Bone mineral density is associated with estrogen receptor gene polymorphism in men

In order to identify genetic effects of allelic variation on bone mineral density (BMD), association studies have been performed recently. Examining the relation between PvuII and XbaI restriction fragment length polymorphism (RFLPs) at the estrogen receptor (ER alpha) gene and BMD, in women or men, have yielded conflicting results. We analyzed the association between this polymorphism and BMD Z score values of cancellous bone at the 3rd finger in 344 members of nuclear families of European population, Chuvasha, living in Russia. The population sample included 183 males, aged 18-84, and 161 females, aged 23-79. The analysis has been performed separately for both sexes and for both generations (parents and offspring). We used a novel direct haplotyping method, which determines simultaneously each of the PvuII and XbaI RFLPs and their relation to each other. The haplotypes were represented as the combination of both polymorphic sites on the same chromosome, by using P/p and X/x for PvuII and XbaI restriction sites, respectively. The subjects were classified into 3 groups of genotypes: A = PXPX (homozygote for the PX haplotype); B = PXPx, PXpx (the heterozygotes for the PX haplotype); C = PxPx, Pxpx, pxpx (genotypes that are lacking the PX haplotype). The PXPX genotype (A) was associated with higher BMD Z score values in comparison to the genotypes that are lacking the PX haplotype (C), in total males [0.618 vs. -0.133 (p = 0.004)] and for the "sons" generation [0.724 vs. -0.198 (p = 0.02)]. Similar tendency was observed for the "fathers" generation (0.539 vs. -0.085), though the difference did not approach statistical significance (p = 0.087). These findings were not found in the female samples, nor in the "mothers" or "daughters" generations. The question if there are differences in the mode of action of estrogen through its receptor on bone mass, between the genders or between the males' generations, have to be further investigated.     

Exonic, but not intronic polymorphisms of ESR1 gene might influence the hypolipemic effect of raloxifene

Studies have shown that selective modulator of estrogen receptor raloxifene, exerts hypolipemic properties at least partially through estrogen receptor alpha activation. To test the hypothesis that polymorphisms of estrogen receptor alpha are associated with the influence of 6 months raloxifene treatment on serum lipids, two intronic (PvuII and XbaI), and one exonic polymorphism (P325P) were analyzed in 49 postmenopausal women, mean age 62.5+/-5.7 years. In all subjects, the total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides were determined before and after 6 months of raloxifene treatment. We were unable to find any relationship between estrogen receptor alpha genotype and serum lipids at baseline. At the end of 6 months treatment with raloxifene, the mean decrease of total cholesterol and LDL cholesterol, independently of genotypes, was highly significant, but no influence on HDL and triglycerides concentrations was found. Neither the PvuII nor XbaI ESR1 gene polymorphisms were associated with the magnitude of lipid changes after 6 months treatment, whereas the subjects with non-CC genotype of P325P mutation had significantly lower total cholesterol and LDL cholesterol concentrations, and higher decline of total cholesterol (p<0.05). CONCLUSION: Our data suggest that exonic, but not intronic polymorphisms of estrogen receptor alpha gene might intensify the cholesterol lowering effect of raloxifene.     

Association between estrogen receptor alpha gene polymorphisms and bone mineral density in Polish female patients with Graves' disease

Graves' (GD) hyperthyroidism leads to reduced bone mineral density (BMD) accompanied by accelerated bone turnover. Ample studies have identified association between estrogen receptor (ESR1) gene polymorphism and decreased BMD and osteoporosis. In contrast, number of publications that link ESR1, BMD and Graves' disease is limited. The purpose of this study was to identify the association between ESR1 polymorphisms and BMD in premenopausal women with GD and to determine whether ESR1 polymorphic variants can predispose to GD. The study included 75 women aged 23-46 years with GD and 163 healthy controls. BMD was measured at lumbar spine and femoral neck. We investigated two SNPs in the ESR1 gene and analyzed genetic variants in the form of haplotypes reconstructed by statistical method. Three out of four possible haplotypes of the PvuII and XbaI restriction fragment length polymorphisms were found in GD patients: px (55.3 %), PX (33.3 %) and Px (11.4 %). Women homozygous for xx of XbaI and for pp of PvuII had the lowest BMD at lumbar spine. Moreover, the px haplotype predisposed to reduced lumbar BMD. No associations were observed for femoral neck BMD. No statistically significant relationship were found between ESR1 polymorphisms or their haplotypes and GD. These results indicate that the PvuII and the XbaI polymorphisms of ESR1 gene are associated with bone mineral density in premenopausal women with GD and may help to estimate the risk of bone loss particularly at lumbar spine. However, none of the ESR1 gene alleles predict the risk of GD in Polish female patients.     

