一氧化氮合酶3基因多态性与复发性早期自然流产的关系

目的探讨一氧化氮合酶3(nitric oxide synthase 3,NOS3)基因第4内含子27bp数目可变串联重复序列(variable number of tandem repeat,VNTR)多态性和第7外显子894(G/T)多态性与复发性早期自然流产(recurrent early spontaneous abortion,RESA)的相关性。方法选取140例RESA患者和140名健康妇女,应用聚合酶链反应-琼脂糖凝胶电泳法检测NOS3基因第4内含子VNTR多态性,聚合酶链反应-限制性片段长度多态性分析技术检测第7外显子894(G/T)多态性。结果RESA组aa ba基因型频率和a等位基因频率与正常对照组相比差异有统计学意义(χ2=4.51,P<0.05;χ2=4.29,P<0.05)。与bb基因型相比,携带a等位基因的妇女与RESA显著相关(OR为1.8,95%CI:1.04~3.24)。RESA组TT GT基因型频率和T等位基因频率与正常对照组相比差异无统计学意义(χ2=1.16,P>0.05;χ2=1.12,P>0.05)。与GG基因型相比,携带T等位基因的妇女与RESA无相关。结论NOS3基因第4内含子27bp数目可变的串联重复序列多态性与复发性自然流产密切相关,NOS3基因第7外显子894G/T多态性与RESA无明显相关性,a等位基因是RESA重要的遗传易感基因。     

MTHFR基因型多态性与反复自然流产相关性的研究

目的研究N5,N10-亚甲基四氢叶酸还原酶(5,10-methylenetetrahydro-folate reductase,MTHFR)基因位点C677T的多态性与反复自然流产(recurrent spontaneous abortion,RSA)发生的关系。方法采用聚合酶链反应-限制性片段长度多态(PCR-RFLP)技术检测134例RSA患者和126例正常妇女MTHFR基因C677T位点的分布和频率。结果①RSA组T/T型出现频率高于对照组,C/C型以及C/T+T/T型频率两组没有显著差异。②RSA组的T等位基因频率高于对照组。结论 MTHFR基因位点T/T型突变是RSA的危险因素。     

洛阳地区不明原因复发性流产女性MTHFR基因C677T位点多态性分析

目的通过研究洛阳地区不明原因复发性流产女性患者亚甲基四氢叶酸还原酶(MTHFR)基因C677T位点多态性分布情况,探索其与不明原因复发性流产(URSA)的关系。方法采用荧光定量PCR方法对109例URSA女性患者和487例健康经产妇MTHFR基因C677T位点进行检测,对比两组女性的等位基因分布频率,分析其多态性与URSA的关系。结果 URSA组MTHFR基因C677T位点T/T型分布频率明显高于对照组,差异具有统计学意义(P0.05);T/T型女性发生URSA的危险性增加(OR=1.942,95%CI:1.012～3.726)。结论洛阳地区女性不明原因复发性流产与MTHFR基因C677T位点多态性相关。     

PAI-1,FV,FⅡ和MTHFR基因多态性对习惯性流产的影响

目的探讨血栓形成因子基因多态性与习惯性流产的关系。方法通过快速循环PCR和荧光共振能量转移技术分析纤溶酶原激活物抑制剂(Plasminogen activator inhibitor-1,PAI-1)5G/4G、凝血因子V(Factor V,FV)G1691A、凝血因子Ⅱ(FactorⅡ,FⅡ)G20210A和亚甲基四氢叶酸还原酶(Methylenetetrahydrofolate reductase,MTHFR)C677T的基因多态性在130例习惯性流产妇女和130例健康妇女之间分别频率的差异。结果在习惯性流产妇女中,FV和FII G/A杂合基因型频率(FV:11.5%,FⅡ:15.4%)显著高于对照组(FV:3.8%,FⅡ:2.3%)(P0.01);等位基因A的突变频率(FV:5.8%,FⅡ:7.7%)显著高于对照2组(FV:1.9%,FⅡ:1.2%)(P0.01)。PAI-1 5G/4G杂合子频率(40.8%)显著高于对照组(23.8%)(P0.05),且病例组纯合子4G/4G、5G/5G和等位基因频率与对照组之间没有显著性差异。病例组MTHFR C677T的基因型和等位基因频率与对照组之间没有显著性差异。结论 FV G1691A和FII G20210A G/A杂合基因型是习惯性流产发生的高危险因素,PAI-1 5G/4G杂合基因型是习惯性流产发生的低危险因素,而MTHFR C677T基因型与习惯性流产发生没有直接关系。     

