Association of estrogen receptor alpha gene polymorphisms with bone mineral density in postmenopausal Indian women

Bone mineral density (BMD) is the major determinant of osteoporotic fracture risk with a particular genetic background. However, consensus on the association of BMD with specific gene locus has not been reached. In the present study, we investigated the potential association of estrogen receptor alpha (ER alpha) gene intron I polymorphisms with BMD in 246 postmenopausal Indian women (average age 54.2+/-3.4 years). All the subjects were genotyped for XbaI and PvuII polymorphisms and underwent BMD measurements at spine and hip by dual energy X-ray absorptiometery. The average BMD of subjects with the genotypes XX and PP (absence of restriction sites for XbaI and PvuII, respectively) was 12.7 and 5.4% higher at the spine and 13.1 and 4.6% higher at the hip, respectively, than those with genotypes xx and pp. In age vs. BMD scatterplot, the intercept and slope of regression lines for genotypes xx and pp at spine and hip demonstrated comparatively rapid decrease in BMD across the age. The genotype XX was significantly prevalent (p<0.001) in women with normal bone mass (32%) and genotype xx in women with osteoporotic bone mass (35.3%), within the group. A significantly higher relative risk was associated with xx genotype. The study concludes that genetic variations at ER alpha gene locus, perhaps, are associated with BMD in Indian women and may influence some determinant of bone metabolism resulting in accelerated bone loss with age.     

Association of polymorphisms of the estrogen receptor alpha gene with bone mineral density of the femoral neck in elderly Japanese women

The estrogen receptor alpha gene is a candidate locus for genetic influence on bone mass. The possible association between two polymorphisms in the first intron of this gene, alone or in combination, and bone mineral density at various sites was examined in participants in the National Institute for Longevity Sciences Longitudinal Study of Aging, a population-based prospective cohort study of aging and age-related diseases. The relationship of the TC ( PvuII) and AG ( XbaI) polymorphisms in the first intron of the estrogen receptor alpha gene to bone mineral density was determined in 2230 subjects (1120 men, 1110 women) and in 2238 subjects (1128 men, 1110 women), respectively, all of whom were community-dwelling individuals aged 40-79 years. Bone mineral density at the radius was measured by peripheral quantitative computed tomography and that for the lumbar spine, right femoral neck, right trochanter, right Ward's triangle, and total body was measured by dual-energy X-ray absorptiometry. Estrogen receptor alpha genotypes were determined with an automated fluorescent allele-specific DNA primer assay system. Analysis of the TC ( PvuII) polymorphism revealed that bone mineral density for the total body, femoral neck, and trochanter was significantly lower in women aged 60 years or over with the CC genotype than in those with the TT genotype, but statistical significance was not achieved after adjustment for age, body mass index, and smoking status. Analysis of the AG ( XbaI) polymorphism revealed that bone mineral density for the femoral neck was significantly lower in women aged 60 years or over with the GG genotype than in those with the AA genotype. After adjustment for age, body mass index, and smoking status, bone mineral density for the femoral neck was significantly lower in women aged 60 years or over with the GG genotype than in those with the AA or AG genotypes. Analysis of combined genotypes in women aged 60 years or over revealed that bone mineral density for the femoral neck was significantly lower in women with the CC/ GG genotype than in those with the TT/ AA or TC/ AA genotypes. After adjustment for age, body mass index, and smoking status, bone mineral density for the femoral neck was significantly lower in women aged 60 years or over with the CC/ GG genotype than in those with other genotypes. No differences in bone mineral density at the various sites were detected among TC ( PvuII), AG ( XbaI), or combined genotypes in women aged under 60 years or in men. These results suggest that the estrogen receptor alpha gene is a susceptibility locus for bone mass, especially for the femoral neck, in elderly Japanese women.     

