雌激素受体和骨钙素基因多态性位点联合PXh单倍型对绝经后妇女骨密度的影响

目的 探讨雌激素受体(ER)基因(Xba Ⅰ、Pvu Ⅱ)、骨钙素基因(Hind Ⅲ)多态性位点联合型与绝经后妇女骨密度的相关性.方法 采用双能X线(DXA)骨密度仪检测307例绝经后妇女腰椎和左侧股骨上端骨密度,聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术检测ER基因Xba Ⅰ、PvuⅡ和Hind Ⅲ多态性.结果 (1)XX型大转子骨密度C(O.600±0.104)g/cm2]低于xx型[(0.653±0.119)g/cm2],P<0.05;Xx型、有X等位基因组的股骨颈[分别为(0.695±0.087)g/cm2和(0.697±0.088)g/cm2]、大转子[(0.592±0.106)g/cm2和(0.594±0.105)g/cm2]、Ward's三角[分别为(0.500±0.115)g/cm2和(0.505±0.123)g/cm2]骨密度低于xx型[分别为(0.737±0.108)g/cm2、(0.653±0.119)g/cm2、(0.554±0.130)g/cm2]、无X等位基因组[分别为(0.737±0.108)g/cm2、(0.653士0.119)g/cm2、(0.554±0.130)g/cm2],均P<0.05.(2)PP型、有P等位基因组Ward's三角骨密度分别低于pp型、无P等位基因组(P<0.05).(3)hh型、有h等位基因组的股骨颈、大转子、Ward's三角骨密度低于HH型,无h等位基因组骨密度低于HH型(均P<0.05).(4)含有PX、PXh单倍型组股骨颈、大转子、Ward's三角骨密度分别低于元PX、无PXh单倍型组(均P<0.05).结论 ER基因Xba Ⅰ、骨钙素基因Hind Ⅲ多态性与绝经后妇女骨密度相关,X、h等位基因对骨密度有不利影响,PXh单倍型可作为福州地区绝经后妇女骨质疏松的遗传标记物.     

Does polymorphism C1377T of the calcitonin receptor gene determine bone mineral density in postmenopausal women?

In a cross-sectional study we investigated the potential association between CALCR polymorphism (C1377T) and bone mineral density in 114 postmenopausal women. T homozygotes had higher BMD (g/cm2) at the femoral neck compared with carriers of C allele (p < 0.02, ANCOVA). Means of BMD at the lumbar spine did not differ among the genotypes (ANCOVA). In conclusion, the CALCR gene is associated with bone mass at the femoral neck in postmenopausal women.     

Interaction between birthweight and polymorphism in the calcium-sensing receptor gene in determination of adult bone mass: the Hertfordshire cohort study

OBJECTIVE: We sought evidence of interaction between single-nucleotide polymorphisms (SNP) in the calcium-sensing receptor (CASR) gene and early life in determination of bone mineral density (BMD) among individuals from the Hertfordshire Cohort Study. METHODS: Four hundred ninety-eight men and 468 women aged 59-71 years were recruited. A lifestyle questionnaire was administered and BMD at lumbar spine and femoral neck was measured. DNA was obtained from whole blood samples using standard extraction techniques. Five SNP of the CASR gene termed CASRV1 (rs1801725, G-->T, S986A), CASRV2 (rs7614486, T-->G, untranslated), CASRV3 (rs4300957, untranslated), CASRV4 (rs3804592 G-->A, intron), and CASRV5 (rs1393189, T-->C, intron) were analyzed. RESULTS: Among women the 11 genotype of the CASRV3 SNP was associated with higher lumbar spine BMD within the lowest birthweight tertile, while the opposite pattern was observed among individuals in the highest birthweight tertile (test for interaction on 1 df, p = 0.005, adjusted for age, body mass index, physical activity, dietary calcium intake, cigarette and alcohol consumption, social class, menopausal status, and hormone replacement therapy use). Similar relationships were seen at the total femur (p = 0.042, fully adjusted) with birthweight and at the total femur according to weight at 1 year tertile among women (p < 0.001, fully adjusted). One haplotype was associated with lumbar spine BMD in women (p = 0.008, fully adjusted); these findings were replicated in a second cohort. CONCLUSION: We have found evidence of an interaction between a SNP of the CASR gene and birthweight in determination of bone mass in a UK female population.     

