新疆2型糖尿病绝经后女性LRP5rs41494349、rs2306862位点基因多态性及突变与骨代谢的关系

目的探讨2型糖尿病(type 2 diabetes mellitus,T2DM)绝经后女性LRP5rs41494349、rs2306862位点基因多态性及突变与骨代谢的关系。方法收集新疆绝经后汉族女性资料,根据血糖及骨密度(bone mineral density,BMD)分为4组:糖耐量正常伴骨量正常组(A组)、T2DM伴骨量正常组(B组)、糖耐量正常伴骨量异常组(C组)、T2DM伴骨量异常组(D组)。检测各临床指标,测定LRP5rs41494349、rs2306862位点基因型。结果①与A组相比,B组、D组FPG、HbA1c%升高,C组、D组TG、BMD(L1~4)、BMD(股骨颈)降低(P<0.05)。②rs2306862位点,突变型(CT/TT)与野生型(CC)相比,B组P升高,D组BMD(L1~4)、P降低(P<0.05);rs41494349位点,突变型(AG/GG)与野生型(AA)相比,D组的BMD(L1~4)降低(P<0.05)。③多元线性回归分析显示,绝经年限、体质量指数是BMD(L1~4)及BMD(股骨颈)的影响因素,TG是BMD(L1~4)的影响因素,两位点的基因多态性是BMD(股骨颈)的影响因素。结论LRP5rs41494339、rs2306862位点基因多态性及突变通过影响BMD及骨代谢指标,可能参与了绝经后女性的T2DM合并骨质疏松的发生和发展。     

新疆绝经后2型糖尿病女性SOST蛋白表达及基因 rs851056、rs1230399位点多态性与骨代谢关系的研究

目的检测新疆石河子地区绝经后2型糖尿病(type 2 diabetes mellitus,T2DM)女性血清硬化蛋白(sclerostin,SOST蛋白)表达水平,探讨SOST蛋白表达及基因rs851056、rs1230399位点基因多态性与骨代谢的关系,筛选骨质疏松症(osteoporosis,OP)早期诊断和治疗的潜在候选基因位点,为OP患者的临床个体化治疗提供理论依据。方法共纳入136例研究对象,根据OGTT及骨量分为A(-/-)、B(+/-)、C(-/+)、D(+/+) 4组。收集各组的一般资料并计算体质量指数(body mass index,BMI)、腰臀比。通过罗氏生化仪检测受试者FPG、Hb A1c、TG、Ca、P等糖、骨、脂代谢指标;运用双能X线法测定受试者腰椎(L_(1～4))及股骨颈骨密度(bone mineral density,BMD);运用ELISA法测定SOST蛋白表达水平;通过Mass ARRAY质谱仪测定rs851056、rs1230399位点基因多态性。运用协方差分析比较各组间生化指标及BMD差异、χ~2检验分析比较两个位点各基因型和基因频率、相关分析SOST蛋白与骨密度相关性,多元线性回归分析BMD影响因素。结果 (1)B组、D组与A组相比,SOST基因rs851056位点基因型和等位基因频率比较差异有统计学意义(P0.01); rs1230399位点基因型和等位基因频率比较差异无统计学意义(P0.05);(2)rs851056位点不同基因型相比,C组中GG型HDL、Ca、ALP均低于GC/CC型(P0.05),D组中GG型BMD(L_(1～4))高于GC/CC型(P0.05);(3)与A组相比,C组、D组SOST蛋白表达水平升高;(4) SOST蛋白水平与BMD(L_(1～4))呈负相关;(5)rs851056位点突变、BMI及TG降低是BMD(L_(1～4))降低的危险因素。BMI降低、ALP及绝经年限增加是BMD(股骨颈)降低的危险因素。结论 (1)新疆绝经后T2DM女性中,SOST基因rs851056位点基因多态性及基因频率分布可能与骨、糖代谢异常有关。该位点的基因突变可能与BMD的下降及脂代谢有关;(2)SOST蛋白表达水平与骨密度有关,是BMD降低的危险因素;(3)绝经后T2DM女性,低BMI、低TG、高ALP以及绝经年限长是BMD降低的危险因素。     