北京地区汉族妇女雌激素受体基因XbaI多态性与骨密度和体重指数的关系

为探讨北京地区汉族妇女雌激素受体（ER）基因XbaI多态性与骨密度的关系,采用双能X线吸收仪检测腰椎、股骨及前臂骨密度;采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）法,对179例北京地区汉族妇女ER基因XbaI多态性进行分析。北京地区汉族妇女ER基因XX、Xx和xx基因型频率分布为0.302、0.464和0.234,绝经前与绝经后妇女XbaI型基因频率分布有明显差异,绝经后妇女腰椎骨密度（0.836±0.18）g/cm²明显低于绝经前妇女（1.038±0.14);绝经后妇女骨质疏松症的发病率为54%。ER基因XbaI基因型频率分布有明显的种族差异并受绝经影响,ER基因XbaI基因型与骨密度无明显相关性。与体重和BMI有明显相关性。     

Estrogen receptor alpha and vitamin D receptor gene polymorphisms and bone mineral density: association study of healthy pre- and postmenopausal Chinese women

In the present study, we tested the association between the estrogen receptor alpha (ER-alpha) and vitamin D receptor (VDR) genes with bone mineral density (BMD). A total of 649 healthy Chinese women, classified as pre-menopausal (N=388) and post-menopausal (N=261) groups, were genotyped at the ER-alpha PvuII, XbaI, and VDR ApaI sites. BMDs at the lumbar spine (L(1)-L(4)) and total hip were measured by dual-energy X-ray absorptiometry. For the VDR ApaI locus, AA carriers had lower spine BMD than Aa (p=0.02) and aa carriers (p<0.01) in the pre-menopausal group. For the ER-alpha gene, carriers of haplotype px had lower spine BMD than the non-carriers (p=0.03) in the pre-menopausal group. Furthermore, we observed significant interaction between the ER-alpha and VDR genes in the post-menopausal group: with AA genotype (or A allele) at the VDR ApaI locus, pX carriers had higher spine BMD than the non-carriers (p=0.02), and PX carriers had lower hip BMD than the non-carriers (p=0.04). Our data suggest that the ER-alpha and VDR genes may be associated with the BMD variation in Chinese women.     

Codon 325 sequence polymorphism of the estrogen receptor alpha gene and bone mineral density in postmenopausal women

Estrogen receptor alpha (ER alpha) encoding gene is one of the candidate genes to be involved in the development of osteoporosis. Until now correlation between three ER gene polymorphisms (identified with PvuII, XbaI and BstUI) and bone mineral density (BMD) have been investigated. The results of these studies are contradictory. Thus the aim of our work was to search for new, yet unknown, and probably more informative polymorphism(s) of the ER alpha gene. For detection of mutations the whole coding region of the ER alpha gene was screened systematically. In a group of 85 late postmenopausal women all of the eight exons were amplified by polymerase chain reaction (PCR) and fragments were further analyzed by single-stranded conformation polymorphism (SSCP) analysis. Mutations were confirmed by direct DNA sequencing. In the whole coding region of the ER alpha gene two silent mutations in codon 87 and 325, respectively, were found. The silent mutation in codon 85 of exon 1 (GCG-->GCC; A87A) was described previously, as BstUI polymorphism. On the other side, the silent mutation in codon 325 (CCC-->CCG; P325P), located in exon 4, has not been analyzed so far in correlation with BMD. According to the distribution of genotypes CC:CG:GG=49.4:41.2:9.4, we can affirm the existence of genetic polymorphism in codon 325 in our population of late postmenopausal women. The mean femoral neck BMD, but not the lumbar spine BMD, was significantly lower (P=0.029) in the homozygous GG-women with CCG/CCG codon 325 as compared to the homozygous CC-women with the normal codon CCC/CCC. Our results suggest that codon 325 sequence polymorphism of the ER alpha gene might be one of the factors associated with low femoral neck BMD.     