北京地区汉族女性Cbfa1基因多态性与骨密度相关性研究

目的了解北京地区汉族女性核心结合因子α1（core binding factor α1,Cbfa1）基因多态性的分布,并分析其与骨密度的相关性。方法利用异源双链分析技术和直接测序方法,检测北京地区204名无亲缘关系的女性受试者的Cbfa1基因型。受试者中,30—39岁年轻妇女91名（35±3岁）,自然停经1年以上的绝经后妇女113名（63±8岁）。研究对象的骨密度（BMD）采用双能X线骨密度仪（DXA）进行测量。测量部位包括腰椎1-4、股骨颈、Wards三角区及大转子部位。结果（1）北京地区汉族女性Cbfa1基因型分布频率依次为G／G占85．3％,G／A占8．3％,A／A占1．0％,G／11Ala占3．9％,A／11Ala占1．0％,11Ala／11Ala占0．4％。Cbfal等位基因频率为G占94．4％,A占5．6％。（2）校正了年龄、身高、体重和BMI的协方差分析显示,北京地区汉族妇女股骨颈部位和Wards三角区G／A基因型的BMD较G／G基因型高（分别为0．896±0．168比0．823±0．148和0．759±0．236比0．714±0．200g／cm^2;P=0．002,0．036）。独立样本T检验结果显示,股骨颈部位含A等位基因组BMD高于不含A等位基因组（0．901±0．153比0．821±0．148g／cm^2,P=0．023）。资料分为青年妇女组和绝经后妇女组进一步分析,结果提示青年妇女组股骨颈部位和Wards三角区G／A基因型的BMD较G／G基因型高（1．017±0．167比0．924±0．103,0．967±0．172比0．861±0．131g／cm^2;P=0．031,0．046）;而在绝经后妇女组,仅股骨颈部位存在A等位基因的保护作用（0．802±0．097比0．730±0．119g／cm^2,P=0．044）。结论（1）北京地区汉族女性Cbfal基因型,以G等位基因频率为主。（2）北京地区汉族妇女股骨颈部位和Wards三角区骨密度G／A基因型者较G／G基因型者高,A等位基因对BMD具有保护作用,它有利于青年妇女峰值骨量的获得。     

WNT3A gene polymorphisms are associated with bone mineral density variation in postmenopausal mestizo women of an urban Mexican population: findings of a pathway-based high-density single nucleotide screening

Osteoporosis (OP) is a common skeletal disorder characterized by low bone mineral density (BMD) and is a common health problem in Mexico. To date, few genes affecting BMD variation in the Mexican population have been identified. The aim of this study was to investigate the association of single nucleotide polymorphisms (SNPs) located in genes of the Wnt pathway with BMD variation at various skeletal sites in a cohort of postmenopausal Mexican women. A total of 121 SNPs in or near 15 Wnt signaling pathway genes and 96 ancestry informative markers were genotyped in 425 postmenopausal women using the Illumina GoldenGate microarray SNP genotyping method. BMD was measured by dual-energy X-ray absorptiometry in total hip, femoral neck, Ward’s triangle, and lumbar spine. Associations were tested by linear regression for quantitative traits adjusting for possible confounding factors. SNP rs752107 in WNT3A was strongly associated with decreased total hip BMD showing the highest significance under the recessive model (P = 0.00012). This SNP is predicted to disrupt a binding site for microRNA-149. In addition, a polymorphism of the Wnt antagonist DKK2 was associated with BMD in femoral neck under a recessive model (P = 0.009). Several LRP4, LRP5, and LRP6 gene variants showed site-specific associations with BMD. In conclusion, this is the first report associating Wnt pathway gene variants with BMD in the Mexican population.

