Tumour necrosis factor superfamily member 11 gene promoter polymorphisms modulate promoter activity and influence bone mineral density in postmenopausal women with osteoporosis

Tumour necrosis factor superfamily member 11 (TNFSF11) gene, that codes for receptor activator of nuclear factor-kappaB ligand, is one of the candidate genes for the genetic susceptibility to osteoporosis. As variations in the TNFSF11 gene promoter could alter its expression, the aim of the study was to evaluate the functional influence of three polymorphisms in the promoter and to investigate their association with bone mineral density (BMD) and biochemical markers in postmenopausal women. A total of 404 postmenopausal women were genotyped for the presence of TNFSF11 gene promoter polymorphisms -290C>T, -643C>T and -693G>C. Two common haplotypes, CCG and TTC, which occur in 44.3 and 49.3% of subjects respectively, were subjected to functional analysis. Amplified fragments were cloned into pGL3-basic reporter plasmid, which was co-transfected with pRL-TK plasmid into HEK293 cells. Dual luciferase reporter assay was performed. BMD and biochemical markers were measured. Reporter gene analysis showed significantly higher luciferase activity in CCG than in TTC haplotype (P=0.018). Both showed association with lumbar spine BMD (BMD-ls; P=0.005 and 0.007 for TTC and CCG respectively), whereas in femoral neck there was no association with BMD. In postmenopausal osteoporosis, association with BMD-ls was established in -290C>T, -643C>T and -693G>C (P values: 0.001, 0.041 and 0.013 respectively). Association with femoral neck BMD was shown in -693G>C (P=0.049). No association was found with biochemical markers in any of the groups. Our results suggest that in postmenopausal osteoporosis, TNFSF11 gene promoter polymorphisms -290C>T, -643C>T and -693G>C play a functional role in the genetic regulation of BMD.     

Association of single nucleotide polymorphisms in secreted frizzled-related protein 1 gene with bone mineral density in Japanese women

Aim:   Recent studies have demonstrated that the Wnt signaling pathway plays an important role in bone metabolism. The purpose of this study was to examine whether the gene of secreted frizzled-related protein 1 ( SFRP1 ), a Wnt antagonist, is involved in the etiology of osteoporosis using association study.
Methods:   Seven single nucleotide polymorphisms (SNP) in the SFRP1 gene were genotyped and analyzed for association with bone mineral density (BMD) in 931 Japanese women (63.5 ± 6.7 years old, mean ± standard deviation).
Results:   One SNP (rs16890444) located in intron and another (rs3242) located in the 3'-untranslated region of the sFRP1 gene were significantly associated with the lumbar spine BMD value, and BMD values for both the femoral neck and the total hip, respectively. Women with the T/T genotype of the former SNP had a lower BMD value of the lumbar spine (L2–L4) compared with those with C/C or C/T (BMD value adjusted for age, duration after menopause, and body mass index: 0.781 vs 0.830, P  = 0.037), while women with the T/T genotype of the latter SNP had higher BMD values of femoral neck and total hip compared with those with C/C or C/T (adjusted BMD value: femoral neck, 0.721 vs 0.633, P  = 0.025; total hip, 0.834 vs 0.737, P  = 0.027).
Conclusion:   These results suggest that the SFRP1 may be a candidate gene for a BMD determinant, but further studies need to consolidate the present findings.     

Evaluation of the effects of vitamin D receptor and estrogen receptor 1 gene polymorphisms on bone mineral density in postmenopausal women