Association of polymorphisms in CYP17A1, MTP, and VLDLR with bone mineral density in community-dwelling Japanese women and men

We examined whether a -34T --> C polymorphism of the gene for cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17A1), a -493G --> T polymorphism of the microsomal triglyceride transfer protein gene (MTP), and a CGG repeat polymorphism of the very low density lipoprotein receptor gene (VLDLR) were associated with bone mineral density (BMD) in community-dwelling Japanese women and men. The -34T --> C polymorphism of CYP17A1 was associated with BMD in postmenopausal women, with the CC genotype being related to increased BMD. The -493G --> T polymorphism of MTP was associated with BMD in premenopausal women, with the TT genotype being related to increased BMD. The CGG repeat polymorphism of VLDLR was associated with BMD in men, with two (CGG)(n > or= 8) alleles being related to increased BMD. These results suggest that CYP17A1 and MTP are susceptibility loci for increased BMD in postmenopausal and premenopausal Japanese women, respectively, and that VLDLR constitutes such a locus in Japanese men.     

Association of estrogen receptor beta gene polymorphism with bone mineral density

Chromosomal mapping of the human estrogen receptor beta (ERbeta) gene by fluorescence in situ hybridization (FISH) reveals that ERbeta is located at human chromosome 14, region q23-24.1, where the aberration of DNA copy number in the bone disorders is frequently involved. Then, we investigated the association between dinucleotide (cytosine-adenine; CA) repeat polymorphism located in the flanking region of ERbeta gene and bone mineral density (BMD) in 204 healthy postmenopausal Japanese women. The genotype was classified into "A" through "O" according to the number of the repeats, from 18 to 32. BMD was expressed in Z score (a deviation from the weight-adjusted average BMD of each age using the standard deviation as a unit). When we separate the subjects into two groups bearing at least one I allele (26 CA repeats) and those who did not, the former subjects had significantly higher Z score of L2-4 BMD (mean +/- standard deviation; 0.674 +/- 1.53 vs 0.128 +/- 1.38; P = 0.027). These data suggest that genetic variation at the ERbeta locus may be associated with some determinants for BMD and the possible involvements of this polymorphism in the cause of postmenopausal osteoporosis in Japanese women.     

The importance of ERα and ERβ gene polymorphisms in PCOS

Estrogens act through binding to estrogen receptor α (ERα) and β (ERβ). Studies in knockout mice have shown that the absence of ERα leads to the polycystic ovary syndrome (PCOS) phenotype. Furthermore, the expression of ERβ gene is lower in follicles derived from women with PCOS compared with healthy women. The aim of this study was to investigate the importance of ERα and ERβ gene polymorphisms in PCOS. A cohort of 180 women with PCOS and 140 healthy controls were recruited, and the PvuII and XbaI polymorphisms of ERα, as well as, the AluI and RsaI polymorphisms of ERβ were genotyped. No difference was found in the distribution of these polymorphisms between patients and healthy controls. However, in PCOS women, carriers of TC and TT genotypes of PvuII polymorphism had lower fasting glucose to insulin ratio compared with carriers of CC genotype (p = 0.029). In addition, the presence of AA genotype of XbaI polymorphism was associated with lower levels of follicle-stimulating hormone (FSH) compared with the presence of AG and GG genotypes (p = 0.03). The association of ERα polymorphisms with insulin resistance indices and FSH levels emphasizes the importance of ERα as a genetic modifier of the PCOS phenotype.     

Hormonal modulation of interleukin-6, tumor necrosis factor and associated receptor secretion in postmenopausal women

Hormone replacement therapy (HRT) reduces the risk for osteoporosis but transiently increases cardiovascular risk for some postmenopausal women. This study investigated the hypothesis that these risks are associated with HRT-induced changes in mononuclear cell secretion of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and associated soluble receptors. Compared to the untreated condition (n=8), estrogen therapy (n=7) and estrogen+progestin therapy (n=7) both caused 2-fold elevations in TNF-alpha secretion. IL-6 secretion was increased (48%, P=0.04) only by estrogen+progestin therapy. Although soluble receptor secretion was not different among groups, soluble TNF receptor type I and IL-6 receptor secretion were inversely related to plasma follicle stimulating hormone (P<0.05). Both therapies reduced plasma osteocalcin (a marker for osteoporosis) by approximately 50% (P<0.002). Plasma C-reactive protein (CRP, a marker for cardiovascular risk) was 3-fold higher in women receiving only estrogen, compared to untreated women (P=0.01), and twice as high as those receiving estrogen+ progestin (P=0.045). Simple linear relationships were not observed between cytokine secretion and these markers, but a significant HRT/TNF-alpha interaction with osteocalcin (P=0.022) and an HRT/IL-6 interaction with CRP (P =0.016) indicated more complex relationships between hormone replacement, cytokine activity, and health risks associated with menopause.     