Electronic supplementary material

The online version of this article (doi:10.1007/s11357-014-9635-2) contains supplementary material, which is available to authorized users.     

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.     

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.     

HOXD4基因多态性与老年男女性低骨量的关系

目的同源异形盒（homeobox,HOX）基因在调节软骨分化和成骨细胞中扮演了很重要的角色。本研究目的是探讨HOXD4基因多态性与老年男性和女性低骨量的关系。方法筛选711名（年龄61．8±6．9岁）老年男性（其中419例健康男性、276例骨量减少患者和16例骨质疏松患者）和617名（年龄58．9±6．4岁）绝经后妇女（其中272例健康女性、291例骨量减少患者和54例骨质疏松患者）共1328个研究对象,所有对象均为居住在上海30年以上的汉族人。双能X线吸收仪（GE Lunar Prodigy和Hologie QDR2000）检测左侧股骨颈BMD（bone mineral density,BMD）。骨量减少和骨质疏松的诊断分别按照股骨颈BMD为同性别正常峰值BMD的-1和-2．5个标准差,同时排除继发性低骨量的存在。使用Taqman荧光探针法检测HOXD4的3个标签位点：rs1867863、sr13418078和rs4972504的单核苷酸多态性（single nucleotide polymor-phisms,SNPs）。结果与其他人群不同,在我们的研究中rs13418078只发现CC基因型。在711例老年男性中,rs1867863的基因型频率依次为AA（40．5％）、AC（45．7％）、CC（13．8％）,rs4972504的基因型频率依次为CC（51．6％）、CT（40．5％）、TT（7．9％）;在617例老年女性中,~1867863的基因型频率依次为AA（42．3％）、AC（43．1％）、CC（14．6％）,rs4972504的基因型频率依次为CC（53．5％）、CT（38．7％）、TT（7．8％）;等位基因频率分布均符合Hardy—Weinberg定律。未发现此两位点SNP在骨质疏松组、骨量减少组和骨量正常组之间频率分布的差异（P均〉0．05）。结论本研究第一次提示了HOXD4的rs1867863和rs4972504位点多态性可能不是中国汉族老年男性和女性低骨量的风险因子。     

Polymorphisms in the CLCN7 gene modulate bone density in postmenopausal women and in patients with autosomal dominant osteopetrosis type II

CONTEXT: Genetic factors are important determinants of bone mineral density (BMD). The fact that mutations in the ClC-7 chloride channel cause autosomal dominant osteopetrosis (ADOII) make the CLCN7 gene an attractive candidate for the regulation of bone density. OBJECTIVE: The objective of the study was to investigate the association between polymorphisms in the CLCN7 gene and BMD in postmenopausal women and with clinical variability in ADOII. DESIGN: This was a genetic association study using five single-nucleotide polymorphisms and a variable number tandem repeat (VNTR) polymorphism in the CLCN7 gene. PARTICIPANTS: A total of 425 postmenopausal women aged 64 +/- 7 yr participated in the study. We also investigated an ADOII family with low penetrance comprising 18 mutation carriers. MAIN OUTCOME MEASURE(S): In our postmenopausal cohort, individual single-nucleotide polymorphism genotypes and haplotypes were analyzed for association with BMD at the lumbar spine and the femoral neck and with the bone resorption marker deoxypyridinoline (D-Pyr/Crea). The same polymorphisms on the nonmutated CLCN7 allele were investigated for association with the variability of the ADOII phenotype. RESULTS: Analysis by multiple linear regression revealed a significant association between the ss genotype of the VNTR and higher Z-score values (P = 0.029). The haplotype 4, which comprises the long allele of the VNTR, was found to be significantly associated with lower femoral neck Z-score values (P = 0.011). Furthermore, we found an association of the ss genotype of the VNTR with lower levels of the bone resorption marker D-Pyr/Crea (P = 0.015), whereas haplotype 4 was associated with higher D-Pyr/Crea levels (P = 0.039). In the ADOII family, we could demonstrate that haplotype 3, which contains the s-allele of the VNTR, is associated with a slightly higher probability that mutation carriers develop osteopetrosis (P = 0.029). In both cases the association seems largely to be driven by the VNTR genotype but is further strengthened if surrounding polymorphisms are added to the analysis. CONCLUSION: We observed a significant association of CLCN7 polymorphisms with the variance of BMD and bone resorption marker levels in postmenopausal women and with the variability of the ADOII phenotype.     