Association between single nucleotide polymorphisms of estrogen receptor alpha gene and efficacy of HRT on bone mineral density in post-menopausal Japanese women

BACKGROUND: Although HRT for post-menopausal women can protect against bone loss, variations in bone responses exist. We studied whether single nucleotide polymorphisms (SNP) of the estrogen receptor-alpha (ERalpha) gene contribute to the effect of HRT on lumbar spine bone mineral density (BMD). METHODS: Subjects were 84 post-menopausal women who had been taking HRT for 3 years to treat osteopenia or osteoporosis. Eighteen SNP in the ERalpha gene were characterized by a single nucleotide primer extension assay. RESULTS: Genotyping of the 84 individuals revealed that all SNP were quite common, the minor allele frequency being > or = 20%. A SNP in intron 6 (IVS6+14144) was significantly associated with the response to HRT for the first 3 years after starting treatment (P = 0.043, 0.025 and 0.032 for the first, second and third years respectively). Haplotype analysis revealed that a combination of SNP IVS6+14144 and IVS4+4238 was significantly correlated with the response to HRT; women with haplotype G-G (IVS6 14144-IVS4 4238) showed a significantly higher response (P = 0.014, 0.043 and 0.010 for the first second and third year respectively). CONCLUSIONS: These results suggest that a specific SNP and the haplotype of the selected SNP could be used to predict the effect of HRT on lumbar BMD.     

Correlation of estrogen receptor beta gene polymorphisms with spinal bone mineral density in peri- and post-menopausal Greek women

Estrogens play a significant role in bone physiology. Their action is mainly exerted through their receptors. Estrogen receptor alpha (ER) plays a major role in bone homeostasis and there is evidence suggesting that estrogen receptor beta (ERβ) has also an effect on BMD.

We investigated the possible effect of two ERβ gene polymorphisms on spinal bone mineral density (BMD) and metabolic bone markers in Greek women.

Spine BMD as well as biochemical bone markers were measured in 147 healthy peri- and post-menopausal women [mean age (S.D.) 54 (7.9) years]. Genotyping was performed for two restriction fragment length polymorphisms (RFLPs) of ERβ gene, RsaI in exon 5 and AluI in exon 8. For each polymorphism studied the cohort was divided into two groups: the “wild-type” group (RR and AA, respectively) and the “carrier” group including subjects with at least one allele with the restriction site (Rr&rr and Aa&aa, respectively).

The distribution of RsaI genotypes was RR: 91.2% (n = 134), Rr: 8.2% (n = 12), and rr: 0.6% (n = 1) and of AluI genotypes AA: 36.7% (n = 54), Aa: 57.2% (n = 84), and aa: 6.1% (n = 9). No linkage disequilibrium was found between the two polymorphic sites studied. Spine BMD did not differ significantly in the two groups of either polymorphism, after adjusting for age, weight, height, and years since menopause [mean BMD (S.D.) for RR 0.841 (0.17) g/cm² versus Rr&rr 0.798 (0.13) g/cm², p = 0.25, and mean BMD (S.D.) for AA 0.828 (0.16) g/cm² versus Aa&aa 0.848 (0.17) g/cm², p = 0.32]. No significant differences were noted in metabolic bone markers except for a marginal difference of RR versus Rr/rr in urinary hydroxyproline/creatinine ratio [median (IQR) 3.88 (6.04) μmol/mmol in RR versus 8.2 (4.32) μmol/mmol in Rr/rr, p = 0.05]. Furthermore, no interaction between the two polymorphisms on BMD was found.

In conclusion, in a Greek female post-menopausal population, the two ERβ gene polymorphisms were not associated with BMD, or metabolic bone markers.     

Association of vitamin D receptor gene polymorphisms with bone mineral density in postmenopausal women of Hellenic origin

OBJECTIVES: There are numerous indications that genetic factors play an important role in the pathogenesis of osteoporosis, a common condition characterized by reduced bone mass and increased fracture risk. The vitamin D receptor (VDR) gene has been suggested as a possible candidate gene for the regulation of bone mass but the relationship between VDR polymorphisms and bone mineral density (BMD) is controversial and has not been confirmed by all workers in different ethnic groups studied. METHODS: In order to evaluate the contribution of the VDR alleles in bone mass loss, the BsmI, ApaI and TaqI polymorphisms in the VDR gene were studied in 126 postmenopausal women. RESULTS: It was found that the bb, aa and TT genotypes and the bAT and baT haplotypes were associated with a lower BMD measured at the forearm. CONCLUSIONS: Our analysis reveals a significant association between VDR gene alleles and bone mass in the population studied.     