KITLG基因rs995030和rs4474514位点单核苷酸多态性与男性不育相关性研究

目的:探讨酪氨酸激酶受体的特异性配体(KITLG)基因rs995030和rs4474514位点单核苷酸多态性与男性不育之间的相关性。方法:收集南京周边地区特发性男性不育患者360例(病例组),已生育的健康男性338例(对照组);按照WHO《人类精液检查与处理实验室手册》第5版,将病例组分为无精子症组(n=143)、严重少精子症组(n=159)和少精子症组(n=58)。收集所有研究对象的临床基本资料,并采集病人外周血提取基因组DNA,用Sequence Mass-Array技术检测KITLG基因rs995030和rs4474514位点的基因型,通过Logistic回归分析两位点基因多态性与男性不育的相关性。结果:病例组与对照组比较,精子浓度[(13.23±24.52)×10~6/ml vs(78.74±61.25)×10~6/ml]、前向运动精子百分率[(18.71±15.19)%vs(39.36±9.75)%]、FSH[(16.09±17.31) IU/L vs(4.56±2.41) IU/L]差异显著(P0.01)。经Logistic回归分析,未发现各基因型与男性不育有统计学意义的相关性,亚组分析也未发现相关性。结论:KITLG基因rs995030和rs4474514位点的单核苷酸多态性与男性不育无显著相关性,后续可以通过扩大样本量以及样本选取范围来进一步研究验证。     

MTHFR基因多态性与蒙古族绝经后妇女骨质疏松的相关性研究

目的探讨本地区蒙古族绝经后妇女亚甲基四氢叶酸还原酶(methylenetetrahydrofolate reductase,MTHFR)基因的多态性位点C677T、A1298C基因多态性与内蒙古地区蒙古族绝经后女性骨质疏松症(osteoporosis,OP)遗传易感性的关系。方法收集150例门诊及住院(确诊为骨质疏松)蒙古族绝经后妇女为观察组,对照组来自门诊按年龄配比的骨含量正常的蒙古族绝经后妇女145例,均以双能X线骨密度仪测定腰椎和髋部骨密度,以T值≤-2.5诊断为骨质疏松,-2.5≤T≤-1.0为骨含量减少,T值-1.0为骨含量正常,并进行MTHFR C677T及A1298C基因多态性检测。结果骨质疏松组MTHFR基因受体C677T基因型CC、CT、TT频率分别为29.3%、44.0%和27.7%,对照组基因型CC、CT、TT频率分别为42.8%、44.8%和12.4%,两组差异有统计学意义(P=0.017)。骨质疏松症组中的T等位基因频率为48.7%,显著高于对照组(34.8%,P=0.005),提示T等位基因是骨质疏松发生的危险因素(OR=1.77,95%CI=1.18~2.64,P=0.001)。与CC基因型相比,TT基因型携带者的骨质疏松发生风险增加至3.15倍(95%CI=1.45~6.86,P=0.004),该作用在年龄≥60岁及体重指数偏高的女性中表现更明显。而MTHFR A1298C的多态性位点对绝经后骨质疏松的发生没有显著影响(P=0.513)。结论 MTHFR C677T基因变异与蒙古族绝经后妇女骨质疏松易感性明显相关,MTHFR A1298C的多态性位点与蒙古族绝经后妇女骨质疏松的发生没有明显相关性。     