贵州荔波汉族与雷山苗族MTHFR基因多态性分布的比较

目的比较贵州汉族、苗族亚甲基四氢叶酸还原酶基因(MTHFR)多态性的分布情况,获取 MTHFR C677T和A1298C位点的群体遗传学数据.方法应用PCR-RLFP技术调查了贵州荔波汉族及雷山苗族MTHFR基因型的分布.结果汉族MTHFR 677位T等位基因频率为22.7%低于中国北方汉族,与苗族(10.64%)差异有显著性.苗族1298位C等位基因频率为48.66%高于有文献报道的种族和民族,与汉族(28.85%)差异有显著性.677TT/1298CC双杂合子的分布频率分别是16.66%,11.11%.在苗族还发现一例677TT/1298CC双纯合子.结论 MTHFR两个位点多态性在贵州汉族和苗族有民族差异;苗族A1298C位点C等位基因频率是有文献报道最高的民族.     

重型抑郁症患者亚甲基四氢叶酸还原酶基因多态性检测

目的 探讨北方汉族人群5,10-亚甲基四氢叶酸还原酶基因多态性与重型抑郁症的关系。方法 采用病例-对照研究。聚合酶链反应-限制性片段长度多态性技术检测MTHFR C677T及 A1298C基因多态性。结果 （1）对照组677TT基因型频率及T等位基因频率分别为为13.16％和39.80%;1298CC基因型和C等位基因频率分别为1.32%和12.83％;（2）抑郁症组MTHFR 677TT基因型频率（35.53％）明显高于正常对照组（13.16％）（P＜0.001）,677 T等位基因频率（57.24%）明显高于对照组（39.80%）（P＜0.001）。（3）Ligistic回归分析, C677T基因型与疾病的发生有关（P<0.001）。结论MTHFR C677T基因变异与本组重症抑郁症发病有关,是其发病的危险因素;MTHFR A1298C基因变异与本组重症抑郁症发病无关联。     

MTHFR基因多态性与银屑病的遗传易感性

【摘要】　目的　探讨亚甲基四氢叶酸还原酶(methylenetetrahydrofolate reductase,MTHFR)基因单核苷酸多态与中国北方地区银屑病的关系。方法　针对123例寻常型银屑病患者和129名正常对照个体,分别用PCR-RFLP和AS-PCR的方法,分析C677T、G1793A和A1298C 3个多态位点基因型,并进行统计分析。 结果 在病例组中,MTHFR 677 C、T等位基因频率分别为45.13%、54.87%,1298A、C等位基因频率为88.37%、11.63%,1793G、A等位基因频率为95.12%、4.88%。在正常对照组中,677 C、T等位基因频率分别为44.96%、54.87%,1298A、C等位基因频率为86.44%、13.56%,1793G、A等位基因频率为96.12%、3.88%。经统计学分析,MTHFR C677T 、A1298C、G1793A 各多态位点基因型、等位基因频率在病例组和对照组中的分布差异无显著性意义,C677T与A1298C基因型联合分析也未发现有统计学意义。结论 MTHFR基因的3个多态位点（C677T、A1298C、G1793A）与寻常型银屑病无明显的相关关系,可能与寻常型银屑病的易感性无关。     