The aim of this study is to evaluate the effects of estrogen receptor 1 (ESR1) and vitamin D receptor (VDR) gene polymorphisms on bone mineral density (BMD) in a group of previously untreated osteoporotic women. Effects of demographic, environmental, and hormonal factors were also evaluated in this context. Fifty women who did not have a prior diagnosis or treatment of osteoporosis were compared with 50 nonosteoporotic postmenopausal women. Demographic and morphometric characteristics, medical history, dietary habits, exercise history, and sunlight exposure were recorded. The diagnosis of osteoporosis was made with regard to BMD measurements with DEXA. Blood samples were obtained for serum biochemistry, bone turnover markers, and VDR and ESR1 gene polymorphism analysis. Polymorphic sites of VDR and ESR1 genes were amplified by polymerase chain reaction and examined using restriction fragment length polymorphism. Bb genotype was significantly higher in the osteoporotic group when compared to controls (p = 0.022). Each 1 U decrease in the body mass index (BMI) increased the risk of osteoporosis by 8% independent of the genotype. We could not observe a significant effect of ESR1 polymorphism on BMD or osteoporosis risk. The interaction of ApaI and BsmI genotypes were found to be significant (p = 0.041) and the AaBb genotype, when corrected for BMI, was shown to increase the risk of osteoporosis five times (p = 0.005). However, the results demonstrated insignificant p values when correction for multiple testing was performed with the Bonferroni method in the logistic regression model. A predominance of Bb genotype of the VDR gene was evident in this group of postmenopausal Turkish women. Moreover, the combined genotype AaBb conferred a five times increased risk for osteoporosis when corrected for clinical variables.     

Searches for the genes determining bone mineral density with gene polymorphisms

The genes determining bone mineral density have been searched by association and linkage studies using gene polymorphisms. Candidate gene approaches as well as genome-wide studies with single nucleotide polymorphisms have produced many products. In addition, rare mutations causing monogenic hereditary bone diseases gave novel aspects for the genes contributing the variation in bone mineral density. Furthermore, studies of functional SNPs would explain the variation in bone mineral density and basic pathophysiology of osteoporosis.     

Vitamin D receptor polymorphisms, bone ultrasound and mineral density in post-menopausal women

BACKGROUND AND AIMS: Bone structure, geometry and mineral content represent complex traits with a significant heritable component. However, the specific contributing genes have not been unambiguously identified. The aim of the present cross-sectional study was to analyse an association between heel ultrasound measurements, partly reflecting bone quality, and VDR (Vitamin D receptor) gene polymorphisms in post-menopausal women, and to assess whether these associations differ from those of bone density or not. METHODS: BUA (broadband ultrasound attenuation, dB/MHz) at the right heel and BMD (bone mineral density, g/cm2) at the lumbar spine and hip were measured in 114 post-menopausal women of Caucasian origin (62.4 +/- 9.8 years). All probands were genotyped for common VDR polymorphisms--FokI, BsmI, Apal and TaqI--by restriction analysis of the PCR product. RESULTS: ANCOVA revealed significant associations between calcaneal BUA adjusted for BMI (body mass index) and YSM (years since menopause), and BsmI, Apal and TaqI genotypes in the VDR gene (p < 0.02; p < 0.0003; p < 0.02 ANCOVA, respectively). BMI- and YSM-adjusted BMD was significantly associated with Fokl genotypes in the VDR gene (p < 0.028 at lumbar spine, p < 0.007 at hip). CONCLUSIONS: The present data show that post-menopausal BMD and BUA are determined by different polymorphisms within the VDR gene. Non-coding polymorphisms in the 3' end of the VDR gene (BsmI, Apal, TaqI) are related to heel ultrasound while the FokI polymorphism in exon 2, located at the opposite site of the VDR gene, is associated with BMD measurements. Further studies are required to determine whether different polymorphic markers within a single gene independently determine various components of post-menopausal bone.     