The ESR2 AluI gene polymorphism is associated with bone mineral density in postmenopausal women

Multiple factors may contribute to the pathogenesis of postmenopausal osteoporosis including environmental, life-style and genetic factors. Common variants in ESR2 gene encoding for ER-beta, highly expressed in bone tissue, have recently been proposed as candidates for affecting bone phenotype at the population level, particularly in postmenopausal women. In this study, we examined the genetic background at ESR2 AluI (rs4986938, 1730G>A) locus in 89 osteopenic, postmenopausal women (age range 49-56 years) together with BMD at lumbar spine and femoral neck sites as well as variations in plasma levels of bone metabolism and turnover markers. Genotyping for ESR2 G1730A polymorphism showed that the frequency of A mutated allele accounted for 0.4 in our cohort of postmenopausal women; moreover, the GA1730 heterozygous individuals were the most represented (50.6%) compared with GG (37.8%) and AA homozygous ones (14.6%). A regression analysis showed that lumbar spine BMD values were significantly associated with both ESR2 AA1730 genotype (p=0.044) and time since the onset of menopause (p=0.031), while no significant association was detected between biochemical markers and genetic background. Interestingly, 85% of patients with AA1730 genotype presented the smallest lumbar spine BMD values. These findings first indicate a worsening effect of ESR2 AluI polymorphism on lumbar spine BMD reduction in postmenopause, suggesting that the detection of this ESR2 variant should be recommended in postmenopausal women, particularly in populations with a high prevalence of ESR2 AA1730 homozygous genotype.     

Association between VDR Apal Polymorphism and Hip Bone Mineral Density Can Be Modified by Body Mass Index:A Study on Postmenopausal Chinese Women

Osteoporosis is a major public health problem for old people.Genetic factors are considered tobe major contributors to the pathogenesis of postmenopausal osteoporosis.The vitamin D receptor(VDR)gene is a prominent candidate gene for the regulation of postmenopausal bone mass;however,despite exten-sive studies,controversy remains regarding its association with postmenopausal body mineral density(BMD)variation.In this study,a total of 260 healthy postmenopausal Chinese women were genotyped at the VDRApaI locus using polymerase chain reaction(PCR)-restriction fragment length polymorphism (RFLP).Rawhip BMD was significantly associated with VDR ApaI polymorphism with and without adjusting for age(P=0.015 and 0.040,respectively).This genetic effect can explain 3.32% of hip BMD variation.However,the significant association vanished after correcting for both age and body mass index(BMI)(P=0.169).Inaddition,we observed a significant association between VDR ApaI polymorphism with unadjusted BMI(P=0.042)or BMI adjusted for age(P=0.049).The raw hip BMD was also found to be significantly corre-lated with BMI(r=0.517,P=0.0001),with BMI explaining 26.35% of the variation of hip BMD.All of thesefacts prompt us to conclude that the significant association between the VDR ApaI genotype and hip BMDmay be modified by BMI in postmenopausal Chinese women.Our findings may partially explain the earlierinconsistent association results concerning the VDR gene and BMD,and highlight the importance of incorpo-rating covariates such as BMI into osteoporosis association studies.     

绝经后女性CYP19基因Val80及OPG基因A163G多态性与骨密度的相关性研究

探讨细胞色素P450 19 (CYP19) 基因Val80多态性及护骨素(OPG) 基因A163G多态性与绝经后女性骨密度 (BMD) 的关系。随机选择居住在重庆的绝经后女性200例, 采用多聚酶链反应-限制性片段长度多态性法检测Val80及A163G多态性, 采用Norland公司XR-46系列双能X线骨密度仪测量股骨近端及腰椎BMD。 200名绝经后女性中Val80基因型GG、GA及AA的频率分别为19.5％、44.5％及36.0％; A163G基因型GG、GC 及CC的频率分别为: 13.0％, 42.0％及45.0％; 基因型频率分布均符合Hardy-Weinberg平衡 (P＞0.05)。协方差分析及多元逐步回归分析显示CYP19基因第3外显子Val80多态性与绝经后女性BMD无相关性 (P＞0.05)。除大转子外, A163G位点AG/GG/AG+GG基因型者股骨颈、Ward’s三角及腰椎BMD均较AA基因型者低, A163G基因型与股骨颈、Ward’s三角及腰椎BMD有相关性 (P＜0.05)。OPG基因启动子区A163G多态性分布存在明显的种族差异, 且与绝经后女性BMD有一定关联, AA型对BMD具有一定的保护作用, G等位基因是BMD降低的危险因素。     