亚甲基四氢叶酸还原酶基因多态性与青海汉族妊娠期高血压疾病的相关性

目的 探讨亚甲基四氢叶酸还原酶（MTHFR）基因-677C/T（rs1801133）多态性与青海汉族妇女妊娠期高血压疾病（HDP）的相关性。 方法 选择青海省HDP患者 139 例（HDP组）,正常妊娠孕妇 145 例（对照组）,应用限制性内切酶片段长度多态性聚合酶链反应（PCR-RFLP）方法,检测HDP组和对照组MTHFR-677C/T多态性分型并测序验证。 结果 HDP组和对照组MTHFR基因CC、CT、TT基因型频率分别为54.68%、35.25%、10.07% 和69.66%、22.06%、8.28%,CC基因型频率HDP组54.68%低于对照组69.66%（P<0.05）,CT基因型频率HDP组35.25%高于对照组22.06%（P<0.05）,而TT基因型频率HDP组和对照组之间差异无统计学意义（P>0.05）;HDP组和对照组MTHFR-677C/T多态性C和T等位基因频率分布有差异（P<0.05）,HDP组T等位基因频率高于对照组（χ²=5.568,P<0.05）。 结论 MTHFR基因-677C/T多态性与青海汉族HDP相关,MTHFR基因-677C/T多态性中T等位基因可能是HDP的易感基因,CT基因型为HDP的易感基因型。     

eNOS基因和MTHFR基因多态性与子痫前期发病关系的研究

目的探讨内皮型一氧化氮合酶(eNOS)基因第7外显子G894T突变和N5,N10-亚甲基四氢叶酸还原酶(MTHFR)基因C677T突变与子痫前期的关系。方法应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术,对53例子痫前期患者(子痫前期组)和49例正常妊娠妇女(对照组)的eNOS基因G894T突变和MTHFR基因C677T突变进行检测。结果子痫前期组eNOS基因Glu/Glu、Glu/Asp、Asp/Asp基因型频率分别为71.7%、28.3%、0.0%;MTH-FR基因CC、CT、TT基因型频率分别为22.7%、39.6%、37.7%。对照组eNOS基因Glu/Glu、Glu/Asp、Asp/Asp基因型频率分别为83.7%、16.3%、0.0%;MTHFR基因CC、CT、TT基因型频率分别为20.4%、61.2%、18.4%。子痫前期患者TT基因型频率(37.7%)显著高于对照组(18.4%)(P<0.05),而CT基因型频率子痫前期组(39.6%)显著低于对照组(61.2%)(P<0.05),而eNOS基因型和等位基因频率两组比较差异均无显著性(P>0.05)。携带TT基因型个体发生子痫前期的风险增加2.69。结论eNOS基因G894T突变与子痫前期发病无关;MTHFR基因TT基因型能增加子痫前期的患病风险;eNOS基因和MTHFR基因在子痫前期发病中无协同作用。     

MTHFR基因C677T多态性与冠心病患者血浆同型半胱氨酸和叶酸水平相关

目的研究宁夏地区汉族人群5,10-亚甲基四氢叶酸还原酶基因(MTHFR)C677T多态性、同型半胱氨酸水平(Hcy)及叶酸水平与冠心病(CHD)的相关性。方法用病例-对照研究方法、应用限制性片段长度多态性扩增技术(PCR-RFLP)分析宁夏地区汉族202例冠心病患者及199例正常人群MTHFRC677T基因型频率及基因频率的分布特点。荧光偏振免疫分析法测定血浆Hcy水平,化学发光免疫分析法测定血清叶酸、VitB12浓度。结果 (1)病例组与对照组MTHFRC677T基因型频率分别为CC型23.3%vs20.7%、CT型52.3%vs54.5%和TT型24.4%vs24.8%,两组间基因型及等位基因频率分布无差异。(2)冠心病患者组中MTHFR基因C677TCC基因型患者血浆Hcy浓度(10.84μmol/L)较T基因携带者(12.24μmol/L)低(P<0.01)。CC基因型患者血浆叶酸浓度(5.38μg/L)较T基因携带者(3.72μg/L)高(P<0.05)。结论 MTHFRC677T的3种基因型频率在宁夏汉族冠心病患者和正常人群中的分布无统计学意义。MTHFR基因C677T多态性与冠心病的危险因素Hc...     