女性护骨素基因启动子区G209A与T245G多态性和骨密度及骨转换的关系

研究护骨素基因启动子区G209A与T245G多态性和女性骨密度及骨转换生化指标的关系，结果显示G209A与T245G多态性和骨密度及骨转换生化指标无关。     

绝经后妇女白介素1受体拮抗物基因多态性与骨密度的关系

目的 研究绝经后妇女白介素1（IL-1）受体拮抗物基因（IL-1RN）多态性与骨密度，骨生化指标之间的相互关系。方法 采用PCR和电泳检测IL-1RN多态性，双能X线骨密度仪（DEXA）测定腰椎和股骨颈骨密度。结果 在166例绝经后妇女中发现了A1A1，A1A2和A1A4三种IL-1RN基因型，91%的绝经后妇女属于A1A1型，杂合子A1A2/A4型的腰椎骨密度低于纯合子A1A1型，但这种差异受到体重的影响。两组的骨生化指标差异无显著性。结论 IL-1RN多态性与体重有关，但与骨密度无直接关系。     

北京地区汉族妇女维生素D受体基因和降钙素受体基因多态性与骨密度的关系

目的　探讨维生素D受体基因起始密码子 (VDRSC)和降钙素受体 (CTR)基因多态性与 30～ 39岁健康妇女峰值骨量和绝经后妇女骨密度 (BMD)及骨折的关系。方法　应用PCR RFLP方法测定 89名 30～ 39岁健康妇女和 12 7名绝经后妇女VDRSC及CTR基因型 ;用双能X线吸收法测定BMD。结果　本研究人群VDRSC和CTR基因型频率分布均符合Hardy Weinberg定律。 6 6例骨质疏松伴 (或 )骨折组与 6 1名正常绝经后妇女组VDRSC和CTR基因型频率分布差异无显著性 ;VDRSC多态性与 30～ 39岁妇女峰值骨量和绝经后妇女BMD值均无关联 ;30～ 39岁妇女组CTRTC基因型在L2 4和大转子区BMD值高于CC基因型的对应部位 (P <0 .0 5 ) ,CTR基因型与绝经后妇女BMD值无关联 ;协同分析VDRSC和CTR基因型与BMD的关系显示 ,30～ 39岁妇女组TCFF基因型在L2 4和大转子区有较高的峰值骨量 (P <0 .0 5 ) ,但是VDRSC多态性与CTR基因型对妇女峰值骨量的影响无协同作用。结论　VDRSC多态性对 30～ 39岁妇女峰值骨量及绝经后妇女BMD无潜在影响 ;CTR基因型与 30～ 39岁妇女峰值骨量的达到和维持有关 ,而且独立于VDRSC基因型 ;VDRSC和CTR基因型不能作为预测中国汉族妇女发生骨质疏松危险性的遗传学标志。     

Serum adiponectin and bone mineral density in women

CONTEXT: Bone mineral density (BMD) is positively associated with body weight. This association persists even at non-load bearing sites, suggesting that a nonmechanical factor such as an adipocyte-derived hormone may modulate BMD. OBJECTIVE: The objective of the study was to evaluate the relationship between adiponectin, an adipocyte-derived hormone, and BMD. DESIGN, SETTING, PARTICIPANTS: A total of 1735 nondiabetic women were recruited from a large, population-based cohort (mean age, 50.0 yr). We employed linear regression methods to estimate the relationship between adiponectin and BMD. MAIN OUTCOME MEASURES: Percentage change in BMD (as measured at total hip, spine, femoral neck, and forearm) and markers of bone turnover associated with a doubling of fasting serum adiponectin levels were measured. RESULTS: Employing age-adjusted analysis, each doubling of serum adiponectin was associated with a mean 2.7% decrease in BMD [total hip, -3.2% (95% confidence interval, -4.1, -2.3); femoral neck, -3.1% (-4.0, -2.1); forearm, -2.0 (-2.6, -1.4); spine, -2.6 (-3.5, -1.7)]. After adjustment for potential confounding factors, including BMI, serum leptin, central fat mass, hormone replacement therapy, smoking, and exercise, this relationship persisted, although decreased in magnitude. When stratified by menopausal status, the relationship between serum adiponectin and BMD strengthened in postmenopausal women but disappeared in premenopausal women. Serum adiponectin was positively associated with serum osteocalcin but not with urine deoxypyridinoline. CONCLUSIONS: After adjustment of measures of body fat, increasing levels of adiponectin were associated with a decrease in BMD, even at non-load bearing sites. These data suggest that adiponectin, an adipocyte-derived hormone, may play a role in bone metabolism through nonmechanical mechanisms and that this effect may be mediated by menopausal status.     

