evidence for linkage of the ER-alpha with the hip PBD variation. In conclusion, this study suggests that the ER-alpha gene may have minor effects on PBD variation in our Chinese population.     

Estrogen receptor gene polymorphism and bone mineral density in postmenopausal Chinese women

PvuII and XbaI restriction fragment length polymorphisms (RFLPs) for the estrogen receptor gene (ERG) and its relation to bone mineral density (BMD) were examined in 454 postmenopausal Chinese women, aged 55-79 years. The RFLPs were represented as P or p (PvuII) and X or x (XbaI), with capital letters signifying the absence of and small letters the presence of restriction sites. There was no significant difference in BMD between the PP, Pp, and pp genotypes. However, women of the XX genotype had significantly higher BMD at the spine than women of the Xx or xx genotype. The magnitude of the difference in BMD was 80% of a standard deviation (SD) for BMD in elderly women and 40% of a SD in postmenopausal women. There was no statistically significant interaction between the PvuII genotype and the XbaI genotype in determining BMD. We conclude that postmenopausal Chinese women who were homozygous for the XX genotype had slightly higher BMD than the others. However, the difference in BMD was small and was unlikely to have any clinical significance. The ERG is not a major determinant of BMD in Chinese women in Hong Kong.     

Association of estrogen receptor alpha and collagen type I alpha 1 gene polymorphisms with bone mineral density in postmenopausal women

Summary  

In this study, ERα gene PvuII and XbaI polymorphisms and COL1A1 gene Sp1 polymorphisms in postmenopausal women were compared with lumbar vertebra and femoral neck BMD values. In conclusion, it was designated that PvuII polymorphism was effective on average lumbar vertebra BMD value in postmenopausal women of our study group.     

Association of polymorphisms of the estrogen receptor alpha gene with bone mineral density and fracture risk in women: a meta-analysis.

The contribution of genetic polymorphisms to bone mineral density (BMD) and fracture risk in women is a controversial topic. We evaluated the effect of the XbaI and PvuII polymorphisms of the estrogen receptor a to BMD and fracture risk in a meta-analysis, including published data and additional information from investigators. Five thousand eight hundred thirty-four women from 30 study groups were analyzed with fixed and random effects models. The PvuII polymorphism was not associated with BMD at any skeletal site examined and 95% CIs exclude effects over 0.015 g/cm2 for both the femoral neck and the lumbar spine. Conversely, XX homozygotes (women carrying two copies of the gene variant without an XbaI restriction site) consistently had higher BMD than other subjects. The magnitude of the effect was similar in the femoral neck and lumbar spine (0.014 g/cm2 [95% CI, 0.003-0.025] and 0.015 g/cm2 [95% CI, 0.000-0.030], respectively; no between-study heterogeneity for either). Total body BMD was also significantly higher in XX homozygotes (by 0.039 g/cm2 and 0.029 g/cm2 compared with Xx and xx, respectively). Available data on fractures suggested a protective effect for XX (odds ratio [OR], 0.66 [95% CI, 0.47-0.93] among 1591 women), but not PP (OR, 0.93 [95% CI, 0.72-1.18] among 2,229 women). In summary, we have found that XX homozygotes may have higher BMD and also a decreased risk of fractures when compared with carriers of the x allele, whereas the PvuII polymorphism is not associated with either BMD or fracture risk.     

Estrogen receptor beta gene polymorphisms are associated with higher bone mineral density in premenopausal,but not postmenopausal southern Chinese women