Association of KIT gene polymorphisms with bone mineral density in postmenopausal Korean women

Bone mineral density (BMD) is a major factor for determining bone strength and osteoporotic fracture risk, and is determined by environmental and multiple genetic factors. KIT, which encodes a transmembrane receptor with tyrosine kinase activity, plays an important role in the differentiation of osteoclasts. We examined the associations between KIT gene polymorphisms and BMD in postmenopausal Korean women. All exons, their boundaries, and the promoter region (approximately 1.5 kb) from 24 individuals were directly sequenced. Eighteen polymorphisms were identified, and three single-nucleotide polymorphisms (SNPs) were genotyped in all study participants (n = 946). BMD at the lumbar spine and femoral neck was measured using dual-energy X-ray absorptiometry. The mean age of the study subjects was 58.9 ± 7.5 years, and the mean number of years since menopause was 9.6 ± 7.9 years. None of the three SNPs (−1694G>T, +41894A>G, and +49512G>A) was significantly associated with BMD value. However, multivariate analysis showed that the ht3 (−1694T-+41894A-+49512G) was significantly associated with lower BMD at the femoral neck (P = 0.007 in the recessive model). These findings indicate that KIT-ht3 may be a useful genetic marker for osteoporosis and that KIT may have a role on bone metabolism in humans. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. S.-Y. Kim and J.-Y. Lee are co-first authors.     

Association of the osteoprotegerin gene polymorphisms with bone mineral density in postmenopausal women

OBJECTIVES: Osteoprotegerin (OPG) is a recently discovered member of the tumour necrosis factor receptor superfamily. It plays a crucial role in the control of bone resorption and its gene could therefore be a good candidate gene for osteoporosis. The aim of our work was to find polymorphisms in the OPG gene and to investigate their possible contribution to the genetic susceptibility to osteoporosis by testing for their association with bone mineral density (BMD). METHODS: The whole OPG gene coding region was screened for the presence of polymorphisms in a group of 60 osteoporotic women by single-strand conformation polymorphism analysis (SSCP) approach. Association of the discovered polymorphisms with bone mineral density was investigated in 136 Slovenian postmenopausal women. RESULTS: We detected eight OPG gene polymorphisms that were confirmed by direct DNA sequencing, deletion 4752_4753delCT and nucleotide substitutions 1181G>C, 1217C>T, 1284G>A, 4501C>T, 6893A>G, 6950A>C and 8738T>A. Nucleotide substitutions 1284G>A and 8738T>A have not been previously described. Polymorphisms 4752_4753delCT, 6893A>G and 6950A>C were in complete linkage and the same was true for 1217C>T and 4501C>T. The association with BMD was found only for polymorphism 1181G>C. Subjects with genotype 1181GG had significantly lower lumbar spine BMD than subjects displaying 1181GC. CONCLUSIONS: By our approach we detected eight polymorphisms in the OPG gene. According to our analysis polymorphism 1181G>C is associated with BMD and could therefore be considered as an element of genetic susceptibility to osteoporosis.     

Association between bone mineral density and LDL receptor-related protein 5 gene polymorphisms in young Korean men