Vitamin D receptor gene polymorphisms are associated with the risk of fractures in postmenopausal women, independently of bone mineral density

CONTEXT: Osteoporosis is a systemic disease with a strong genetic component. Vitamin D receptor (VDR) gene polymorphisms explain only a small part of the genetic influence on the level of bone mineral density (BMD), whereas their effect on fracture remains uncertain. OBJECTIVE: The objective of this study was to investigate the relationships between VDR genotypes and fracture risk. DESIGN: A prospective population-based cohort was studied. SUBJECTS: A total of 589 postmenopausal women (mean age, 62 yr) were followed prospectively during a median (interquartile) of 11 (1.1) yr. MAIN OUTCOME MEASURE: The study measured incidents of vertebral and nonvertebral fractures. RESULTS: VDR allele B was significantly and dose dependently overrepresented in women who fractured, including 34 and 86 women with first incident vertebral and nonvertebral fragility fractures, respectively. This corresponded to an odds ratio of 1.5 (95% confidence interval, 0.95-2.40) for heterozygous carriers (bB, n = 286) and 2.10 (95% confidence interval, 1.16-3.79) for homozygous carriers (BB, n = 90) of the B allele, compared with women with the bb genotype (n = 213). VDR genotype groups did not differ for demographics, physical activity, grip strength, personal and maternal history of fracture, and calcium intake. The association was independent of BMD of the spine, hip, and radius, and of the BMD loss at the radius. The relationship between VDR polymorphisms and fracture risk was not altered after adjustment for baseline circulating levels of bone turnover markers, estradiol, dehydroepiandrosterone sulfate, SHBG, IGF-I, intact PTH, and 25 hydroxyvitamin D. CONCLUSION: VDR genotypes are associated with the risk of fracture in postmenopausal women independently of BMD, rate of postmenopausal forearm BMD loss, bone turnover, and endogenous hormones. The mechanisms by which VDR genotypes influence bone strength remain to be determined.     

Influence of IL-6, COL1A1, and VDR gene polymorphisms on bone mineral density in Crohn's disease

BACKGROUND: Osteoporosis is an important cause of morbidity in patients with Crohn's disease. The pathogenesis of reduced bone mineral density (BMD) is multifactorial. A range of genetic factors have been implicated in other populations of patients with osteoporosis. AIM: To investigate the influence of interleukin 6 (IL-6), collagen type 1alpha1 (COL1A1), and vitamin D receptor gene (VDR) single nucleotide polymorphisms (SNP) on BMD in patients with Crohn's disease. PATIENTS: A cohort of 245 well characterised patients with Crohn's disease were recruited from the inflammatory bowel disease register at the Freeman Hospital and Royal Victoria Infirmary, Newcastle upon Tyne, and the Queen Elizabeth Hospital, Gateshead, UK. METHODS: Patients were genotyped for IL-6 C-174G SNP, COL1A1 Sp1 binding site G T SNP, VDR Taq1, and Fok1 SNPs, and CARD15 R702W, G908R, and L1007fs SNPs. BMD was measured at the lumbar spine (LSP) and hip using dual energy x ray absorptiometry. RESULTS: A total of 158 female and 87 male patients, aged 24-70 years (mean 44), were recruited. There were no significant differences in the distribution of the tested SNPs when analysed for age, body mass index, pre/post-menopausal status, smoking, or steroid use. Two hundred and thirteen patients were genotyped for the IL-6 SNP. LSP and total hip BMD was significantly lower in patients with the GG genotype (48%) than the CC genotype (15%) (p = 0.041, p = 0.014). One hundred and eighty patients were genotyped for the COL1A1 SNP. There was no significant difference in BMD at LSP. Hip BMD was significantly lower in heterozygous patients compared with homozygous wild-types (p = 0.034). There were no significant differences in BMD between genotypes for the two VDR SNPs or the CARD15 genotypes examined. CONCLUSION: IL-6 and COL1A1 gene polymorphisms influence BMD in patients with Crohn's disease but the particular VDR gene polymorphisms studied do not have a major effect.     