超氧化物歧化酶2基因rs4880位点单核苷酸多态性与男性不育发病风险的相关性研究

目的:探讨超氧化物歧化酶2(SOD2)基因rs4880位点单核苷酸多态性与男性不育发病风险的相关性。方法:采用病例-对照研究的方法,选取519例特发性男性不育患者作为病例组,年龄19~40(28.92±4.37)岁,并按精子浓度和前向运动(PR)精子百分率分为无精子症组(n=143)、严重少精子症组(n=175)、少精子症组(n=89)和弱精子症组(n=112)4个亚组;以338例正常生育的男性作为对照组,年龄19~40(28.40±4.25)岁,进行临床数据的采集。用Sequenom Mass Array技术对SOD2 rs4880位点进行基因分型,用Logistic回归模型分析SOD2 rs4880位点不同基因型与男性不育之间的关系。结果:病例组与正常对照组FSH、PR精子百分率、精子浓度存在显著差异(P0.01)。与野生型纯合TT比较,杂合突变型TC(OR=0.90,95%CI:0.65~1.25,P=0.516)与纯合突变型CC(OR=1.49,95%CI:0.38~5.81,P=0.566)均显示与男性不育无相关性;亚组分析中均显示该基因位点与男性不育不存在相关性:无精子症组中,TC/TT(OR=0.99.95%CI:0.62~1.58,P=0.967),CC/TT(OR=1.58,95%CI:0.26~9.59,P=0.619;严重少精子症组中,TC/TT(OR=1.07.95%CI:0.70~1.64,P=0.750),CC/TT(OR=1.31,95%CI:0.22~7.96,P=0.767;少精子症组中,TC/TT(OR=0.83.95%CI:0.47~1.48,P=0.535),CC/TT(OR=1.22,95%CI:0.13~11.90,P=0.865);弱精子症组中,TC/TT(OR=0.59.95%CI:0.33~1.05,P=0.074),CC/TT(OR=1.84,95%CI:0.30~11.16,P=0.510)。结论:SOD2 rs4880位点基因多态性与男性不育不存在相关性,但是由于实验样本条件的限制,需要更大的样本量以及样本选取范围来进一步研究验证。     

胰岛素降解酶基因单核苷酸多态性与前列腺癌的关系研究

目的研究胰岛素降解酶(IDE)基因单核苷酸多态性与前列腺癌之间的关系。方法运用TaqMan探针SNP分析法测定192例胰腺癌患者和258例正常对照IDE基因rs4646953和rs2251101两个位点基因型,并分析IDE基因多态性与前列腺癌的关系。结果病例组IDE基因rs4646953位点TT、CT以及CC3种基因型等位基因频率分别为85.4%、14.1%和0.5%;对照组3种基因型等位基因频率分别为88.4%、10.1%和1.6%。病例组rs2251101位点TT、CT以及CC3种基因型频率分别为81.8%、16.7%和1.6%;对照组3种基因型等位基因频率分别为73.6%、23.3%和3.1%。病例组IDE基因rs4646953位点的基因型分布与正常对照组比较未见统计学差异(P=0.348),rs2251101位点病例组CT和CC基因型低于正常对照组(P=0.039)。结论 IDE基因rs2251101位点变异与前列腺癌相关。     

TP53基因rs1042522单核苷酸多态性与男性不育相关性研究

目的:探讨肿瘤蛋白p53(TP53)基因rs1042522位点单核苷酸多态性与男性不育的关系。方法:采用病例-对照研究,收集南京地区特发性男性不育患者380例(病例组),有生育史的健康男性398例(对照组);并将病例组分为无精子症组(n=140)和少精子症组(n=240)。用Sequence Mass Array技术检测TP53基因rs1042522位点的基因型,通过Logistic回归分析该位点多态性与男性不育的相关性。结果:病例组与对照组前向运动精子百分率[(10.38±5.57)%vs(42.55±9.57)%]、精子浓度[(13.13±24.96)×106/ml vs(77.34±49.24)×106/ml]、T[(14.07±5.36)nmol/L vs(11.89±4.50)nmol/L]、FSH[(16.80±18.20)U/L vs(4.55±7.17)U/L]存在显著性差异(P0.05)。经Logistic回归分析,未发现各基因型与男性不育有统计学意义的相关性,亚组分析也未发现相关性。结论:TP53基因rs1042522位点的单核苷酸多态性与男性不育无显著相关性。     

