基因多态性与骨密度的相关性

骨密度受遗传因素影响,骨密度测定是诊断骨质疏松的主要依据.维生素D受体、Ⅰ型胶原、雌激素受体、降钙素受体参与骨形成和骨代谢,其基因多态性决定骨密度.研究发现Wnt蛋白、人类白细胞抗原等基因多态性也与骨密度有关.本文就基因多态性与骨密度的相关性进行论述.     

Association of a single nucleotide polymorphism in the constitutive androstane receptor gene with bone mineral density

Background:   Nuclear receptors play an important role in bone metabolism. In bone cells, the vitamin D receptor (VDR) and the steroid and xenobiotic receptor (SXR) are activated by vitamin D and vitamin K2, respectively. VDR and SXR are the NR1I subfamily members of nuclear receptors. We speculated that the constitutive androstane receptor ( CAR ), the third member of the NR1I subfamily, also could be implicated in the regulation of bone metabolism. Therefore, we analyzed expression of CAR mRNA in osteoblasts and then examined association of a single nucleotide polymorphism (SNP) in the human CAR gene at intron 2 (IVS2–99C>T, rs2502815) with bone mineral density (BMD).
Methods:   Expression levels of CAR mRNA were analyzed during the culture course of rat primary osteoblasts. Association of an SNP in the CAR gene with BMD was examined in 548 healthy Japanese postmenopausal women.
Results:   CAR mRNA increased at day 16 and then increased during culture of rat primary osteoblasts. The increase of CAR mRNA was parallel with the increase of alkaline phosphatase expression, a differentiation marker of osteoblasts. As a result of association study of an SNP in the CAR gene at intron 2, subjects with the CC genotype ( n  = 208) had significantly higher BMD than subjects with the TT or CT genotype ( n  = 340) (lumbar spine BMD, P  = 0.0185; total body BMD, P  = 0.0416).
Conclusion:   CAR mRNA was expressed and regulated in primary osteoblasts. A genetic variation at the CAR gene locus is associated with BMD, suggesting an involvement of the CAR gene in bone metabolism.     

Association of tumor necrosis factor receptor 1 gene polymorphism with bone mineral density

Background:   Estrogen deficiency in postmenopausal women causes an increased production of proinflammatory cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α. These cytokines are associated with an increase of bone turnover and an acceleration of bone loss. Tumor necrosis factor-α is known to promote osteoclastogenesis via TNFR1, one of the tumor necrosis factor receptors (TNFR). Therefore, the purpose of the present report was to investigate the association of TNFR1 gene polymorphism with bone mineral density (BMD) in postmenopausal Japanese women.
Methods:   The question of whether a polymorphism of the TNFR1 gene would correlate with osteoporosis in 320 unrelated healthy postmenopausal women in Japan, was investigated. A single nucleotide polymorphism (SNP) located at Pro12 (CCA to CCG) in exon 1 of TNFR1 was utilized.
Results:   The subjects were categorized into three genotypes: AA, AG, and GG. The frequency of each genotype was 72.2%, 23.8%, and 4.0%, respectively. The association of this polymorphism with BMD of the lumbar spine and total body, and several bone metabolic markers was then examined. Concerning the TNFR1 gene, the AA group had significantly low total body BMD, compared with the AG + GG group (Z score; 0.285 vs 0.568; P  = 0.03), although BMD of the lumbar spine was not statistically different.
Conclusion:   These results suggest an association between this SNP of the TNFR1 gene and BMD, and an involvement of TNFR1 in postmenopausal osteoporosis among Japanese.     