Is leptin a significant predictor of bone mineral density in postmenopausal Turkish women?

The objective of the present study was to investigate the relationship between leptin and bone mineral density in postmenopausal Turkish women. A total of 122 healthy postmenopausal women were enrolled in this cross-sectional study. Blood samples were obtained for analysis of serum leptin. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry at the lumbar spine, femoral neck and trochanter on the same day. Leptin levels was significantly correlated with BMD of L(1-4) (P = 0.04), but not of femoral neck (P = 0.13), and trochanter (P = 0.39). However, Z scores of L(1-4) (P = 0.009), femur neck (P = 0.009), and femur trochanter (P = 0.025) were positively correlated with leptin levels. In multiple linear regression analysis, leptin was not found to be a statistically significant independent predictor for BMD. Leptin was associated with BMD and Z scores at various body sites; however, it was not an independent predictor of BMD.     

Evidence of sexual dimorphism in relationships between estrogen receptor polymorphisms and bone mass: the Hertfordshire study

OBJECTIVE: To examine the relationship between estrogen receptor (ER) a and ss gene polymorphisms and bone mass. METHODS: Bone mineral density (BMD) was measured at the lumbar spine and proximal femur twice, 4 years apart, in a cohort of 147 men and 125 women aged 61-73 years. Genomic DNA was extracted from whole blood samples, and genotyping for the ER (PvuII, XbaI, and AluI) was undertaken. RESULTS: There were no significant associations between either the XbaI or PvuII polymorphisms and bone mass, or bone loss in the cohort as a whole. However, men homozygous for the aa beta receptor polymorphism had higher BMD at the lumbar spine (p = 0.05), femoral neck (p = 0.01), and total femur (p = 0.01). Women homozygous for aa had lower femoral neck and total femoral BMD than women of the AA or Aa genotypes (p = 0.01 and p = 0.02). Gender*ERbeta interaction terms were statistically significant (p = 0.02 for lumbar spine BMD, p = 0.0004 for femoral neck BMD, and p = 0.0003 for total femoral BMD, each test with 2 degrees of freedom unadjusted). Adjustment for sex hormone concentration and lifestyle factors made little difference to our results. CONCLUSION: We found relationships between the ERbeta gene and the determination of bone mass among men and women in their seventh decade.     

JAG1 and COL1A1 polymorphisms and haplotypes in relation to bone mineral density variations in postmenopausal Mexican-Mestizo Women

Osteoporosis is characterized by low bone mineral density (BMD). One of the most important factors that influence BMD is the genetic contribution. The collagen type 1 alpha 1 (COL1A1) and the JAGGED (JAG1) have been investigated in relation to BMD. The aim of this study was to investigate the possible association between two single-nucleotide polymorphisms (SNPs) of COL1A1, their haplotypes, and one SNP of JAG1 with BMD in postmenopausal Mexican-Mestizo women. Seven hundred and fifty unrelated postmenopausal women were included. Risk factors were recorded and BMD was measured in lumbar spine, total hip, and femoral neck by dual-energy X-ray absorptiometry. DNA was obtained from blood leukocytes. Two SNPs in COL1A1 (rs1800012 and rs1107946) and one in JAG1 (rs2273061) were studied. Real-time PCR allelic discrimination was used for genotyping. The differences between the means of the BMDs according to genotype were analyzed with covariance. Deviations from Hardy–Weinberg equilibrium were tested. Pairwise linkage disequilibrium between single nucleotide polymorphisms was calculated by direct correlation r², and haplotype analysis of COL1A1 was conducted. Under a dominant model, the rs1800012 polymorphism of the COL1A1 showed an association with BMD of the lumbar spine (P = 0.021). In addition, analysis of the haplotype of COL1A1 showed that the G–G haplotype presented a higher BMD in lumbar spine. We did not find an association between the s1107946 and rs2273061 polymorphisms of the COL1A1 and JAG1, respectively. Our results suggest that the rs1800012 polymorphism of the COL1A1, in addition to one haplotype, were significantly associated with BMD variation in Mexican-Mestizo postmenopausal women.     