Increased frequency of combined methylenetetrahydrofolate reductase C677T and A1298C mutated alleles in spontaneously aborted embryos

The pathogenesis of spontaneous abortion is complex, presumably involving the interaction of several genetic and environmental factors. The methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphisms are commonly associated with defects in folate dependent homocysteine metabolism and have been implicated as risk factors for recurrent embryo loss in early pregnancy. In the present study we have determined the prevalence of combined MTHFR C677T and A1298C polymorphisms in DNA samples from spontaneously aborted embryos (foetal death between sixth and twentieth week after conception) and adult controls using solid-phase minisequencing technique. There was a significant odds ratio of 14.2 (95% CI 1.78-113) in spontaneously aborted embryos comparing the prevalence of one or more 677T and 1298C alleles vs the wild type combined genotype (677CC/1298AA), indicating that the MTHFR polymorphisms may have a major impact on foetal survival. Combined 677CT/1298CC, 677TT/1298AC or 677TT/1298CC genotypes, which contain three or four mutant alleles, were not detected in any of the groups, suggesting complete linkage disequilibrium between the two polymorphisms. The present finding of high prevalence of mutated MTHFR genotypes in spontaneously aborted embryos emphasises the potential protective role of periconceptional folic acid supplementation.     

Gene-gene interaction between fetal MTHFR 677C>T and transcobalamin 776C>G polymorphisms in human spontaneous abortion

BACKGROUND: Genetic polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) and transcobalamin (TC) genes influence homocysteine metabolism which in turn may influence the risk of spontaneous abortion. It was hypothesized that there may be a significant interaction between MTHFR and TC genotypes which affects the pathogenesis of spontaneous abortion. METHODS AND RESULTS: A total of 76 fetal tissue samples from spontaneous abortions between weeks 6 and 20 of pregnancy, and 114 control samples from healthy blood donors were genotyped for the MTHFR 677C>T and 776C>G polymorphisms. Subjects with combined MTHFR 677TT/TC 776GG and combined MTHFR 677TT/TC 776CG genotypes gave an odds ratio for spontaneous abortion of 3.8 (95% confidence interval 1.4-9.9, P = 0.005). CONCLUSIONS: Embryos that have combined MTHFR 677TT and TC 776CG or 776GG genotypes; genotypes that individually are associated with impaired homocysteine metabolism in adults, are at increased risk for spontaneous abortion compared with embryos that have only one of these genotypes.     

Polymorphisms of methylenetetrahydrofolate reductase and methionine synthase genes and bladder cancer risk: a case–control study with meta-analysis

Folate deficiency due to the methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MS) variants leads to carcinogenesis by affecting DNA synthesis, repair, and methylation. We hypothesized that the MTHFR C677T, A1298C, and MS A2756G polymorphisms are associated with risk of bladder cancer. In a case-control study of 239 bladder cancer cases and 250 cancer-free controls, we found that the MTHFR 677TT genotype was statistically significantly associated with an increased risk of bladder cancer compared with the 677CC genotype (OR = 2.06, 95% CI = 1.16-3.64). Furthermore, the TA haplotype was associated with a significantly increased bladder cancer risk (OR = 1.38, 95% CI = 1.05-1.81) than was the most common haplotype, CA (e.g., CA denotes MTHFR 677C -1298A). We also found that the combined genotypes with 4-6 variant (risk) alleles (i.e., MTHFR 677T, 1298A, and MS 2756G alleles) were associated with an increased risk of bladder cancer (OR = 1.62, 95% CI = 1.03-2.53) compared with those with 0-3 variants, and this increased risk was more pronounced among subgroup of older people (OR = 1.71, 95% CI = 1.03-2.83). A meta-analysis of seven studies did not show a significant risk of bladder cancer in the MTHFR polymorphisms. The MTHFR polymorphisms and their haplotypes appear to jointly contribute to risk of bladder cancer.     