绝经后妇女MMP-2和TIMP-2水平及其与骨密度和骨代谢指标的关系

目的 探讨绝经后妇女血清基质金属蛋白酶2（MMP-2）和组织金属蛋白酶抑制因子2（TIMP-2）水平及其与骨密度和骨代谢指标的关系。方法 对192名48～65岁绝经后妇女用酶联免疫吸附法（ELISA）测定的血清MMP-2、TIMP-2以及骨碱性磷酸酶（BAP）、骨钙素、Ⅰ型胶原交联C端肽（CTX），尿Ⅰ型胶原交联N端肽（NTX），计算MMP-2／TIMP-2比值，用双能X线吸收法（DEXA）测定腰椎正位，股骨颈，Ward三角和大粗隆的骨密度，按WHO标准将绝经后妇女分为骨密度正常、低骨量和骨质疏松3组。结果 （1）绝经后妇女骨质疏松患者血清MMP-2的水平（1388±121）μg／L高于骨密度正常组（1126±141）μg／L（P〈0．05），而TIMP-2的水平（44．3±38．2）μg／L稍低于骨密度正常组（47、3±30．2）μg／L（P〉0．05）。（2）血清MMP-2和MMP-2／TIMP-2比值与腰椎正位和Ward三角骨密度、血清BAP和骨钙素呈负相关（均P〈0．05），和尿NTx／Cr呈正相关（P〈0．05），MMP-2／TIMP-2比值还与股骨颈骨密度呈负相关（P〈0．05）。TIMP-2与腰椎正位和Ward三角骨密度、血清BAP和骨钙素呈正相关（均P〈0．05），和尿NTX／Cr呈负相关（P〈0．05）。在校正年龄和体重指数后，TIMP-2与腰椎正位骨密度和骨钙素无相关性（P〉0．05）。（3）骨质疏松组中血清MMP-2和MMP-2／TIMP-2比值与腰椎正位、股骨颈和Ward三角骨密度、血清BAP和骨钙素呈负相关（均P〈0．05），和尿NTX／Cr呈正相关（均P〈0．05），TIMP-2和Ward三角骨密度和BAP呈正相关（均P〈0．05）；在低骨量组中仅MMP-2与腰椎正位和Ward三角骨密度、骨钙素呈负相关（P〈0．05），和尿NTX／Cr呈正相关（P〈0．05），MMP-2／TIMP-2比值与Ward三角骨密度和血清BAP呈负相关（均P〈0．05）。结论 绝经后女性尤其是骨质疏松症妇女血清MMP-和MMP-2／TIMP-2比值与骨密度和骨代谢指标BAP、骨钙素和尿NTX／Cr具有关联性，血清MMP-2和MMP-2／TIMP-2比值增高可能为绝经后骨质疏松症伴随骨代谢转换过程增快的表现。     

基质金属蛋白酶9基因多态性与2型糖尿病血管病变的相关性研究

目的 探讨基质金属蛋白酶9(MMP-9)基因C-1562T多态性与2型糖尿痫血管病变的关系．方法 运用PCR-RFLP检测110名健康对照者和450例2型糖尿病(DM)患者(其中单纯2型DM者100例、大血管病变者120例、糖尿病肾病(DN)患者130例、糖尿病视网膜病变患者100例)的MMP-9基因型，比较各组的基因型和等位基因频率。结果 (1)所有糖尿病视网膜病变患者的基因型均为CC型。(2)与对照组和单纯2型DM组相比，大血管病变组的T基因型和T等位基因频率显著升高，而DN组的TT基因型和T等位基因频率明显下降。(3)Logistic回归分析显示MMP-9 T等位基因、血清MMP-9、总胆固醇、低密度脂蛋白胆固醇、脂蛋白(a)是大血管病变发生的危险因素；尿白蛋白排泄率、脂蛋白(a)、HbA1C是DN发生的危险因素。结论 MMP-9基因C-1562T多态性与2型DM血管病变的发生有关，T等位基因是大血管病变的易感基因，是DN的保护基因。     