Impaired estrogen sensitivity in bone by inhibiting both estrogen receptor alpha and beta pathways

Although it is well established that estrogen deficiency causes osteoporosis among the postmenopausal women, the involvement of estrogen receptor (ER) in its pathogenesis still remains uncertain. In the present study, we have generated rats harboring a dominant negative ERalpha, which inhibits the actions of not only ERalpha but also recently identified ERbeta. Contrary to our expectation, the bone mineral density (BMD) of the resulting transgenic female rats was maintained at the same level with that of the wild-type littermates when sham-operated. In addition, ovariectomy-induced bone loss was observed almost equally in both groups. Strikingly, however, the BMD of the transgenic female rats, after ovariectomized, remained decreased even if 17beta-estradiol (E(2)) was administrated, whereas, in contrast, the decrease of littermate BMD was completely prevented by E(2). Moreover, bone histomorphometrical analysis of ovariectomized transgenic rats revealed that the higher rates of bone turnover still remained after treatment with E(2). These results demonstrate that the prevention from the ovariectomy-induced bone loss by estrogen is mediated by ER pathways and that the maintenance of BMD before ovariectomy might be compensated by other mechanisms distinct from ERalpha and ERbeta pathways.     

Association between VDR ApaI Polymorphism and Hip Bone Mineral Density Can Be Modified by Body Mass Index： A Study on Postmenopausal Chinese Women

Osteoporosis is a major public health problem for old people. Genetic factors are considered to be major contributors to the pathogenesis of postmenopausal osteoporosis. The vitamin D receptor (VDR) gene is a prominent candidate gene for the regulation of postmenopausal bone mass; however, despite extensive studies, controversy remains regarding its association with postmenopausal body mineral density (BMD) variation. In this study, a total of 260 healthy postmenopausal Chinese women were genotyped at the VDR ApaI locus using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). Raw hip BMD was significantly associated with VDR ApaI polymorphism with and without adjusting for age (P=0.015 and 0.040, respectively). This genetic effect can explain 3.32% of hip BMD variation. However, the significant association vanished after correcting for both age and body mass index (BMI) (P=0.169). In addition, we observed a significant association between VDR ApaI polymorphism with unadjusted BMI(P=0.042) or BMI adjusted for age (P=0.049). The raw hip BMD was also found to be significantly correlated with BMI (r=0.517, P=0.0001), with BMI explaining 26.35% of the variation of hip BMD. All of these facts prompt us to conclude that the significant association between the VDR ApaI genotype and hip BMD may be modified by BMI in postmenopausal Chinese women. Our findings may partially explain the earlier inconsistent association results concerning the VDR gene and BMD, and highlight the importance of incorporating covariates such as BMI into osteoporosis association studies.     

Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts

Estrogen prevents osteoporotic bone loss by attenuating bone resorption; however, the molecular basis for this is unknown. Here, we report a critical role for the osteoclastic estrogen receptor alpha (ERalpha) in mediating estrogen-dependent bone maintenance in female mice. We selectively ablated ERalpha in differentiated osteoclasts (ERalpha(DeltaOc/DeltaOc)) and found that ERalpha(DeltaOc/DeltaOc) females, but not males, exhibited trabecular bone loss, similar to the osteoporotic bone phenotype in postmenopausal women. Further, we show that estrogen induced apoptosis and upregulation of Fas ligand (FasL) expression in osteoclasts of the trabecular bones of WT but not ERalpha(DeltaOc/DeltaOc) mice. The expression of ERalpha was also required for the induction of apoptosis by tamoxifen and estrogen in cultured osteoclasts. Our results support a model in which estrogen regulates the life span of mature osteoclasts via the induction of the Fas/FasL system, thereby providing an explanation for the osteoprotective function of estrogen as well as SERMs.     