Recently, It has been reported that the LDL receptor-related protein 5 (LRP5) regulates bone formation, and that mutations of the gene cause osteoporosis-pseudoglioma syndrome or high bone mass phenotypes. However, the mutations cannot explain a genetic trait for osteoporosis in the general population because of their rarity. From 219 Korean men aged 20-34 yr, we looked for six known polymorphisms causing amino acid changes in the LRP5 coding region, and investigated their association with bone mineral density (BMD) at the following anatomical sites: lumbar spine (L2-L4) and the left proximal femur (femoral neck, Ward's triangle, trochanter and shaft). We found that the Q89R polymorphism was significantly associated with BMD at the femoral neck and Ward's triangle (p=0.004 and <0.001, respectively). However, after adjusting for age, weight and height, a statistically significant association only occurred at the Ward's triangle (p=0.043), and a marginal association was observed at the femoral neck (p=0.098). No A400V, V667M, R1036Q and A1525V polymorphisms were found, and no statistically significant association was found between the A1330V polymorphism and BMD at any sites. Although we failed to demonstrate a clear association between the LRP5 polymorphism and peak bone mass in young men, the present study suggests that larger-scale studies on the Q89R polymorphism need to be performed.     

Association of the estrogen receptor alpha gene polymorphisms with osteoporosis in the Mexican population

The estrogen receptor gene (ER alpha) has been implicated in the development of osteoporosis. In this study, the association of two ER alpha gene polymorphic markers (a TA dinucleotide repeat and a single nucleotide polymorphism, G2014A) with osteoporosis was tested in 70 osteoporotic women, 70 non-osteoporotic women and 500 subjects from the Mexican population. According to the genetic analysis of the Mexican population using eight unlinked polymorphic markers, we found that our population is structured into three subpopulations; therefore, the allele-phenotype relationship was analyzed with a statistical method that considered population stratification. We found that the G2014A polymorphism is associated with the presence of osteoporosis while the TA dinucleotide repeat is not. The G allele and the GG genotype frequencies of the G2014A marker were significantly higher in osteoporotic than in non-osteoporotic women. Likewise, subjects bearing the G allele in heterozygous or homozygous displayed lower values for lumbar bone mineral density and T score than those who did not present any G allele. The effect of confounders for osteoporosis on the association of G allele-osteoporosis was ruled out. In summary, we conclude that the G2014 polymorphism may become a useful marker for genetic studies of osteoporosis in the Mexican population.     

Association of TNFSF11 gene promoter polymorphisms with bone mineral density in postmenopausal women

OBJECTIVES: The receptor activator of nuclear factor-kappaB ligand (RANKL) is recognized as one of the important regulators of osteoclastogenesis. The expression of the tumour necrosis factor superfamily, member 11 (TNFSF11) gene, which encodes for RANKL protein, is increased relative to the expression of osteoprotegrin in cases of senile osteoporosis with hip bone fracture. Our aim was to find polymorphisms in the TNFSF11 gene promoter and to investigate their possible association with bone mineral density (BMD). METHODS: The TNFSF11 gene promoter region was screened for the presence of new sequence variations by direct sequencing. DNA sequencing revealed the presence of four sequence variations: -290C>T, -643C>T, -693G>C and -1594G>A. Association of the discovered polymorphisms with BMD was investigated in 115 Slovenian postmenopausal women, using restriction fragment length polymorphism analysis. After a year, bone loss in the association with the identified sequence variations was evaluated in 43 postmenopausal women. RESULTS: Three of the discovered sequence variations (-290C>T, -643C>T, -693G>C) proved to be polymorphic, whereas variation -1594G>A was only found in one patient. The frequencies of genotypes were as follows: CC (27.8%), CT (43.5%), TT (28.7%) for -290C>T polymorphism; CC (23.5%), CT (47.8%), TT (28.7%) for -643C>T polymorphism; and GG (22.6%), GC (51.3%), CC (26.1%) for -693G>C polymorphism. A statistically significant association of genotype with BMD at the femoral neck was observed only in the -290C>T polymorphism. Genotype CC was associated with lower BMD than the TT genotype (P = 0.022). In polymorphism -693G>C, a significant difference in bone loss rate was observed in total hip (P = 0.011) and femoral neck BMD (P = 0.037). CONCLUSIONS: Four sequence variations were identified in the studied region of TNFSF11 gene promoter. Our results of preliminary clinical evaluation suggest that the -290C>T polymorphism in the TNFSF11 gene promoter could contribute to the genetic regulation of BMD.     