糖尿病维生素D受体基因多态性与骨密度相关性研究

目的　探讨糖尿病 (DM )患者维生素D受体 (VDR)基因多态性与骨密度 (BMD)及骨转化的关系。方法　采用PCR RFLP技术 ,检测 6 8例 2型DM患者、5 4例 1型DM患者和 6 2例健康人的VDR基因型。并采用双能X线吸收法测BMD ,放免法测血清BGP、降钙素和 2 5 (OH)D3 ,免疫放射法测血清完整PTH及Ⅰ型胶原羧基末端前肽。结果　 (1)DM组VDR基因型分布与健康组差异无显著性 ;(2 )健康组AA基因型者腰椎和大转子BMD高于aa型 ,股骨颈和Ward′s三角BMD高于aa和Aa型 (P <0 .0 5 ) ,而 2型DM组Aa基因型者股骨颈和大转子BMD高于aa型 ,1型DM组Aa基因型者仅股骨颈BMD高于aa型 (P <0 .0 5 ) ;(3)VDR基因TaqⅠ位点多态性与BMD无明显相关性。结论　DM患者VDR基因ApaⅠ位点的多态性与BMD存在相关性。     

基质金属蛋白酶9基因-1562位点C>T多态性与冠心病关系的Meta分析

目的:评价基质金属蛋白酶-9基因-1562位点C>T多态性与冠心病的关系。方法: 通过PubMed,Elsevier,EMbase,CNKI等数据库搜索2012年11月30日以前发表的基质金属蛋白酶-9基因-1562位点C>T多态性与冠心病关联性的病例对照研究文章,剔除不符合要求的文献,并根据各入选文献结果的同质性检验结果进行数据合并,计算总OR值,Meta分析采用Revman5.0及Stata11.0统计软件。结果: 共有13篇病例对照研究纳入。Meta分析TT+CT基因型比CC基因型OR=1.29(95%CI为1.13～1.47,P<0.01) ;T等位基因比C等位基因OR=1.27(95%CI为1.13～1.42,P<0.01);CT基因型比CC+TT基因型OR=1.29（95%CI:1.13～1.48）,P<0.01)。结论: 基质金属蛋白酶-9基因1562位点C>T多态性与冠心病发病相关,基质金属蛋白酶-9基因1562位点T等位基因是冠心病易感性的标记基因。     

基质金属蛋白酶9及其基因多态性与冠心病的相关性研究

基质金属蛋白酶（MMPs）是细胞基质降解所必需的锌离子依赖性的内源性蛋白酶家族,是细胞外基质（ECM）的主要生理性调节物质,在基质成分合成和降解的过程中起着重要的作用。对血管系统的基质成分而言,最重要的MMPs是胶原酶和明胶酶。其中明胶酶-B（即MMP-9）在细胞外基质重塑中具有重要作用,在许多病理损伤方面,如冠状动脉粥样硬化斑块不稳定、心室重塑、心力衰竭进展及心血管疾病预后等中亦扮演着重要的角色。     

Association of a single nucleotide polymorphism in the secreted frizzled-related protein 4 (sFRP4) gene with bone mineral density

Background:   Wnt-β-catenin signaling pathway is involved in the regulation of bone mineral density (BMD). Secreted frizzled-related protein (sFRP) 4 that antagonize Wnt signals may modulate Wnt-β-catenin signaling pathway in the bone. Therefore, we analyzed expression of sFRP4 mRNA in primary osteoblasts and the association of a single nucleotide polymorphism (SNP) in the sFRP4 gene with BMD.
Methods:   Expression levels of sFRP4 mRNA were analyzed during the culture course of rat primary osteoblasts. Association of a SNP in the sFRP4 gene at Arg262 (CGC to CGT) with BMD was examined in 372 healthy post-menopausal Japanese women.
Results:   sFRP4 mRNA was detected and increased during the differentiation of rat primary osteoblasts. As an association study of the SNP in the sFRP4 gene, the subjects without the T allele (CC; n  = 129) had significantly higher lumbar BMD than the subjects bearing at least one T allele (TT + CT; n  = 243) (Z score; 0.054 versus −0.324; P  = 0.0188).
Conclusion:   sFRP4 mRNA was expressed and regulated in primary osteoblasts. A genetic variation at the sFRP4 gene locus is associated with BMD, suggesting an involvement of sFRP4 gene in the bone metabolism.     