Influence of muscle strength and body weight and composition on regional bone mineral density in healthy women aged 60 years and over.

Although weight, lean mass, fat mass and muscular strength are often found to be intercorrelated, the respective role of each parameter in bone mineral density (BMD) remains unknown in older women. The aim of the present study was to investigate the relationship between body weight and composition and quadriceps strength on femoral neck and lumbar spine BMD in healthy postmenopausal women. The relationship between isokinetic quadriceps strength measured by Biodex and BMD measured by dual energy X-ray absorptiometry was studied in 56 women aged 60-81 (70.5 +/- 6.2) years in multiple regression models adjusted for age, body composition and menopausal treatment. Weight and age were associated with femoral neck BMD (33 and 10% of variance accounted for, respectively) and lumbar spine BMD (23 and 8% of its variance). When body weight and quadriceps strength were excluded from the model, lean mass and age were associated with femoral neck BMD (29 and 14% of variance explained, respectively) and lumbar spine BMD (28 and 11% of variance explained, respectively). When quadriceps strength was entered into the model, it was strongly associated with femoral neck BMD (30% of variance accounted for), in addition to lean mass (9%) and age (7%), whereas it was not associated with lumbar spine BMD. In conclusion, lean mass explains a great part of the strong association between body weight and femoral neck and lumbar spine BMD. Quadriceps strength explains a great part of the association between lean mass and BMD at the femoral neck site but not at the lumbar spine site. These results suggest a site-specific effect of muscular strength on bone and a potential role of the age-related decline of muscle strength in age-related bone loss in postmenopausal women.     

Angiotensin-I converting enzyme genotype-dependent benefit from hormone replacement therapy in isometric muscle strength and bone mineral density

Low bone mineral density (BMD) and muscle weakness are major risk factors for postmenopausal osteoporotic fracture. Hormone replacement therapy (HRT) reverses the menopausal decline in maximum voluntary force of the adductor pollicis and reduces serum angiotensin-I converting enzyme (ACE) levels. The insertion (I) allele of the ACE gene polymorphism is associated with lower ACE activity and improved muscle efficiency in response to physical training. Therefore, we examined whether the presence of the I allele in postmenopausal women would affect the muscle response to HRT. Those taking HRT showed a significant gain in normalized muscle maximum voluntary force slope, the rate of which was strongly influenced by ACE genotype (16.0 +/- 1.53%, 14.3 +/- 2.67%, and 7.76 +/- 4.13%, mean +/- SEM for II, ID, and DD genotype, respectively; P = 0.017 for gene effect, P = 0.004 for I allele effect). There was also a significant ACE gene effect in the response of BMD to HRT in Ward's triangle (P = 0.03) and a significant I allele effect in the spine (P = 0.03), but not in the neck of femur or total hip. These data suggests that low ACE activity associated with the I allele confers an improved muscle and BMD response in postmenopausal women treated with HRT.     