Association between bone mineral density and polymorphisms of the VDR, ERalpha, COL1A1 and CTR genes in Spanish postmenopausal women

Bone mineral density (BMD), the major determinant of osteoporotic fracture risk, has a strong genetic component, and several candidate gene polymorphisms have been implicated in the regulation of this process. In view of the reported associations between the BMD and polymorphisms in the collagen type I alpha 1 gene (COL1A1), vitamin D receptor (VDR), estrogen receptor (ER)alpha and calcitonin receptor (CTR) genes, an association study was performed between VDR, COL1A1, CTR and ER genotypes and lumbar spine, femoral neck and Ward's triangle BMD in postmenopausal Spanish women. We statistically controlled for many confounding factors, such as height, weight, age, years since menopause, use of hormone replacement therapy (HRT), tobacco consumption, use of oral contraceptives, calcium dietary intake or exercise practice. No association between COL1A1 or ER genotypes and BMD was detected. However, we described a statistically significant association between a personal history of fractures and COL1A1 genotype. The ss genotype was found to be over-represented between those women who had a personal history of fractures. The analyses of the VDR polymorphisms showed that FF subjects reached the highest values of BMD at the three measured sites, whereas Ff individuals had an intermediate BMD and ff women had the lowest values. However, the VDR-BsmI gene polymorphism was not found to be associated with adjusted BMD. For the CTR polymorphisms, our study showed that women with the aa genotype had a lower adjusted BMD at the femoral neck. In conclusion, in our postmenopausal Spanish women cohort we found a statistically significant association beteween the VDR and CTR gene polymorphisms and the BMD. However, we did not find any association between the ER and COL1A1 gene and the BMD. The COL1A1 gene was found to be associated with the prevalence of osteoporotic fractures. Of all the studied gene polymorphisms, the FokI VDR gene polymorphism seems to be the strongest BMD genetic determinant of postmenopausal Spanish women.     

Normative bone mineral density values in Filipino women

Objective: To obtain reference values of bone mineral density (BMD) for Filipino women in order to make a population‐specific diagnosis of osteoporosis. Method: Sudy design: Cross‐sectional. Setting: Osteoporosis Unit, Joint and Bone Center, Section of Rheumatology and Clinical Immunology, Department of Medicine, University of Santo Tomas Hospital, Manila, Philippines. Participants: 442 healthy Filipino women volunteers recruited from the outpatient department, Rheumatology and Clinical Immunology Clinic of the University of Santo Tomas Hospital and from within the University of Santo Tomas campus. Subjects with known underlying illness or conditions or intake of drugs that predispose to osteoporosis were excluded from the study. Intervention: Bone mineral density (BMD) measurements, expressed in grams per square centimenter of the lumbar spine, non‐dominant femur and non‐dominant forearm were done in 442 consecutive healthy Filipino women using the LUNAR DPX‐IQ machine. Results: Means and standard deviations of BMD measurements at each site were calculated using Kwikstat software Version 3.6, Release 7. Results were grouped in decades to serve as reference per decade. Conclusion: Bone mineral density measurements of these 442 healthy Filipino women may serve as an initial reference guide for the diagnosis of osteoporosis in Filipino women.     