miR-143/miR-145簇启动子区rs4705342基因突变与汉族人群前列腺癌发病的相关性研究

目的:选择miR-143/miR-145基因启动子区rs4705342突变位点,研究其与汉族人群前列腺癌发病率的相关性。方法:156例确诊为前列腺癌的患者为病例组,188例健康男性为对照组,采用TaqMan法对miR-143/miR-145基因启动子区rs4705342进行多态性检测;并针对肿瘤家族史、体质量指数(BMI)、年龄、吸烟及饮酒等进行分层分析。结果:病例组与对照组的年龄(P=0.32),BMI(P=0.79),吸烟(P=0.47)、饮酒(P=0.34)状况未发现有统计学意义,肿瘤家族史比例病例组显著高于对照组(P=0.01)。TT/CT联合基因型与CC基因型分布无统计学意义(P=0.07)。在不吸烟亚组中,CC基因型与TT/CT联合基因型的分布具有统计学意义(P=0.02);在饮酒亚组中,CC基因型与TT/CT联合基因型的分布具有统计学意义(P=0.03);在前列腺癌临床分期中,CC基因型与TT/CT联合基因型的分布未发现明显差异(P=0.81),PSA分层分析中CC基因型与TT/CT联合基因型的分布未发现明显差异(P=0.39)。结论:miR-143/miR-145簇启动子区rs4705342基因突变与汉族人群前列腺癌发病有明显关联。     

绝经前后妇女OPG基因多态性与骨密度相关性研究

目的 分析OPG基因的单核苷酸多态性（SNP)与绝经前后妇女骨密度的关系。方法 在235名绝经前后妇女中,采用基质辅助激光解吸电离飞行时间质谱技术对6个护骨素（OPG)基因的SNP进行分型。应用双能X线骨密度仪测定腰椎、髋部和股骨颈骨密度（BMD)。结果rs6993813TT基因型股骨颈BMD显著高于CC型,CC型各部位的BMD均低于TC/TT型 (P <0. 05)。rs4355801GG 型股骨颈的 BMD 高于 AG/AA 型（P <0. 05)。rs1032129 AA 型股骨颈的 BMD 高于 AC/CC 型（P < 0.05)。rs2073618 的 CC 基因型股骨颈的 BMD 显著高于 GG/GC 型（P < 0. 05)。结论 rs6993813,rs4355801,rs1032129 和rs2073618均与中国绝经前后女性BMD有关,其危险基因分别为C,A,C和G,而T,G,A和C则具有保护作用,含有保护基因者骨密度高于含有危险基因者,但确切的机制尚需在今后工作中进一步研究阐明。     

Association of Transforming Growth Factor-b1 (TGFb1) T29?C Gene Polymorphism with Bone Mineral Density (BMD), Changes in BMD, and Serum Concentrations of TGF-b1 in a Population-Based Sample of Postmenopausal German Women

TGF-beta1 is thought to play an important role in bone turnover. Thus, the gene encoding TGF-beta1 is a prime candidate for the genetic regulation of bone density. Recent studies have suggested that a T29 --> C polymorphism in the signal sequence region of the TGF-beta1 gene may be related to bone mineral density (BMD) and bone loss in postmenopausal Japanese women. In the present study, we examined the relationship between this polymorphism and BMD in a population-based sample of 102 estrogen-deficient postmenopausal women from the Heidelberg cohort of the European Vertebral Osteoporosis Study (EVOS). Average BMD in women with the TT genotype was approximately 10% higher at both the lumbar spine and the femoral neck compared with women with the CC genotype (spine: 980 vs. 887 mg/cm2, P = 0.05; femoral neck: 755 vs. 674 mg/cm2; P = 0.02). Women with the TT genotype also experienced less overall bone loss at the total hip, compared with women with the CC genotype. Serum levels of TGF-beta1 were higher in women with the TT genotype than in those with the CC genotype (46.5 ng/ml vs. 32.3 ng/ml, P = 0.001). These data are clearly in contrast to findings in postmenopausal Japanese women where the CC genotype was associated with higher BMD and decreased bone loss. Further studies are therefore necessary to clarify the relationship between this polymorphism and BMD.     