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.     

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。     

Association of Ob-R gene polymorphism and insulin resistance in Japanese men

Leptin and its receptors are known to play a role in glucose metabolism. We succeeded in cloning human Ob-R cDNA and revealed 7 single nucleotide polymorphisms (SNPs) (Lys109Arg, Arg223Gln, Ser343Ser, Ser492Thr, Lys656Asn, Ala976Asp, and Pro1019Pro) in the coding region of Ob-Rb. Although these 7 SNPs were not associated with an obese phenotype, several studies have reported that some of them were associated with impaired glucose metabolism. To clarify whether the Arg223Gln and A3057G (Pro1019Pro) polymorphisms influence glucose metabolism in Japanese, 696 Japanese men were genotyped. Individually, the Arg223Gln and the A3057G polymorphisms were not associated with the glucose metabolic parameters. No associations were found between haplotype and clinical parameters. However, in 327 subjects with normal glucose tolerance (NGT), the subjects with Arg/Gln or Gln/Gln + A/A haplotype showed significantly higher serum insulin levels and homeostasis model assessment (HOMA) index than those with Arg/Arg + A/A haplotype and Arg/Gln or Gln/Gln + A/G or G/G haplotype. The subjects with Arg/Gln or Gln/Gln + A/A haplotype showed a significantly lower fasting glucose to insulin (GI) ratio than those with Arg/Arg + A/A haplotype. These results suggest that the Ob-R gene may serve as a modifier gene for insulin resistance in Japanese men.     

Association of apolipoprotein E polymorphism with bone mineral density in postmenopausal women with rheumatoid arthritis

SIR, Pathological bone loss can occur by marginal erosions,juxta-articular osteoporosis and generalized osteoporosis inrheumatoid arthritis (RA) [1]. Several studies demonstratedthat these different types of bone involvement are similarlymediated by receptor activator of nuclear factor B ligand (RANKL),a factor stimulating osteoclast differentiation [2, 3]. Therefore,generalized osteoporosis has been suggested as a risk factorfor severe joint destruction in RA. In fact, joint erosionsrelated to generalized osteoporosis and high Larsen scores associatedstrongly with bone mineral density (BMD) reduction have beenfound in patients with     

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.     

北京地区汉族青年女性钙敏感受体基因多态性分布及其与骨密度相关性的研究

目的 了解北京地区汉族青年女性钙敏感受体(Calcium-sensing Receptor,CaSR)基因多态性的分布,探索其与汉族妇女峰值骨密度的相关性.方 法分别采用突变分离PCR和错配PCR-RFLP方法检测北京地区202名无亲缘关系的汉族青年健康女性(20～35岁)受试者CaSR基因A986S、G990R基因型,测定其血钙(Ca)、磷(P)及甲状旁腺素(PTH)水平,以及肝肾功能等指标,应用双能X线骨密度仪(OXA)测定腰椎、股骨上段部位的骨密度(BMO).结果 (1)北京地区汉族女性中存在CaSR基因A986S、G990R多态性,从、AS基因型频率分别为95.0%和5.0%,等位基因A和S的频率分别为97.5%和2.5%;RR、GR及GG基因型频率分别为21.3%、51.0%和27.7%,等位基因R和G的频率分别为46.8%和53.2%.(2)校正年龄、身高、体重、BMI及血Ca、P、PTH水平后,多因素协方差分析显示从、AS基因型组之间L2-4、股骨颈、ward's三角及大转子部位的BMD无显著差异(P=01090～0.671);GG、GR及RR基因型组之间L2-4、股骨颈、ward's三角及大转子部位的BlVID也无显著差异(P=0.089～0.493).结论 (1)北京地区汉族青年女性中CaSR基因A986S、G990R多态性的分布频率,以A、G等位基因频率较高.(2)未发现CaSR基因A986S、G990R多态性与北京地区汉族青年女性峰值骨密度相关.     