Association of a single-nucleotide polymorphism in the promoter region of leukemia inhibitory factor receptor gene with low bone mineral density in adult women

Background:   Osteoporosis is believed to result from the interaction among multiple environmental and genetic determinants that regulate bone-mineral density (BMD).
Methods:   To investigate a potentially predisposing genetic factor in the onset of osteoporosis, we looked for a possible association between BMD in adult Japanese women and known polymorphisms in the leukemia inhibitory factor receptor gene (LIFR).
Results:   An association analysis of chromosomes from 384 volunteer subjects revealed significant correlation between the −603T > C variant of LIFR and radial BMD ( r  = 0.11, P  = 0.032) in this test population. Comparisons of mean values of adjusted radial BMD among separate genotypic groups implied an allelic dosage effect, because homozygous carriers of T alleles of that SNP had the highest adjusted BMDs (0.403 ± 0.054 g/cm²); women homozygous for the C-allele had the lowest (0.373 ± 0.042 g/cm²), and heterozygous individuals had intermediate scores (0.394 ± 0.056 g/cm²).
Conclusion:   This polymorphism in LIFR may be an important determinant of predisposition to postmenopausal osteoporosis.     

Oestrogen-receptor-alpha gene polymorphism affects response in bone mineral density to oestrogen in post-menopausal women

OBJECTIVE: An oestrogen-receptor-alpha (ERalpha) gene polymorphism has been variably reported to be related to bone mass. To investigate whether this ERalpha gene polymorphism is associated with a functional difference, we assessed the response in bone mineral density (BMD) to oestrogen therapy in post-menopausal women in relation to ERalpha gene polymorphism. PATIENTS AND MEASUREMENTS: Subjects consisted of 124 Thai post-menopausal women. Sixty-three of the women were less than 6 years post-menopausal and 61 were more than 10 years post-menopausal with vertebral or femoral osteoporosis as defined by BMD T-score less than - 2.5. Subjects were randomly allocated to receive 0.3 mg (n = 67) or 0.625 mg (n = 57) of conjugated equine oestrogen (CEE). All subjects also took 5 mg medroxyprogesterone acetate. Vertebral and femoral neck BMD were measured at baseline and 1 year after treatment. Data were expressed as mean +/- SEM. Capital P represents the absence of the restriction site while lower-case p indicates the presence of the restriction site. RESULTS: For subjects on 0.625 mg CEE, BMD at L2-4 increased significantly after 1 year in those with pp (n = 20) Pp (n = 29) and PP genotypes (n = 8) (P < 0.001). However, in subjects on 0.3 mg CEE, BMD at L2-4 increased significantly after 1 year in subjects with Pp (n = 34, + 7.6 +/- 1.5%, P < 0.001) and PP genotypes (n = 13, + 6. 9 +/- 1.0%, P < 0.001), but not in those with pp genotype (n = 20, + 2.3 +/- 2.1%, P = NS). After adjusting for age and years since menopause, the change in vertebral BMD was still lower in those without the P allele compared to those with the P allele (P < 0.05). Femoral BMD did not significantly change regardless of dose of CEE and genotype. CONCLUSIONS: We conclude that ERalpha gene polymorphism affects skeletal response to oestrogen in post-menopausal women. The effect of ERalpha gene polymorphism appears to be site-specific and does not relate to biochemical markers of bone turnover. Determination of ERalpha genotype may help identify post-menopausal women who will have more skeletal benefit from oestrogen therapy.     

Simvastatin increases bone mineral density in hypercholesterolemic postmenopausal women