Association of transforming growth factor beta1 genotype with therapeutic response to active vitamin D for postmenopausal osteoporosis.

Transforming growth factor beta (TGF-beta) is an important regulator of bone metabolism, its effects being intertwined with those of estrogen and vitamin D. A T-->C polymorphism in exon 1 of the TGF-beta1 gene, which results in the substitution of proline for leucine, is associated with bone mineral density (BMD). However, it is not known whether this polymorphism affects the response to treatment with active vitamin D or to hormone replacement therapy (HRT) in individuals with osteoporosis. Changes in BMD at the lumbar spine (L2-L4 BMD) were compared among TGF-beta1 genotypes in 363 postmenopausal Japanese women who were divided into three groups: an untreated, control group (n = 130), an active vitamin D treatment group (n = 117), and an HRT group (n = 116). TGF-beta1 genotype was determined with an allele-specific polymerase chain reaction assay. In the control group, the rate of bone loss decreased according to the rank order of genotypes TT (homozygous for the T allele) > TC (heterozygous) > CC (homozygous for the C allele), with a significant difference detected between the CC and TT genotypes. The positive response of L2-L4 BMD to HRT increased according to the rank order of genotypes TT < TC < CC, although the differences among genotypes were not statistically significant. Individuals with the CC genotype responded to active vitamin D treatment with an annual increase in L2-L4 BMD of 1.6%, whereas those with the TT or TC genotypes similarly treated lost bone to a similar extent as did untreated subjects of the corresponding genotype. These results suggest that TGF-beta1 genotype is associated with both the rate of bone loss and the response to active vitamin D treatment.     

FDPS､LRP5基因多态性与绝经后妇女骨质疏松的关系

目的探讨FDPS、LRP5基因多态性与绝经后妇女骨质疏松的关系。方法在2017年6月至2019年8月期间,共纳入364名绝经后妇女,其中228名确诊为骨质疏松症(OP),为骨质疏松组,另136名骨质正常者为对照组。收集所有参与者的临床数据和血液样本,分别采用Taq Man荧光探针及限制性片段长度多态性(PCR-RELP)法对FDPS rs2297480、LRP5rs3736228位点进行基因分型,统计其与骨密度(BMD)和骨质疏松的关系。结果 FDPS rs2297480 TT基因型腰椎和全髋关节的BMD值明显较低,T等位基因的存在与骨质疏松症有显著相关性。LRP5 rs3736228携带CC基因型的股骨颈和全髋关节骨密度值较低。结论在绝经后的骨质疏松症妇女中,BMD和FDPS基因多态性之间有很强的相关性,与LRP5基因多态性之间存在较低的关连。     

Bone mass effects of a BMP4 gene polymorphism in postmenopausal women

The pathogenesis of osteoporosis involves both genetic and environmental factors. On the basis of linkage data suggesting gene effects on bone density at chromosome 14q and data locating the BMP4 gene to 14q, we performed a positional candidate study to examine a possible association of BMP4 gene polymorphisms, hip bone density (n = 1012) and fracture rates (n = 1232) in postmenopausal women (mean age 75). On genotype analysis of the three selected single nucleotide polymorphisms (SNP), the 6007C > T polymorphism was associated with total and intertrochanteric hip BMD and BMD was lower in the 32% of subjects homozygous for the C allele. This polymorphism codes for a nonsynonymous amino acid change with the T allele coding for valine, while the C allele codes for alanine. The difference in BMD was 3.1% (TT vs. CC) and 2.3% (CT versus CC) for the total hip (P = 0.023), and 3.7% (TT vs. CC) and 2.8% (CT versus CC) for the intertrochanter site (P = 0.012). Haplotype analysis demonstrated 6 haplotypes of frequency greater than 2%. A major haplotype defined by G-C-T alleles in SNPs -5826G > A, 3564C > T and 6007C > T respectively, showed association with high bone mass. No SNP showed association with fracture rates. We conclude that a polymorphism found in the BMP4 gene, affecting amino acid sequence, is associated with hip bone density in postmenopausal women, presumably via regulation of anabolic effects on the skeleton.     