Bone mineral density (BMD), the main determining risk factor for osteoporotic fractures, has a strong genetic component. Estrogen and its receptors play a critical role in both skeletal maturity and bone loss. We investigated the association between dinucleotide (cytosine-adenine; CA) repeat polymorphisms located in the flanking region of the estrogen receptor beta gene and bone mineral density (BMD) in 325 healthy southern Chinese women. BMD at the lumbar spine and hip region were measured using dual-energy X-ray absorptiometry (DEXA). The number of the repeats observed in our population ranged from 16 to 28. After adjusting for age, height, weight, and years of estrogen exposure, we observed that premenopausal subjects (n = 120) bearing at least one allele of 20 CA repeats had significantly higher BMD at the L2-4 lumbar spine (1.049 +/- 0.016 vs. 0.984 +/- 0.015; p = 0.01), total hip (0.836 +/- 0.014 vs. 0.813 +/- 0.013; p < 0.02), femoral neck (0.773 +/- 0.014 vs. 0.728 +/- 0.013; p = 0.02), trochanter (0.665 +/- 0.013 vs. 0.614 +/- 0.012; p = 0.01), and Ward's triangle (0.715 +/- 0.017 vs. 0.651 +/- 0.016; p = 0.02). There was no difference in the vertebral area of L-3 and femoral neck width in these premenopausal women with or without 20 CA repeats. However, in postmenopausal women (n = 205), Estrogen receptor beta (ER beta) gene polymorphisms were not related to BMD at any skeletal site. We conclude that ER beta gene polymorphisms are associated with higher BMD in premenopausal women, suggesting that the ER beta gene may have a modulatory role in bone metabolism in young adulthood.     

Association of estrogen receptor α gene polymorphisms with bone mineral density in Chinese women: a meta-analysis

Introduction and hypothesis A large number studies have examined the association between estrogen receptor alpha (ESR-α) gene polymorphisms and bone mineral density (BMD) in the Chinese population. We conducted a meta-analysis to assess their pooled effects. Methods We searched for all published articles indexed in MEDLINE, the Chinese Biomedical Database, and the Chinese Journal Full-text Database from January 1994 to April 2006. Any cross-sectional study that tested the association between ESR-α PvuII or XbaI genotypes and BMD at the femoral neck or spine in Chinese women was included in the review. Data were extracted independently by two reviewers using a standardized data extraction form. Sixteen eligible studies involving 4,297 Chinese women were identified. Results The overall frequencies of X and P alleles were 28% and 40%, respectively. The PvuII polymorphism was statistically significantly associated with BMD at the femoral neck (P = 0.038 for PP = Pp = pp) but not at the lumbar spine in all women. The BMD difference for the contrasts of PP versus Pp/pp genotypes was −0.0105 (95%CI, −0.0202 ∼ −0.0008) g/cm² (P = 0.036). The XbaI polymorphism was not associated with BMD at the femoral neck or lumbar spine. Conclusion The PvuII polymorphism had a very weak association with femoral neck BMD whereas XbaI polymorphism was unlikely to be a predictor of femoral neck or spine BMD in Chinese women.     

维生素D受体等位基因多态性与骨密度相关性分析

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两个新钙感觉受体基因多态性与中国女性骨密度相关性研究

目的钙感觉受体(CaSR)基因是引人关注的与骨质疏松症敏感性相关的侯选基因,为了解CaSR基因两个新多态位点与中国女性人群骨密度(BMD)的关系。方法采用双能X线吸收仪对352名研究对象进行腰椎及股骨扫描,应用PCR限制性片段长度多态性(PCRRFLP)方法检测CaSR基因R990G和E1011Q两个新多态位点基因型,用广义线性模型分析CaSR基因与腰椎及股骨BMD关系。结果发现CaSR基因的E1011Q多态位点在调整相关影响因素前后均与女性股骨颈、股骨柄和股骨三角区的BMD呈显著相关,P值分别为0.011、0.04和<0.001;R990G多态位点在调整影响因素前后,显示与女性股骨颈密度有相关趋势P=0.055,而A986S基因多态未显示与股骨、腰椎BMD相关。结论这一结果提示,CaSR基因E1011Q多态性可能是中国女性股骨BMD降低的危险因素。这个发现的意义及是否适用于大样本人群还有待进一步研究证实。     

Lack of association between the SOST gene and bone mineral density in perimenopausal women: analysis of five polymorphisms

