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.     

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。     

Association of the 163A/G and 1181G/C osteoprotegerin polymorphism with bone mineral density.

The aim of the study was to investigate the distribution of 163 A/G osteoprotegerin gene promoter and 1181 G/C osteoprotegerin exon 1 polymorphisms in a group of women with different hormonal status and to analyze their relationship with BMD. Osteoprotegerin polymorphisms and BMD were analyzed in 332 women (69 premenopausal and 263 postmenopausal). BMD was quantified at the lumbar spine (L 2-4), femoral neck, and total hip. Genotyping for the presence of different polymorphisms was performed using the Custom Taqman ((R)) SNP Genotyping assays. There were not significant differences in BMD according to 163 A/G genotype. However, significant differences in lumbar spine BMD were found according to 1181 G/C alleles. Thus, women with CC genotype had significant higher BMD at the lumbar spine than those with GC or GG genotype. No differences were found in femoral neck and total hip BMD. In age-adjusted models, the 1181 G/C OPG polymorphism explained 2.2% of BMD variance at the spine, 0.3% at the femoral neck, and 0.9% at the total hip in the whole group. In the subgroup of premenopausal women, the polymorphism was strongly related to spine BMD, and explained 11.5% of the variance, whereas body weight explained 7.9%. The 1181 G/C polymorphism was associated with lumbar spine BMD in Spanish women. Premenopausal women with the CC genotype had a higher 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.     

Combined effects of collagen type I alpha1 (COL1A1) Sp1 polymorphism and osteoporosis risk factors on bone mineral density in Turkish postmenopausal women

Identification of risk factors for osteoporosis has been essential for understanding the development of osteoporosis. The collagen type I alpha1 (COL1A1) gene is suggested to be implicated in reduced bone mineral density (BMD) in osteoporosis. In the present study, the investigation of the effects of Sp1 polymorphic variants of COL1A1 gene on BMD values, and the determination of the association between COL1A1 Sp1 gene variants and osteoporosis risk factors in the context of gene–environment interaction in Turkish postmenopausal women were aimed. For the detection of COL1A1 Sp1 polymorphism, PCR-RFLP techniques have been used. BMD for lumbar spine (L1–L4) and hip (femoral neck and total hip) was measured by DXA. This study was carried out using a sample of 254 postmenopausal women. We observed a trend decrease in BMD values in the subjects with “ss” genotype having lower BMD of lumbar spine, femoral neck and total hip than those with “SS” and “Ss” genotype, however the differences did not reach statistical significance (P > 0.05). We also found that the frequencies of the BMD under mean values at the femoral neck (57.5%) and total hip (76.2%) increased considerably in the subjects carrying “Ss/ss” genotypes in combination of having family history of osteoporosis (61.5% for femoral neck) and smoking history (90.0% for total hip). This population-based study indicates that COL1A1 Sp1 polymorphism may contribute to the development of osteoporosis in combination of osteoporosis risk factors in Turkish postmenopausal women.     

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.     

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。     

Association of serum sex steroid levels and bone mineral density with CYP17 and CYP19 gene polymorphisms in postmenopausal women in Turkey

Many clinical conditions, including osteoporosis, are associated with serum levels of sex steroids. Enzymes that regulate rate-limiting steps of steroidogenic pathways, such as CYP17 and CYP19, are also regarded as significant factors that may cause the development of these conditions. We investigated the association of two common polymorphisms, in the promoter region (T→C substitution) of CYP17 and exon 3 (G→A) of CYP19, with bone mineral density (BMD) in the lumbar spine and femoral neck and serum androgen/estradiol, in a case-control study of 172 postmenopausal women aged 62.3 ± 9.6 years (mean ± SD). The CYP17 TC genotype was significantly overrepresented in patients compared to controls, and TC genotype neck T-score and lumbar T-score values were significantly higher in patients compared to controls. CYP17 TC and TT genotype testosterone and DHEA-SO(4) levels were lower in patients compared to controls. All three genotypes of CYP19 had almost the same distribution among patients. The CYP19 AG genotype, however, was most frequent among controls. CYP19 lumbar BMD levels were close to each other among the different genotypes; however, AA and AG genotypes were significantly lower in patients. Testosterone and DHEA-SO(4) levels in the CYP19 GG genotype were higher compared to those of the other genotypes in patients but not in controls. CYP19 GA individuals had lower E(2) levels and lower BMD in controls and patients. Femoral neck BMD and lumbar T-score were also diminished with GA transition. In conclusion, CYP17 and CYP19 gene polymorphisms were found to be associated with osteoporosis in postmenopausal women in Turkey.     