Folate gene polymorphisms and the risk of Down syndrome pregnancies in young Italian women

Maternal impairments in folate metabolism and elevated homocysteinemia are known risk factors for having a child with Down syndrome (DS) at a young age. The 80G>A polymorphism of the reduced folate carrier gene (RFC-1) has been recently demonstrated to affect plasma folate and homocysteine levels, alone or in combination with the 677C>T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene. We performed the present study on 80 Italian mothers of DS individuals, aged less than 35 at conception, and 111 Italian control mothers, to study the role of the RFC-1 80G>A, MTHFR 677C>T, and MTHFR 1298A>C genotypes to the risk of a DS offspring at a young maternal age. When polymorphisms were considered alone, both allele and genotype frequencies did not significantly differ between DS mothers and control mothers. However, the combined MTHFR677TT/RFC-1 80GG genotype was borderline associated with an increased risk (OR 6 (CI 95%: 1.0-35.9), P = 0.05), and to be MTHF1298AA/RFC-1 80(GA or AA) was inversely associated with the risk (OR 0.36 (CI 95%: 0.14-0.96), P = 0.04). Present results seem to indicate that none of the RFC-1 80G>A, MTHFR 677C>T, and MTHFR 1298A>C polymorphisms is an independent risk factor for a DS offspring at a young maternal age; however, a role for the combined MTHFR/RFC-1 genotypes in the risk of DS pregnancies among young Italian women cannot be excluded.     

Comparison of thrombophilic gene mutations among patients experiencing recurrent miscarriage and deep vein thrombosis

PROBLEM: Inherited thrombophilia has been shown to be a risk factor for cardiovascular disease including deep venous thrombosis as well as reproductive disorders including recurrent pregnancy loss. We have previously reported three out of the 10 thrombophilic mutations studied, plasminogen activator inhibitor-1 (PAI-1) 4G/5G, factor XIII V34L, and homozygous MTHFR C667T, correlated significantly with recurrent pregnancy loss compared with controls. This study was undertaken to compare the frequencies of nine inherited thrombophilias among women with a history of recurrent pregnancy loss with individuals experiencing deep venous thrombosis and fertile controls. METHOD OF STUDY: Six hundred thirty-four participants including 550 women with a history of recurrent pregnancy loss, 43 individuals with deep vein thrombosis and 41 fertile women without a history of recurrent miscarriage. All participants had buccal swabs taken for DNA analyses of nine gene polymorphisms including factor V G1691A, factor V H1299R (R2), factor II Prothrombin G20210A, factor XIII V34L, beta-fibrinogen -455G>A, PAI-1 4G/5G, human platelet antigen 1 a/b (L33P), MTHFR C677T, MTHFR A1298C. Frequencies of thrombophilic gene polymorphisms were compared among the three populations studied. RESULTS: Individuals with a history of DVT had a significantly higher frequency of all of the polymorphisms studied compared with women experiencing a history of recurrent pregnancy loss and the fertile controls. The frequencies of mutations for V34L and PAI-1 4G/5G were significantly increased among women experiencing recurrent pregnancy loss compared with controls. The most prevalent polymorphisms were factor XIII V34L and PAI-1 4G/4G for both individuals with a history of deep vein thrombosis and recurrent pregnancy loss compared with controls. CONCLUSION: Screening for risk factors for inherited thrombophilia with only polymorphisms for factor V von Leiden, factor II prothrombin and MTHFR may be missing the more prevalent identifiers of jeopardy.     