Osteoporosis is a common disease characterized by a decrease in bone mass, architectural deterioration of the bone tissue, and an increased risk of fracture. The condition is under strong genetic control, involving a large variety of gene products, but to date the genes responsible remain poorly defined. Although population-based studies have identified polymorphisms in several candidate genes that are associated with bone mineral density (BMD), these account for only a small proportion of the population variance in bone mass. In this study, we looked for evidence of an allelic association between polymorphisms in the SOST gene and BMD. This gene was analyzed because loss-of-function mutations in SOST cause sclerosteosis, a sclerosing bone dysplasia associated with increased bone mass due to increased bone formation. We identified 26 different polymorphisms in the SOST gene and selected 5 of these for association analysis in a case-control study of 619 women with either high or low BMD, drawn from a random population-based survey of 5119 perimenopausal white women. The high BMD group comprised 326 women in whom lumbar spine BMD values adjusted for age, height, and weight were in the highest 16% of the population distribution, and the low BMD group comprised 293 women in whom BMD values were in the lowest 16% of the population distribution. The distribution of genotypes and alleles for each Single Nucleotide Polymorphism (SNP) examined did not differ in the low and high BMD groups. We conclude that, in this population, common allelic variations in the SOST gene do not contribute significantly to the regulation of high or low BMD.     

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.     

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.     

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。     

褪黑素受体1B基因多态性与青少年骨密度的相关性

目的探讨褪黑素受体1B基因(MTNR1B)多态性与骨密度之间的相关性。方法选取140名16~20岁之间的正常女性,采用双能X线骨密度吸收仪测量双侧近端股骨的骨密度。同时,采取外周静脉血,采用试剂盒提取DNA。根据人类单倍体图计划(HapMap)提供的汉族人数据,我们在MTNR1B基因上选取了6个标签SNP(tagSNPs)。通过PCR-RFLP的方法检测褪黑素受体1B基因上6个标签SNP的基因型。采用ANOVA的统计学方法比较不同基因型对应骨密度大小。结果MTNR1B基因6个多态性位点各基因型所对应的骨密度,没有明显差异(P>0.05)。结论褪黑素受体1B基因多态性与骨密度之间没有相关性。     

A susceptibility haplotype within the endothelial nitric oxide synthase gene influences bone mineral density in hypertensive women

The influence of the coordinated effect of various single-nucleotide polymorphisms (SNPs) within the endothelial nitric oxide synthase (eNOS) gene on the risk of osteoporosis in hypertension has remained undetermined. Four pertinent SNPs of the eNOS gene, rs2070774, rs1799983, rs1800780 and rs3918181, were examined for the risk of osteoporosis in 313 hypertensive postmenopausal women in Northwest India. All the hypertensive women were verified with dual energy X-ray absorptiometry and categorized as 150 with osteoporosis and 163 without osteoporosis. The minor allele (T) of rs1799983 exerts a statistically significant risk for osteoporosis both in dominant [odds ratio (OR) 3.71, 95 % confidence interval (CI) 2.12–6.49, P < 0.001] and recessive mode (OR 5.75, 95 % CI 1.24–26.69, P = 0.036) after Bonferroni correction. Bone mineral density (BMD) values (corrected for the effects of risk variables) according to eNOS SNP genotypes revealed a significant association with rs1799983 at both the lumbar spine (P = 0.001) and femoral neck (P = 0.023). Risk association analyses revealed a susceptibility haplotype TTAG which influences the risk of osteoporosis (OR 2.02, 95 % CI 1.05–3.39, P = 0.042) in hypertension after adjusting for the effects of risk factors. Furthermore, this haplotype was significantly associated with BMD at the lumbar spine (P = 0.029) and femoral neck (P = 0.021) in a dose-dependent manner. The results suggest that possession of the TTAG haplotype of the eNOS gene may increase the risk of osteoporosis two-fold in hypertensive postmenopausal women in Northwest India.     