Association between vitamin D receptor gene polymorphisms and bone mineral density in Chinese women

Vitamin D receptor (VDR) is implicated in the regulation of bone mineral density (BMD). In this study, we performed a meta-analysis to evaluate the association between the VDR BsmI (rs1544410) and ApaI (rs7975232) polymorphisms and BMD in Chinese women. Literature was retrieved from PubMed and other databases. The studies on the association between VDR BsmI and ApaI genotypes and BMD at the lumbar spine, the femoral neck, the trochanter or the Ward’s triangle in Han Chinese women were included in this meta-analysis. Pooled BMD differences and 95% confidence intervals (CIs) were calculated using random- or fixed- effects model. Twenty-five eligible studies, which included 4,075 Chinese women, were identified. No significant difference was observed for either genotype when the meta-analysis was limited to premenopausal women. In postmenopausal women, BMD differences were significant for BB vs. Bb [−0.029 (95% CI −0.056, −0.002) g/m², P = 0.037] at the femoral neck, AA vs. Aa [−0.029 (95% CI −0.051, −0.006) g/m², P = 0.012] at the lumbar spine, and Aa vs. aa [0.022(95% CI 0.011, 0.033) g/m², P = 0.000] at the trochanter. These results suggest a modest but statistically significant association between VDR BsmI and ApaI polymorphisms and BMD in Chinese postmenopausal women, with higher BMD in heterozygous subjects. More epidemiological and mechanistic studies are needed to further investigate the role of VDR gene polymorphisms in regulating BMD and osteoporosis in the future.     

Alendronate Therapy in Men With Primary Hyperparathyroidism

ObjectiveTo determine the skeletal effects of alendronate therapy in men with primary hyperparathyroidism (PHPT) in comparison with those in postmenopausal women.MethodsThere essentially are no published data on the effects of bisphosphonate therapy in men with PHPT. We previously conducted a double-blind, randomized, single-crossover trial of alendronate, 10 mg daily, in PHPT and reported that alendronate significantly increases bone mineral density (BMD) at 12 months relative to baseline values. That study sample included both women (n = 28) and men (n = 9) and both premenopausal (n = 4) and postmenopausal (n = 24) women. Study subjects were randomly assigned to receive either alendronate or placebo during the first year, and all subjects received alendronate during the second year. Among the men, 3 received alendronate and 6 received placebo during the first year. The current analysis focuses on the skeletal effects of alendronate therapy in the 9 men during their first year of treatment versus the 6 men during their first year while receiving placebo as well as the 24 postmenopausal women during their first year of alendronate therapy. Paired t tests comparing baseline and 12-month data were performed for the 9 treated men and the 6 control subjects; unpaired t tests were used to compare the 9 treated men and the 24 treated women.ResultsAlendronate therapy for 1 year (n = 9) resulted in a 4.8% increase in BMD at the lumbar spine (P = .1) in comparison with the men who received 1 year of placebo (n = 6). Relative to baseline, men receiving alendronate showed a significant 4.4% gain in BMD at the lumbar spine (P = .009) and a 2.95% gain in total hip BMD (P = .027). A 47% decline in serum levels of bone-specific alkaline phosphatase activity was also noted with alendronate therapy (P = .003). Changes in BMD in the male population were similar to previously reported effects of alendronate therapy in postmenopausal women with PHPT.ConclusionAlendronate therapy in men with PHPT is associated with improvements in BMD and reductions in bone turnover. These data, similar to the findings in postmenopausal women with PHPT, suggest that aminobisphosphonates may be of value in providing skeletal protection for men with PHPT. Further study is needed to confirm skeletal protection and fracture efficacy in this population. (Endocr Pract. 2009;15:705-713)     

Vitamin D receptor gene polymorphisms,bone mineral density and bone turnover: FokI genotype is related to postmenopausal bone mass

The relationship between vitamin D receptor (VDR) intragenic polymorphisms FokI, BsmI, ApaI and TaqI and bone mineral density (BMD) or biochemical markers of bone remodeling were investigated in 114 Czech postmenopausal women, on the average 62.5+/-8.9 years of age. Restriction fragment length polymorphisms in the VDR gene were assessed by PCR amplification and digestion with restriction enzymes FokI, BsmI, ApaI, and TaqI recognizing polymorphic sites in the VDR locus. Bone mineral density was measured at the lumbar spine and at the hip by dual-energy X-ray absorptiometry (DEXA, g/cm2). After adjusting for age and the body mass index (BMI), subjects with the ff genotype had 9.4% lower BMD at the hip than those with the Ff genotype (p=0.0459, Tukey's test). FF individuals had an intermediate BMD at the hip. A similar pattern of lower lumbar spine BMD was also found in ff individuals, but it did not reach statistical significance. There was no relationship between BsmI, ApaI and TaqI VDR polymorphisms and BMD at any skeletal site. Subjects with Aa (ApaI) genotypes had higher levels of propeptide of type I collagen (PICP) than homozygous AA (p=0.0459, Tukey's test). In FokI, BsmI and TaqI restriction sites the biochemical markers of bone remodeling did not differ by genotype. In addition, no significant difference was observed in VDR genotypic distribution between osteoporotic women and non-osteoporotic controls in the study group. To conclude, the FokI genotype of the vitamin D receptor gene is related to bone mass at the hip in Czech postmenopausal women, whereas the importance of remaining VDR genotypes was not evident.     