Statins are able to reduce cardiovascular morbility and mortality mainly through their hypocholesterolemic effect. Beyond the inhibition of cholesterol synthesis, the identification of "ancillary" mechanisms has motivated studies evaluating the relationship between the use of statins and the modification of bone mineral density (BMD). To date, clinical trials have provided discordant results. The aim of our study was to evaluate whether simvastatin treatment (40 mg/d) could modify BMD in hypercholesterolemic women (n = 40) after a 2-year treatment as compared with a control group treated only with diet (n = 20) and matched by gender, age, body mass index (BMI), lipids, menopausal age, and BMD and the number of osteopenic, osteoporotic, and normal women (on the basis of T-score value). Exclusion criteria were secondary hyperlipemias and osteoporosis and current or previous therapy with statins, bisphosphonates, and estrogens. The BMD was measured at the lumbar spine and hip by dual energy x-ray absorpiometry (DEXA). In the group treated by simvastatin, BMD, both on the spine and femoral hip, showed a significant increase after 8 and 24 months, respectively (0.878 +/- 0.133 v 0.893 +/- 0.130 and 0.907 +/- 0.132; 0.840 +/- 0.101 v 0.854 +/- 0.101; and 0.863 +/- 0.10, P <.001); there was a percentage increase of 1.7% after 8 months and 3.3% after 24 months at the spine; at the femoral hip, BMD increased 1.6% after 8 months and 2.7% after 24 months. The group treated only with hypolipidic diet demonstrated after 8 and 24 months a slight decrease in BMD both on the spine and femoral hip (respectively, 0.884 +/- 0.175 v 0.872 +/- 0.174 and 0.861 +/- 0.164; 0.860 +/- 0.110 v 0.853 +/- 0.096 and 0.847 +/- 0.095; P <.05). In conclusion, as partly suggested by retrospective or observational data, this longitudinal study indicates that simvastatin treatment exerts a beneficial effect on BMD.     

绝经后妇女护骨素基因G1181C多态性与骨密度变化相关

目的　寻找护骨素基因(OPG)外显子中的单核苷酸多态性 (SNP),并分析其与绝经后妇女骨密度的关系。方法　在 205名绝经后妇女中,采用PCR和直接测序法确定OPG基因的SNP及基因型。应用双能X线骨密度仪测定腰椎和股骨颈骨密度 (BMD)。同时检测血清骨钙素 (BGP)、尿Ⅰ型胶原交联N端肽(NTx),以及血清护骨素(OPG)和核因子κB受体活化子配体 (RANKL)。结果　在OPG基因第一外显子中发现一个G1181C的SNP,该SNP的基因型频率分布依次为GG型占 0. 566、GC型 0. 346、CC型0. 088。去除年龄和体重的影响后,CC型的腰椎BMD明显高于GC和GG型 (P<0. 05),多元回归分析提示OPG基因型与绝经后妇女腰椎、股骨颈BMD相关 (P<0. 01)。Logistic回归分析显示OPG基因是绝经后妇女发生骨量减少和骨质疏松的独立危险因子,GG型发生骨量减少和骨质疏松的危险是CC型的 2. 83倍(P<0. 05)。结论　OPG基因的G1181C多态性与绝经后妇女BMD存在一定的关联,CC型对绝经后妇女腰椎BMD具有保护作用。     

Genetic variant in the aquaporin 9 gene is associated with bone mineral density in postmenopausal women

This study investigated whether single nucleotide polymorphisms (SNP) in the aquaporin 9 (AQP9) gene is associated with bone mineral density (BMD) in Thai postmenopausal women, after an initial genome-wide screening using high-throughput SNP genotyping in pooled DNA samples. Subjects consisted of 516 postmenopausal women aged 50 or more. High-throughput SNP screening was performed by comparing the estimated allele frequency derived from hybridization signal intensities of pooled DNA samples on the Affymetrix 500 K SNP genotyping chip set. The SNP was then genotyped for each subject individually. Data were expressed as mean ± SEM. Pooled DNA SNP screening revealed the allele frequency of an intronic A/T SNP rs2414539 in the AQP9 gene as being different between subjects with femoral neck BMD in tertiles 1 and 3. Individual genotyping in all subjects revealed that femoral neck BMD in subjects with TT, TA, and AA genotypes were 0.79 ± 0.06 (n = 3), 0.75 ± 0.01 (n = 98), and 0.71 ± 0.01 g/cm(2) (n = 415), respectively. The presence of the T allele in rs2414539 was associated with femoral neck BMD (r = 0.11, P < 0.05) but not with lumbar spine BMD. The relationship was still significant after controlling for body weight and age (P < 0.05). Genetic variation in the AQP9 gene is associated with femoral neck BMD in postmenopausal women, and may represent one of the susceptibility genes for phenotypes related to bone mass.