Biological effects of hormone replacement therapy in relation to serum estradiol levels

OBJECTIVE: Tissues in various parts of the body have different sensitivities to estradiol. However, it is very difficult to measure the serum estradiol levels precisely in women receiving oral conjugated equine estrogen, which is a mixture of estrogens. In the present study, we precisely measured the serum levels of estradiol in postmenopausal women undergoing hormone replacement therapy (HRT), and we clarified the relationships between serum estradiol levels and the effects of HRT on the Kupperman index, bone mineral density (BMD), serum gonadotropin, lipid metabolism and unscheduled bleeding as the clinical endpoints. METHODS: Sixty-eight postmenopausal or bilaterally ovariectomized women, aged 30-64 years, who had been suffering from vasomotor symptoms such as hot flush or atrophy of the vagina were randomly assigned to two groups: one group of 34 patients who received oral administration of 0.625 mg conjugated equine estrogen (CEE, Premarin, Wyeth) and 2.5 mg medroxyprogesterone acetate (MPA, Provera, Upjohn) every other day, and another group of 34 patients who received oral administration of 0.625 mg CEE and 2.5 mg MPA every day. All subjects were re-classified into three groups according to the serum estradiol level after 12 months of treatment: (1) low estradiol group (<15 pg/ml, n = 25); (2) middle estradiol group (> or =15 and <25 pg/ml, n = 27), and (3) high estradiol group (> or =25 pg/ml, n = 16). We examined the relationships between serum estradiol level and the effects of estradiol on the Kupperman index, BMD, serum gonadotropin levels, lipid profile and unscheduled bleeding in these three groups. Results: Results obtained by using our newly developed high-performance liquid chromatography (HPLC)-radioimmunoassay (RIA) system clearly showed that the effects on each tissue in postmenopausal women receiving oral CEE and MPA is closely related to estradiol level. The effects of HRT on BMD, serum gonadotropin levels and lipid profile were shown to be clearly dependent on the serum estradiol levels, while the effect of HRT on the Kupperman index was independent of the serum estradiol level. Furthermore, it was also found that a very low concentration of estradiol (<15 pg/ml) was sufficient to suppress the serum LH and FSH levels and to relieve vasomotor symptoms, and that the minimum concentration of estradiol required to increase BMD was 15 pg/ml. On the other hand, the level of estradiol required to reduce total cholesterol, low density lipoprotein-cholesterol (LDL-C) and apolipoprotein B (Apo B) was found to be more than 25 pg/ml, while the level required to increase high density lipoprotein-cholesterol (HDL-C) and apolipoprotein A1 (Apo A1) was at least 15 pg/ml. The incidence of unscheduled bleeding was also lower in the low estradiol group than in the other estradiol level groups. CONCLUSION: These results suggest that the different clinical endpoints have different response thresholds and thus reflect tissue sensitivity to estradiol levels achieved by HRT.     

Association of a polymorphism of the CC chemokine receptor-2 gene with bone mineral density

The possible association of the 190G-->A (Val64Ile) polymorphism of the CC chemokine receptor-2 gene (CCR2) with bone mineral density (BMD) was examined in 2215 subjects (1125 men, 1090 women), all of whom were community-dwelling individuals aged 40 to 79 years. Among men aged < 60 years, BMD for the distal radius, lumbar spine, or Ward's triangle was significantly greater in those with the AA genotype than in those with the GG or GA genotypes. For postmenopausal women, BMD for the distal radius or femoral neck was significantly greater in those with the AA genotype than in those with the GG or GA genotypes. In contrast, for men aged > or =60 years and for premenopausal women, BMD was not associated with the CCR2 genotype. These results suggest that CCR2 may be a new candidate for a susceptibility locus for bone mass in middle-aged men and postmenopausal women.     

Association of CYP19 Gene Polymorphism with Vertebral Fractures in Japanese Postmenopausal Women

This study investigates aromatase gene polymorphism, which might influence bone strength in terms of mineral density and quality. We explored the relationship between CYP19 polymorphisms and vertebral fractures in postmenopausal Japanese women. In addition, we compared estrogen and testosterone levels in Japanese postmenopausal women with and without fractures. Osteoporotic postmenopausal women showed higher incidences of vertebral fractures than osteopenic women or women with normal lumbar bone mineral density (L2-4 BMD). Estrogen concentrations in postmenopausal women were associated with BMD; however, no association was found between sex hormone levels and the presence of fractures. The C allele rs2470152 was significantly associated with increased risk of vertebral fractures (P = 0.04), whereas none of the CYP19 polymorphisms showed differences in sex steroid levels between subjects with and without fractures. Allelic variants of aromatase genes appear to interact to influence the risk of vertebral fractures in postmenopausal Japanese women.