Association between Levels of Serum Ferritin and Bone Mineral Density in Korean Premenopausal and Postmenopausal Women: KNHANES 2008–2010

Background

As women go through menopause, serum estrogen decreases and ferritin increases. Decreased serum estrogen is well known to cause detrimental effects on bone health; however, data on the associations of serum ferritin with BMD before and after menopause are still lacking. Therefore, this study aimed to investigate the association between serum ferritin levels and BMD in premenopausal and postmenopausal Korean women.

Methods

This study was performed using data from the 2008–2010 Korean National Health and Nutrition Examination Survey, including 7300 women (4229 premenopausal and 3071 postmenopausal). BMD was measured using dual X-ray absorptiometry at the femur and the lumbar spine, and serum ferritin levels were measured by chemiluminescent immunoassay.

Results

Median serum ferritin levels in postmenopausal women were higher than those in premenopausal women despite the same age ranges. Serum ferritin levels were only significantly correlated with BMD on the lumbar spine (β = −0.189, p-value = 0.005) in premenopausal women after adjusting confounding factors. Additionally, BMD on the lumbar spine had tended to decrease as serum ferritin quartiles increase (P for trend = 0.035) in premenopausal women after adjusting confounding factors. On the other hand, there were no significant associations between serum ferritin levels and BMD on the total femur and, femur neck in premenopausal women, and BMD on the total femur, femur neck, and lumbar spine in postmenopausal women.

Conclusion

Increased serum ferritin levels were significantly associated with BMD in premenopausal women, particularly on the lumbar spine, but not in postmenopausal women.     

Influence of CYP3A5, ABCB1 and NR1I2 polymorphisms on prednisolone pharmacokinetics in renal transplant recipients

The objective of this study was to evaluate whether genetic polymorphisms of CYP3A5 (A6986G, CYP3A5*3), ABCB1 (C1236T, G2677T/A, C3435T) and NR1I2 (A7635G) significantly impact the pharmacokinetics of prednisolone in renal transplant recipients. Ninety-five recipients were given repeated doses of triple therapy immunosuppression consisting of prednisolone, tacrolimus and mycophenolate mofetil. Twenty-eight days after renal transplantation, plasma prednisolone concentrations were measured by high-performance liquid chromatography. Comparisons of the CYP3A5 and ABCB1 genotypes revealed no significant differences in the prednisolone pharmacokinetics. The mean prednisolone C(max) for recipients (n=14) having both the ABCB1 3435CC genotype and the CYP3A5*3/*3 genotype was significantly higher than those (n=11) having both ABCB1 3435TT and CYP3A5*3/*3 genotypes (180ng/mL versus 129ng/mL, P=0.0392). The plasma concentrations of prednisolone in recipients having both ABCB1 3435CC and CYP3A5*3/*3 genotypes tended to be higher than those having both ABCB1 3435TT and CYP3A5*3/*3 genotypes. The mean AUC(0-24) and C(max) values for prednisolone in recipients having the NR1I2 7635G allele (AG: n=45, GG: n=32) were significantly lower than in patients having the 7635AA allele (n=18) (7635GG versus 7635AA, P=0.0308 for AUC(0-24), P=0.0382 for C(max) of prednisolone). In conclusion, NR1I2 (A7635G) rather than CYP3A5 or ABCB1 allelic variants affected patient variability of plasma prednisolone concentration. Recipients carrying the NR1I2 7635G allele seemed to possess higher metabolic activity for prednisolone in the intestine, greatly reducing its maximal plasma concentration.     

Heterozygosity for a coding SNP in COL1A2 confers a lower BMD and an increased stroke risk

Genetic variation plays an important role in osteoporosis and a prime candidate gene is Collagen alpha2(I) (COL1A2). A coding polymorphism (rs42524) in COL1A2 has previously been associated with intracranial aneurysms. Here the effects of this polymorphism have been studied in relation to bone mineral density (BMD) and prevalences of stroke and myocardial infarction (MI). rs42524 was genotyped in elderly men (n = 2004) from the Swedish MrOS cohort. Genotypes were analysed for association to BMD and certain health parameters. Significant associations (overall P < 0.05), were observed between rs42524 genotype and BMD at several skeletal sites. Surprisingly, the heterozygote genotype class exhibited lower BMD than either homozygote group. When subjects were classified as heterozygotes or homozygotes, the heterozygous genotype was found to confer a lower BMD at total hip, femoral neck and trochanter Furthermore, the heterozygote genotype had an increased risk of stroke and MI, with population Attributable Risks being 0.12 and 0.08, respectively.     