北京地区汉族青年女性钙敏感受体基因多态性分布及其与骨密度相关性的研究

目的了解北京地区汉族青年女性钙敏感受体（Calcium-sensing ReceptOF,CaSR）基因多态性的分布,探索其与汉族妇女峰值骨密度的相关性。方法分别采用突变分离PCR和错配PCR-RFLP方法检测北京地区202名无亲缘关系的汉族青年健康女性（20～35岁）受试者CaSR基因A986S、G990R基因型,测定其血钙（Ca）、磷（P）及甲状旁腺素（PTH）水平,以及肝肾功能等指标,应用双能X线骨密度仪（DXA）测定腰椎、股骨上段部位的骨密度（BMD）。结果（1）北京地区汉族女性中存在CaSR基因A986S、G990R多态性,AA、AS基因型频率分别为95．0％和5．0％,等位基因A和s的频率分别为97．5％和2．5％;RR、GR及GG基因型频率分别为21．3％、51．0％和27．7％,等位基因R和G的频率分别为46．8％和53．2％。（2）校正年龄、身高、体重、BMI及血Ca、PTH水平后,多因素协方差分析显示AA、AS基因型组之间L2-4、股骨颈、ward＇s三角及大转子部位的BMD无显著差异（P=0J090～0．671）;GG、GR及RR基因型组之间L2。、股骨颈、ward＇s三角及大转子部位的BMD也无显著差异（P=0．089～0．493）。结论（1）北京地区汉族青年女性中CaSR基因A986S、G990R多态性的分布频率,以A、G等位基因频率较高。（2）未发现CaSR基因A986S、G990R多态性与北京地区汉族青年女性峰值骨密度相关。     

Prolactinomas and bone mineral density in men

Throughout the years evidence has been accumulated on the morbidity of hyperprolactinemia, particularly in terms of bone mineral density decrease. This complication of hyperprolactinemia affects both women and men. In this paper, we analyze aspects related to bone loss in men with hyperprolactinemia due to prolactinomas: prevalence, clinical relevance, physiopathology, diagnosis and the consequences of the treatment of hyperprolactinemia and hypogonadism on bone mineral density.     

甲状旁腺素基因多态性对正常女性骨密度的影响

目的 探讨正常女性人群甲状旁腺素（PTH）基因多态性对多部位骨密度的影响。方法 对596名平均年龄（46．3±13．7）岁女性志愿者基因组DNA作限制性内切酶BstBⅠ的PCR-RFLP检测以确定其基因型，存在Bst BⅠ限制性酶切位点用“B”表示，不存在则用“b”表示；采用Hologic QDR4500A DEXA骨密度仪测定不同骨骼部位的骨密度，即腰椎（L1～L4）正位总体（AP）和仰卧侧位总体（Lat）、股骨颈（FN）、髋部总体（T—hip）、Ward三角（Ward）、大转子（Troch）和前臂超远端（RUUD）及远端总体（RUT）的骨密度。结果 （1）596名健康女性PTH基因多态性符合Hardy—Weinberg平衡，BB、Bb和bb基因型分布频率分别为0．784、0．208和0．008；B、b等位基因频率为0．888和0．112。347名绝经后妇女PTH基因多态性频率调查结果显示BB、Bb和bb基因型分布频率分别为0．781，0．210和0．009，B、b等位基因频率为0．886和0．114；绝经前妇女PTH基因多态性频率与绝经后妇女差异无统计学意义。（2）方差分析显示女性BB和Bb基因型在AP、Lat、FN、T-hip、Ward、Troch、RUUD和RUT的骨密度差异无统计学意义。（3）Logistic分析结果显示PTH基因型不是骨量减少或骨质疏松的独立相关变量。结论 女性PTH基因多态性对骨密度的变异无明显影响。