Association between bone mineral density and metabolic syndrome in pre- and postmenopausal women

Metabolic syndrome (MS) has 2 conflicting factors: obesity known to be protective against osteoporosis and an inflammation that activates bone resorption. The aim of this study was to evaluate the difference of bone mineral density(BMD) in women with or without MS according to menopausal state. This is a cross-sectional study of 2,265 women(1,234-premenopausal, 931-postmenopausal) aged over 20 years who visited the Health Promotion Center from January 2006 to December 2009. We measured BMD at the lumbar spine and femoral neck. MS was defined according to the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) criteria. The prevalence of MS was 5.5% in the premenopausal group and 13.5% in the postmenopausal group. In the postmenopausal group, C-reactive protein (CRP) was significantly higher in subjects with MS than those without MS, but it was not in the premenopausal group. In the postmenopausal group, women with MS had a lower BMD at the lumbar spine and femoral neck before or after adjustment. In the premenopausal group, women with MS had a lower BMD at the lumbar spine, but not at the femoral neck. In stepwise linear regression analysis, predictive variables for BMD of the lumbar spine were systolic blood pressure in the premenopausal group and HDL-cholesterol and diastolic blood pressure (DBP) in the postmenopausal group. The predictive variables for BMD of the femoral neck were DBP and waist circumference in the premenopausal group and CRP and DBP in the postmenopausal group. Inflammation might have a more important role in BMD than obesity in the postmenopausal women.     

Positive effect of parathyroidectomy on bone mineral density in mild asymptomatic primary hyperparathyroidism

OBJECTIVES: Patients with mild primary hyperparathyroidism (pHPT) often appear asymptomatic, and have previously been regarded as not requiring treatment. However, increased cardiovascular morbidity and dyslipidaemia have also been recognized in mild pHPT, which also seem to be normalized after parathyroidectomy. The present study explores whether postmenopausal women with mild pHPT have decreased bone mineral density (BMD) compared with age-matched healthy controls, and the effects on BMD of parathyroidectomy. DESIGN, SUBJECTS AND INTERVENTION: A population-based health screening of 5202 postmenopausal women identified 87 overtly asymptomatic patients with mild pHPT as well as age-matched healthy controls. A 5-year follow-up included 49 cases who had undergone parathyroidectomy. BMD was measured with DXA at the femoral neck, the lumbar spine and the total body. RESULTS: At study entry, BMD was 5-6% lower in the lumbar spine (L2-L4) and femoral neck in cases compared with matched controls. After the 5-year follow-up, BMD increased in L2-L4 by 2.9% (P = 0.002) in the parathyroidectomized cases and remained stable in the femoral neck. However, femoral neck BMD increased 4.1% (P = 0.013) for cases <67 years old (50% of the cohort). CONCLUSION: In accordance with recent NIH guidelines for pHPT treatment, the level of BMD per se in the investigated group of patients justifies parathyroidectomy in almost half of the cases with mild pHPT. Surgery could be expected to increase BMD in L2-L4 to the level of the controls, to increase femoral neck BMD in patients <67 years of age and to preserve femoral neck BMD in the elderly population.     

Calcium-sensing receptor gene polymorphism is not associated with bone mineral density in Italian postmenopausal women

OBJECTIVE: Calcium-sensing receptor (CaR) is a candidate gene for osteoporosis susceptibility. Several CaR polymorphisms have been identified and an association between the A986S genotype and serum calcium levels has been found in Canadian postmenopausal women. We investigated whether the presence of 986S allele was associated with bone mineral density (BMD) and osteoporotic fractures. DESIGN: The study group consisted of 164 Italian postmenopausal women without fragility fracture (Fx(-)) and 55 women with fracture (Fx(+)). METHODS: A fragment of exon 7 of CaR gene containing three polymorphisms (A986S, R990G and Q1011E) was amplified by PCR and sequenced. Anthropometric characteristics and BMD were evaluated. RESULTS: The A986S polymorphism was the most commonly observed (27.9%), whereas the other two CaR polymorphisms, R990G and Q1011E, occurred in a minority of cases (8.8 and 5.5% respectively). There was no significant difference in the frequency distribution of any CaR allele between Fx(-) and Fx(+) patients. Body mass index was found to predict BMD at the lumbar spine and femoral neck. The A986S polymorphism and Years since menopause were not independent predictors of BMD at any site. As far as fracture occurrence, there was no statistically significant difference in the prevalence of fractures between women carrying or not carrying the 986S allele. CONCLUSIONS: Our data do not support a role of A986S CaR polymorphism in BMD and in the prevalence of fragility fractures in Italian postmenopausal women.     