Bone mineral density and genetic markers involved in three connected pathways (focal adhesion,actin cytoskeleton regulation and cell cycle): the CUMAGAS-BMD information system

The focal adhesion, the actin cytoskeleton and cell-cycle are connected pathways and their genes are implicated in the pathogenesis of low BMD. Data from 211 studies that investigated the association between BMD and gene variants involved in these pathways were catalogued in a web-based information system and analyzed. In individual studies, significant association was found for 16 variants in lumbar spine, 11 in femoral neck and 5 in hip. In meta-analysis, significant results were shown for the variants COL1A1 rs1800012 (in lumbar spine and femoral neck), COL1A1 rs1107946 (in lumbar spine), TGFB1 rs1982073 (in femoral neck and hip) and TGFB1 rs1800469 (in lumbar spine).     

Bone mineral density and genetic markers involved in three connected pathways (focal adhesion, actin cytoskeleton regulation and cell cycle): the CUMAGAS-BMD information system

The focal adhesion, the actin cytoskeleton and cell-cycle are connected pathways and their genes are implicated in the pathogenesis of low BMD. Data from 211 studies that investigated the association between BMD and gene variants involved in these pathways were catalogued in a web-based information system and analyzed. In individual studies, significant association was found for 16 variants in lumbar spine, 11 in femoral neck and 5 in hip. In meta-analysis, significant results were shown for the variants COL1A1 rs1800012 (in lumbar spine and femoral neck), COL1A1 rs1107946 (in lumbar spine), TGFB1 rs1982073 (in femoral neck and hip) and TGFB1 rs1800469 (in lumbar spine).     

Association of polymorphisms and haplotypes in the 5' region of COLIA1 gene with the risk of osteoporotic fractures in Russian women from Volga-Ural region

The analysis of -1997G/T, -1663indelT, and +1245G/T polymorphic loci of the 5'region of COLIA1 gene in 124 females aged from 50 to 70 years old with low numbers of traumatic fractures as well as 150 healthy individuals from Volga-Ural region has been conducted. The association of -1663indelT and +1245G/T loci with the risk of osteoporotic fractures has been discovered. It has been shown that -1997*G*G/-1663*I*D/+1245*G*T genotype combination and -1997*G/-1663*D/+1245*T haplotype can be considered as markers for fracture development.     

Association of an aromatase TTTA repeat polymorphism with circulating estrogen, bone structure, and biochemistry in older women

Osteoporosis is a disease that is strongly genetically determined. Aromatase converts androgens to estradiol in postmenopausal women, therefore polymorphisms of the gene for this enzyme may be associated with bone mass and fracture. We investigated the association of the TTTA microsatellite polymorphism in intron 4 of the aromatase (CYP19) gene with bone mineral density (BMD) and fracture in 1,257 women aged 70 yr and greater. The data obtained were stratified based on the presence or absence of a [TTTA]n of 7 (A2), determined from a preliminary analysis of hip dual-energy X-ray absorptiometry BMD, which was present in 27% of the population. The presence of an A2 allele was associated with a higher free estradiol index (0.52 +/- 0.49, P = 0.049) compared with the absence of an A2 allele (0.47 +/- 0.45); higher BMD at all sites of the hip (3.4% total hip, 2.3% femoral neck, 3.6% intertrochanter, 4.1% trochanter) and the lumbar spine (12.7%); higher values for the calcaneal quantitative ultrasound parameters broadband ultrasound (1.3%), speed of sound (0.4%), and stiffness (3.7%); and higher peripheral quantitative computed tomography measures for total (3.4%), trabecular (3.3%), and cortical BMD (3.3%) and the derived stress strain index (SSI) parameters SSI polar (6.4%) and SSI x (6.8%) values. A lower deoxypryridinoline creatinine ratio was observed in subjects with an A2 allele (30.3 +/- 10.4 vs. 27.1 +/- 9.1, P = 0.03). The A2 allele was associated with a lower prevalence of vertebral fracture in subjects who were osteoporotic (odds ratio 0.27, confidence interval 0.09-0.79). Therefore, a common polymorphism of the aromatase gene, perhaps in linkage disequilibrium with a functionally significant CYP19 polymorphism, is associated with bone structure and bone turnover, either by local effects or by effects on circulating bioactive estrogen.