Association of RFC1 A80G and MTHFR C677T polymorphisms with Alzheimer's disease

We examined polymorphisms in reduced folate carrier gene (RFC1) and methylenetetrahydrofolate reductase gene (MTHFR) for association with sporadic AD (SAD) in Chinese population. Significant associations of RFC1 A80G G allele and GG genotype with SAD (p=0.008, OR=1.312, 95%CI=1.072-1.605, and p=0.042, OR=1.383, 95%CI=1.012-1.890) were found. Further stratification of total samples by APOE epsilon4 carrier status, age/age at onset and gender revealed that RFC1 A80G G allele was an APOE epsilon4-independent risk factor for late-onset AD, and it might increase the risk of AD in females. No significant associations of MTHFR C677T allele and genotype with AD were observed in total samples, but significant associations of T allele and TT genotype with AD (p=0.031, OR=1.586, 95%CI=1.042-2.414, and p=0.028, OR=2.250, 95%CI=1.074-4.712) were identified in APOE epsilon4 carrier subgroup, suggesting that MTHFR 677 T allele and APOE epsilon4 allele may synergistically act to increase AD risk. No significant effect of RFC1 G80A and MTHFR C677T polymorphisms on plasma folate and homocysteine levels was detected.     

MTHFR基因C677T位点多态性与不明原因重复性自然流产的相关性

目的　检测不明原因重复性流产 (unexplained recurrent spontaneous abortion,URSA)患者亚甲基四氢叶酸还原酶 (methylenetetrahydrofolate reductase,MTH FR)基因 C6 77T位点多态性 ,探讨其与血清同型半胱氨酸、叶酸、维生素 B1 2 及与不同临床特征的关系。　方法　 U RSA非孕期患者 5 7例 ,对照组 5 0名 ,空腹血清总高半胱氨酸 (homocysteine,Hcy)的检测采用高压液相色谱法 ,血清叶酸、维生素 B1 2 的检测采用放射免疫法。MTH FR基因 C6 77T多态性采用聚合酶链反应 -限制性片段长度多态性技术检测。结果　 URSA患者组 C/ C基因型频率显著低于正常对照组者 ,总的突变 T等位基因频率显著高于对照组。MTHFR T/ T基因型患者血清 Hcy水平显著增高 ,血清叶酸水平显著降低 ,MTHFR C6 77T基因型在不同年龄、地区、流产时间、流产性质患者的分布差异无显著性。流产 3次以上 (包括 3次 )的患者 6 77T/ T基因型、携带 T等位基因的 C/ T T/ T基因型频率均大于流产次数少于 3次的患者。　结论　 MTH FRC6 77T基因多态性是 URSA发病的遗传风险因素。     

Plasminogen activator inhibitor-1 4G/5G and 5,10-methylene-tetrahydrofolate reductase C677T polymorphisms in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a heterogeneous conditionwith unknown etiology and is considered to be the most commonendocrine disorder in women of reproductive age. Two meta-analysesare presented here concerning the association of PlasminogenActivator Inhibitor 1 (PAI-1) 4G/5G polymorphism and the methylene-tetrahydrofolatereductase (MTHFR) C677T polymorphism with the risk of developingPCOS. Seven studies were included concerning PAI-1 (1538 cases,710 controls) and six studies concerning MTHFR C677T (223 cases,392 controls). Overall, a significant association was foundfor PAI-1, with the odds ratio (OR) for 4G carriers versus 5Ghomozygotes being equal to 1.600 (95% CI 1.052, 2.434) withstrong evidence for dominant inheritance. There was howevera large between-studies variability (I² = 67.3%). No evidencewas found for association of MTHFR C677T polymorphism with PCOS(OR for the TT+CT versus CC comparison equal to 0.940 with 95%CI 0.561, 1.575). No evidence of publication bias was foundin these meta-analyses. PAI-1 4G/5G polymorphism seems to beassociated with the risk of developing PCOS. Further studiesare needed in order to investigate the etiologic mechanism behindthis association, as well as the interrelations with other componentsof the metabolic syndrome (hypertension, diabetes, etc.).