Association study between C-reactive protein genes and ischemic stroke in Japanese subjects

BACKGROUND: C-reactive protein (CRP) is reported to be involved in the development of atherosclerosis. Elevated CRP levels are considered to be a predictor of ischemic stroke (IS) in elderly individuals. Some single-nucleotide polymorphisms (SNP) are reportedly associated with elevated CRP levels. The aims of this study were to genotype some of the SNP in the human CRP gene and to assess the association between the CRP gene and IS. METHODS: Japanese patients with IS (72.4 +/- 8.2 years of age, n = 152) and elderly Japanese subjects without IS (78.0 +/- 4.2 years of age, n = 304) were genotyped for four SNP of the human CRP gene: rs1341665, rs1800947, rs1130864, and rs1205. Each genotyping was performed using the TaqMan SNP genotyping assay. The haplotype-based association study was assessed with a permutation test. RESULTS: The genotype rs1800947 was statistically significant between patients with IS and control subjects (CC+GC versus GG variant, P = .016 by multiple logistic regression analysis). This analysis revealed that the CC+GC variant of rs1800947 was an independent risk factor of IS. All four SNP were located in one haplotype block. The haplotype was constructed using rs1341665, rs1800947, and rs1130864, in that order. There was a significant association between IS and the C-C-C haplotype (P = .015). CONCLUSIONS: The rs1800947 SNP and the C-C-C haplotype in the CRP gene appear to be prognostic markers of ischemic stroke and this polymorphism could be a useful genetic marker.     

Polymorphisms in the IDE-KIF11-HHEX gene locus are reproducibly associated with type 2 diabetes in a Japanese population

CONTEXT: A genome-wide association study in the French population has detected that novel single-nucleotide polymorphisms (SNPs) in the IDE-KIF11-HHEX gene locus and the SLC30A8 gene locus are associated with susceptibility to type 2 diabetes. OBJECTIVE: We investigated whether SNPs in these loci were associated with type 2 diabetes in Japanese. DESIGN: Two SNPs, rs7923837 and rs1111875, in the IDE-KIF11-HHEX gene locus and one SNP, rs13266634, in the SLC30A8 gene locus were genotyped in Japanese type 2 diabetic patients (n = 405) and in nondiabetic control subjects (n = 340) using the TaqMan genotyping assay system. RESULTS: The G allele of rs7923837 was associated with type 2 diabetes [odds ratio 1.66, 95% confidence interval (CI) 1.28-2.15; P = 0.00014], following the same tendency as in the French population of the previous report. Heterozygous and homozygous carriers of the risk allele had odds ratios of 1.57 (95% CI 1.15-2.16; P = 0.0050) and 3.16 (95% CI 1.40-7.16; P = 0.0038) relative to noncarriers. Although the G allele was a major allele (66.5%) in the French population, it was a minor allele (23.8%) in Japanese. The G allele of rs1111875 was also associated with type 2 diabetes (odds ratio 1.42, 95% CI 1.13-1.78; P = 0.0024). Heterozygous and homozygous carriers of the risk allele had odds ratios of 1.31 (95% CI 0.97-1.77; P = 0.0810) and 2.40 (95% CI 1.34-4.32; P = 0.0028) relative to noncarriers. A significant association with type 2 diabetes was not observed for rs13266634. CONCLUSIONS: Polymorphisms in the IDE-KIF11-HHEX gene locus are associated with susceptibility to type 2 diabetes across the boundary of race.