绝经后T2DM合并OP患者饮食及运动管理与糖、骨代谢及骨密度相关性的临床研究

目的探讨绝经后2型糖尿病(type 2 diabetes mellitus,T2DM)合并骨质疏松(osteoporosis,OP)患者的糖代谢、骨代谢、骨密度(bone mineral density,BMD)与饮食及运动管理的相关性。方法选择562例绝经后妇女T2DM合并OP患者,分为严格管理组(管理组)278例;一般指导组(对照组)284例。分别给予严格管理和一般管理,所有患者均为口服降糖药物,同时每天口服钙尔奇D600mg和骨化三醇0.25μg,在0、24、48 w测定糖代谢指标HbA1C、FPG,和骨代谢指标血清25羟基维生素D3(VitD3)、骨碱性磷酸酶(bone alkaline phosphate,BALP)、抗酒石酸酸性磷酸酶(tartrate-resistant acid phosphatase,TrAP-5b)、血清骨钙素(osteocalcin,OT),用双能X线仪测定不同部位BMD等指标,探讨经过严格管理后各指标的变化情况。结果在24w时,管理组与基线、对照组相比血糖均明显下降,48 w时更加显著,血清HbA1C管理组的不同时间分别为:8.16±1.50%、7.10±1.60%、6.01±1.59%,对照组分别为:8.46±1.65%、8.16±1.03%、8.21±1.02%,观察到无论是管理组还是对照组,糖化血红蛋白都有所下降,但管理组更加明显,组间相比差异均显著(P0.01)。同时TrAP-5b均较对照组明显下降(P0.01),VitD3、BALP、OT升高显著(P0.01),管理组腰椎、股骨颈BMD自24 w始,逐渐上升,对照组呈下降状态,48 w时,两组BMD差异显著(P值均0.01)。结论根据T2DM合并OP患者的具体情况,进行严格的饮食控制、适当的运动等个体化管理后,在原药物治疗的基础上,不但可以有效地控制血糖,同时具有减少骨量丢失,增加骨密度的作用。     

A C >T polymorphism located at position −1 of the Kozak sequence of CD40 gene is associated with low bone mass in Spanish postmenopausal women

SUMMARY: This study evaluated the association of a polymorphism in the CD40 gene with BMD and risk of osteopenia or osteoporosis in a population of 602 postmenopausal women. Results showed that women with the TT genotype had lower BMD at femoral neck and spine sites and increased risk of osteopenia or osteoporosis. INTRODUCTION: Recent findings have demonstrated that the CD40/CD40L system, which is of main importance for the immune system, can also be implied in the regulation of bone metabolism. The main objective of the present work has been to clarify whether single nucleotide polymorphisms (SNPs) affecting genes of CD40/CD40L system could be linked with abnormalities in the level of bone mineral density (BMD) in menopausal women. METHODS: We performed an association study of BMD values with a SNP located at position -1 of the Kozak consensus sequence of CD40 gene (rs1883832; C>T) in a population of 602 postmenopausal women. RESULTS: Women with the TT genotype (8.6% of women) displayed a reduction in femoral neck BMD (FN BMD) and lumbar spine BMD (LS BMD) of 6.2% and of 6.3%, respectively, as compared to women with CC + CT genotype. Logistic regression analysis adjusted for age, weight, and height showed that women with the TT genotype had increased risk for FN (odds ratio: 2.34; 95% CI: 1.12-4.89) and LS (odds ratio: 2.49; 95% CI: 1.19-5.24) osteopenia or osteoporosis. CONCLUSIONS: Women with the TT genotype in rs1883832 SNP affecting to Kozak consensus sequence of CD40 gene had lower BMD at FN and at LS sites and increased risk of osteopenia or osteoporosis.