Association of candidate gene polymorphisms with bone mineral density in community-dwelling Japanese women and men

Although bone mineral density (BMD) is a complex trait that is influenced by both genetic and environmental factors, heritability studies in twins and families have shown that genetic factors account for 60-85% of the variance in BMD. We examined the relations of six candidate gene polymorphisms to BMD in community-dwelling women and men. The 2238 subjects (1110 women, 1128 men) were aged 40-79 years and were randomly recruited to a population-based prospective cohort study of aging and age-related diseases in Japan. BMD at the distal and proximal radius was measured by peripheral quantitative computed tomography, and BMD for the total body, lumbar spine (L2-L4), right femoral neck, and right trochanter was measured by dual-energy X-ray absorptiometry. Genotypes for the 1019Cright curved arrow T (Pro319Ser) polymorphism of GJA4 and the 1462Aright curved arrow G (Lys469Glu) polymorphism of ICAM1 were determined with a fluorescence-based allele-specific DNA primer assay system, and those for the 386Gright curved arrow A (Ala99Thr) polymorphism of PLOD1, the Aright curved arrow G polymorphism of CNR2, the 1583Gright curved arrow A (Arg528Lys) polymorphism of ALAP, and the -514Cright curved arrow T polymorphism of LIPC were determined by melting curve analysis. The polymorphisms of ALAP and PLOD1 were associated with BMD in premenopausal women; those of ICAM1 and LIPC with BMD in postmenopausal women; that of CNR2 with BMD in premenopausal and postmenopausal women; and that of GJA4 with BMD in men. Among these polymorphisms, those of ICAM1, CNR2, and GJA4 were markedly associated with BMD. These results suggest that ALAP, PLOD1, ICAM1, LIPC, and CNR2 are susceptibility loci for reduced bone mass in Japanese women and that GJA4 constitutes such a locus in Japanese men. The polymorphisms of ICAM1 and CNR2 may confer susceptibility to postmenopausal osteoporosis in women, and that of GJA4 to osteoporosis in men.     

雌激素受体基因多态性与老年妇女的骨密度

背景：雌激素受体α基因多态性与骨质疏松的发生相关有一定的关系,但是对于危险基因型的研究还存在商榷余地。 目的：分析雌激素受体基因多态性与老年妇女骨密度的相关性。 方法：选择检查的老年健康妇女120例,提取全血基因组DNA,选择限制性内切酶PvuⅡ和XbaⅠ进行酶切,分析基因型的分布与频率。同时选择双能X射线骨密度仪测股骨颈、大转子及Ward三角处的骨密度值。 结果与结论：XbaⅠ酶切基因型XX 6例,Xx 78例,xx 36例;PvuⅡ酶切PP 32例,Pp 50例,pp 38例。不同基因型老年妇女的年龄、绝经年龄与体质量指数值对比差异无显著性意义(P > 0.05)。PvuⅡ酶切PP基因型妇女的大转子与ward三角处的骨密度值明显大于Pp及pp妇女(P < 0.05);而XbaⅠ酶切基因多态性在老年妇女中股骨颈、大转子与Ward三角的骨密度均无显著差异(P > 0.05)。说明雌激素受体基因多态性与老年妇女骨密度有一定的相关性,P等位基因对老年妇女大转子与Ward三角处的骨密度的维持有一定作用。 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程全文链接：     

Association of vitamin D receptor and estrogen receptor gene polymorphisms with bone mass in postmenopausal Korean women