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。     

The association between vitamin D receptor gene polymorphisms and bone mineral density at the spine,hip and whole-body in premenopausal women

The genetic influence on bone mineral density (BMD) is thought to be mediated in part by alleles at the vitamin D receptor (VDR) locus. In order to assess the effect of VDR on BMD in premenopausal women, we studied 470 healthy white subjects, aged 44–50 years, participating in the Women's Healthy Lifestyle Project. Each participant was genotyped for theBsmI polymorphism at the VDR gene locus. BMD at the lumbar spine, hip and whole-body, and the whole-body soft tissue composition, were measured cross-sectionally using a Hologic QDR 2000 densitometer. The presence of a polymorphic restriction site at the VDR gene locus was specified asb, whereas absence of this site wasB. The frequency distribution of the VDR genotype was:bb, 20.6%;Bb, 39.1%; andBB, 40.2%. Spinal BMD (mean±SD) was significantly lower in women with VDR genotypeBB (1.038±0.11 g/cm²) as compared with those with genotypebb (1.069±0.12 g/cm²,p<0.05). Trochanter BMD was 2.7% lower in those with genotypeBB versusbb (0.685±0.10 g/cm² vs 0.708±0.09 g/cm²). A similar trend was shown at each subregion of the hip, but not at the whole-body. In premenopausal women, allelic status at the VDR locus contributed to variations in spinal and trochanteric BMDs, but the absolute difference in BMDs was small, amounting to 0.26 and 0.23 standard deviations, respectively. It is concluded that in this population of healthy premenopausal women there was a significant association between polymorphisms at the VDR gene locus and both spinal and trochanteric BMDs, yet no association was demonstrated for the whole-body BMD.     

Estrogen receptor (ER) gene polymorphism may predict the bone mineral density response to raloxifene in postmenopausal women on chronic hemodialysis

The estrogen receptor (ER) gene has been considered as a candidate genetic marker for osteoporosis, and PvuII and XbaI polymorphisms of the ERalpha gene have been associated with low bone mineral density (BMD). We investigated whether ER polymorphism could predict the response of BMD in 28 postmenopausal women on hemodialysis with marked osteopenia or osteoporosis, randomized to receive raloxifene, a selective estrogen receptor modulator (SERM), or placebo for 1 year. BMD was assessed by dual X-ray absorptiometry and PvuII and XbaI restriction fragment-length polymorphism of the ER gene was determined using polymerase chain reaction. Baseline lumbar spine or femoral neck BMD parameters were not different between patients presenting either homozygous PP or xx when compared with heterozygous Pp or Xx genotypes. After 1 year, patients on raloxifene, presenting with PP or xx genotypes (but not those with Pp or Xx), showed a significantly higher mean lumbar spine BMD (0.942 +/- 0.18 vs. 0.925 +/- 0.17 g/cm2, p < .01) and lower serum pyridinoline (19.7 +/- 9.7 vs. 30.6 +/- 16.5 nmol/L, p < .02) when compared with baseline values. No changes were detected in the placebo-treated patients or in the femur neck sites. In conclusion, after 1 year on raloxifene, postmenopausal osteoporotic women on chronic hemodialysis, homozygous for the P or x (PP or xx) alleles of the ER, exhibited a better lumbar spine BMD response and decreased serum pyridinoline values when compared with heterozygous women (Pp or Xx), suggesting that ERalpha allelic variants may explain, at least in part, the different outcomes after treatment of osteoporosis with SERM.     

安徽地区绝经后妇女低密度脂蛋白受体相关蛋白5基因多态性与骨密度的关系

目的研究安徽地区绝经后妇女低密度脂蛋白受体相关蛋白5基因（LRP5）Q89R和A1330V多态性位点与骨密度的关系。方法采用PCR-限制性片段长度多态性（PCR．RFLP）方法检测安徽地区247名绝经后妇女LRP5基因Q89R和A1330V多态性位点的基因型,双能X线骨密度仪测定腰椎和股骨的骨密度。结果本研究人群中,LRP5基因Q89R和A1330V多态性呈连锁不平衡（x^2=24、48,P〈0．01）。Q89R位点QR组的股骨颈、Ward’s三角和大转子区骨密度明显低于QQ组,A1330V位点AV/VV组的股骨颈骨密度明显低于AA组。在调整年龄、身高、体重、BMI以及绝经年限这些影响因素后,Q89R多态位点与股骨颈和大转子区骨密度显著相关（P〈0．05）,而A1330V多态性位点则与各位点的骨密度均无相关性。结论LRP5基因Q89R多态性位点可能对绝经后妇女骨密度有影响,提示LRP5基因是影响骨密度的候选基因之一。