OBJECTIVE: To examine the relationship between vitamin D receptor (VDR) and estrogen receptor (ER) gene polymorphism and bone mineral density (BMD). DESIGN: Polymorphisms at the VDR FokI and ER PvuII and XbaI gene sites, serum bone-specific alkaline phosphatase, urinary N-telopeptide of type I collagen, and BMD at the lumbar spine and proximal femur were analyzed in 229 postmenopausal Korean women. RESULTS: The distribution of ER PvuII and XbaI and VDR FokI restriction fragment length polymorphisms was as follows: pp 39.3%, Pp 46.3%, PP 14.4%, xx 34.1%, Xx 61.1%, XX 4.8%. ff 17.0%, Ff 43.7%, and FF 39.3%, respectively (upper-case letters signify the absence, and lower-case letters signify the presence of the restriction site). After adjusting for potential confounding factors such as age, body mass index, and menopause duration, ER PvuII was independently associated with BMD at the lumbar spine and XbaI polymorphism BMD at the femoral neck. The lumbar spine BMD in the pp genotype was 7.5% lower than in the PP genotype, and the femoral neck BMD was 4.8% lower in the Xx genotype than in the xx genotype. By itself, the VDR FokI polymorphism was not related to BMD, but by combining the FokI genotype (FF) with ER genotypes, such as ppxx and the PpXx, the difference in the BMD at the Ward's triangle became significant. There were no significant differences in the levels of biochemical markers between the genotypes of three polymorphisms. CONCLUSION: ER polymorphisms, singly and in relation to VDR FokI polymorphism, influence bone mass in Korean women.     

Association of oestrogen receptor alpha gene polymorphisms with postmenopausal bone loss, bone mass, and quantitative ultrasound properties of bone

Background: The gene encoding oestrogen receptor α (ESR1) appears to regulate bone mineral density (BMD) and other determinants of osteoporotic fracture risk.

Objective: To investigate the relation between common polymorphisms and haplotypes of the ESR1 gene and osteoporosis related phenotypes in a population based cohort of 3054 Scottish women.

Results: There was a significant association between a common haplotype "px", defined by the PvuII andXbaI restriction fragment length polymorphisms within intron 1 of the ESR1 gene, and femoral neck bone loss in postmenopausal women who had not received hormone replacement therapy (n = 945; p = 0.009). Annual rates of femoral neck bone loss were ~14% higher in subjects who carried one copy of px and 22% higher in those who carried two copies, compared with those who did not carry the px haplotype. The px haplotype was associated with lower femoral neck BMD in the postmenopausal women (p = 0.02), and with reduced calcaneal broadband ultrasound attenuation (BUA) values in the whole study population (p = 0.005). There was no association between a TA repeat polymorphism in the ESR1 promoter and any phenotype studied, though on long range haplotype analysis subjects with a smaller number of TA repeats who also carried the px haplotype had reduced BUA values.

Conclusions: The ESR1px haplotype is associated with reduced hip BMD values and increased rates of femoral neck bone loss in postmenopausal women. An association with BUA may explain the fact that ESR1 intron 1 alleles predict osteoporotic fractures by a mechanism partly independent of differences in BMD.

     

与骨关节炎相关性雌激素α受体基因 PvuⅡ、XbaⅠ位点多态性Meta分析

背景：目前有不少探讨雌激素受体α基因多态性与骨关节炎易感性的相关性研究,但结果仍有一定的争议。目的：分析雌激素受体α基因PvuⅡ、XbaⅠ位点多态性与骨关节炎易感性的关系。方法：检索PubMed数据库、web of science数据库、万方数据库、中国知网全文数据库、维普数据库、中国生物医学文献数据库发表的有关雌激素α受体(ERα)基因PvuⅡ、XbaⅠ位点多态性与骨关节炎的病例对照研究文献,OR值及95%CI为效应指标,采用固定或随机效应模型进行合并分析,并进行偏倚评估。应用Revman 5.1软件进行统计学处理。结果与结论：共纳入文献9篇,包括3 228例骨关节炎患者,6 327例健康对照。PvuⅡ位点各等位基因及基因型(C vs. T;CT vs. TT;CC vs. TT;CT+CC vs. TT;CC vs. CT+TT)合并OR值均 < 1;按地区分组提示亚洲合并OR值均 > 1(CT vs. TT除外),欧美合并OR值均 < 1。XbaⅠ位点各等位基因及基因型(G vs. A;GA vs. AA;GG vs. AA;GA+GG vs. AA; GG vs. GA+AA)合并OR值均 < 1;按地区分组提示亚洲合并OR值均 < 1,欧美合并OR值均<1(GG vs. GA+AA除外)。结果说明,雌激素受体α基因PvuⅡ、XbaⅠ位点多态性与骨关节炎遗传易感性无关联。然而,PvuⅡ位点发生等位基因突变时亚洲人群骨关节炎遗传易感风险较欧美稍高,相反,XbaⅠ位点隐性遗传模型发生等位基因突变时欧美人群骨关节炎遗传易感风险较亚洲人群稍高。提示不同种族的遗传背景差异可能影响上述变化。中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程     

Vitamin D receptor gene polymorphisms and bone mineral density in postmenopausal Indian women

OBJECTIVES: Osteoporosis is a common condition in postmenopausal women. Bone mineral density (BMD), the major determinant of osteoporotic fracture risk, has a particular genetic background. However, consensus on the association of BMD with specific gene locus has not been reached. The race and ethnicity specific divergence in association studies must be assessed to predict the susceptibility and therapeutic response of associated genes. We investigated the potential association of Vitamin D receptor (VDR) gene polymorphisms ApaI, BsmI, FokI and TaqI with BMD in 246 postmenopausal Indian women (average age 54.2+/-3.4 years). METHODS: The subjects were genotyped by PCR-RFLP and underwent BMD measurements at spine and hip by dual energy X-ray absorptiometery. RESULTS: The average BMD at spine and hip of women with genotypes aa, bb (presence of restriction sites for ApaI and BsmI), FF and TT (absence of restriction sites for FokI and TaqI) was more than 10% higher than those with genotypes AA, BB, ff and tt, respectively. The interaction between BsmI, ApaI and TaqI genotypes showed significant effect of BsmI-ApaI genotypes (p=0.052) in this combination on BMD. However, presence of T allele in combination showed positive influence on BMD. Within the group, genotypes BB, ff and tt were significantly prevalent in women with osteoporotic bone mass, tt and BB had significantly higher adjusted odd ratio (OR) for age more than 55years. CONCLUSION: Study reveals that VDR gene polymorphisms are associated with BMD in Indian women and perhaps, influence some determinant of bone metabolism. Ethnicity may attribute to frequency variation, however, allele impact remains same.     

Association of polymorphisms of the androgen receptor and klotho genes with bone mineral density in Japanese women

Genetic variants of the androgen receptor and klotho protein may contribute to variation in bone mass as well as to predisposition to osteoporosis. The relationship of a CAG repeat polymorphism of the androgen receptor gene (AR) and of a –395GA polymorphism of the klotho gene (KL) to bone mineral density (BMD) in Japanese women was examined in a population-based study. The subjects (1,101 and 1,110 women for AR and KL polymorphisms, respectively) were aged 40–79 years and were randomly recruited to a population-based prospective cohort study of aging and age-related diseases. BMD for the total body, lumbar spine, right femoral neck, right trochanter, and right Wards triangle was measured by dual-energy X-ray absorptiometry. Genotypes for the AR and KL polymorphisms were determined by polymerase chain reaction based assays. The number of CAG repeats of AR was inversely correlated with BMD for the lumbar spine in premenopausal women but not in postmenopausal women. The (CAG)_n22 and (CAG)_n23 alleles were designated S and L, respectively. Among premenopausal women, BMD for the total body was significantly lower in subjects with the LL genotype than in those with the SS genotype or those in the combined group of SS and SL genotypes. In contrast, BMD was not associated with AR genotype in postmenopausal women. Among all women, BMD for the lumbar spine was significantly lower in subjects with the GG genotype of the –395GA polymorphism of KL than in those with the AA genotype. BMD was not associated with –395GA genotype among premenopausal women. In postmenopausal women, BMD for the total body or lumbar spine tended to be lower in subjects with the GG genotype than in those with the AA genotype or those in the combined group of GA and AA genotypes. These results suggest that AR is a susceptibility gene for reduced BMD in premenopausal Japanese women, and that KL is a susceptibility gene for reduced BMD in all women.     

Gender differences in fracture risk and bone mineral density

We have investigated gender-related differences of bone mineral density and fracture threshold in 136 males (age, 60.7±9.3 years) and 337 females (age, 59.7±7.8 years) without evidence of secondary osteoporosis. Women and men were examined for total amount of spine fractures and bone mineral density by quantitative computed tomography (QCT) of three non-fractured vertebral bodies L1–L5. Females with lumbar fractures (n=96) when compared with non-fracture women (n=241) were older and had lower bone density at their vertebral sites. Males with vertebral fractures (n=52) were older and had a significantly reduced bone mineral density of the spine when compared with healthy males (n=84). When we compared gender-related vertebral fracture rates, we observed a significantly higher prevalence of vertebral fractures in the male population. After matching males and females for age and bone mineral density to exclude an influence of either variable, we compared the prevalence of vertebral fracture risk in both sexes with logistic regression analysis. Data of estimated fracture risk, differed very significantly for sex and bone density at the vertebral site, indicating that men present fracture at a higher bone density level compared with females; in 10% of study population fractures occurred at a QCT level of 105 mg/cm³ in women and 120 mg/cm³ in men. The estimated odds ratio for sex of 3.1 (95% CI) means a three-fold increased risk for vertebral fractures compared to males at a given density level. These results underline that a decreased bone mineral density leads to the occurrence of spine fractures in females and males as well.     

The association between postmenopausal vertebral bone mineral density and estrogen receptor gene alleles in ethnic Japanese living in western Japan.

Bone mass and its mineral content has been shown to be under genetic control. Our purpose in this study was to assess whether estrogen receptor genotypes influence changes in bone mass in post menopausal Japanese women and clarify the regional differences in Japanese women. Pvu II and Xba I restriction enzyme fragment length polymorphism of the estrogen receptor gene and its relationship with vertebral bone mineral density were examined in 300 unrelated post menopausal women, aged 42-69 years, from the Kinki region in Japan. Vertebral bone mineral density was evaluated at the lumbar spine (L2-4) by dual energy X-ray absorptiometry. We found no relationship between any single restriction site polymorphism and the Z-score of bone mineral density. However, the allelic haplotype PPXx was found to be associated with a significantly low bone mineral density (Z-score for the lumbar spine -1.118+/-1.270 vs. PPxx 0.04+/-1.150; p<0.01, vs. ppxx 0.387+/-1.226; p<0.05, respectively). We suggest that ER gene polymorphism is associated with low bone mineral density and that this partly explains the cause of post menopausal bone loss in Japanese women. The contradictory conclusions compared with previous studies in the Japanese population regarding the association of BMD with ER RFLPs demands further investigation.     

Effects of vitamin D and estrogen receptor gene polymorphisms on the changes in lumbar bone mineral density with multiple pregnancies in Japanese women

BACKGROUND: Our aims were to follow the longitudinal changes in lumbar spine bone mineral density (BMD) with multiple pregnancies, and to study whether polymorphisms in the vitamin D receptor (VDR) and estrogen receptor (ER) genes may influence the results. METHODS: We repeatedly measured the BMD of the lumbar spine (L2-L4) of 133 women who had undergone two successive pregnancies and 73 non-pregnant controls, and analysed the restriction fragment length polymorphisms using restriction endonucleases TaqI, ApaI and FokI for the VDR gene, and PvuII and XbaI for the ER gene. RESULTS: Cases and controls had no significant differences in the longitudinal BMD changes. The mean percentage change in lumbar BMD (DeltaBMD%) of the women with the XX/Xx genotype was significantly lower than that of the women with the xx genotype after adjusting for age at each delivery, BMD of the first scan, and interval between the scans (0.2 +/- 3.3 versus 2.0 +/- 4.2%; P=0.030, analysis of covariance). Multiple regression analyses to evaluate the contribution of the XbaI polymorphism of the ER gene on DeltaBMD% showed that the percentage decrease in BMD was greater for women lacking the XbaI restriction site (adjusted R2=0.188, P<0.0001). CONCLUSIONS: The present study suggests that the DeltaBMD% was significantly influenced by the XbaI polymorphism of the ER gene.