Notch3基因多态、MTHFR基因多态和ALOX5AP基因多态的多位点联合交互作用显著增加血栓性脑卒中的风险

目的研究Notch3基因、MTHFR基因和ALOX5AP基因多态之间的多位点交互作用是否与脑卒中的患病风险相关。方法采用病例对照设计，对来自全国7个临床中心的对照和脑卒中患者检测了Notch3、MTHFR、VKORC1、APOA1和ALOX5AP基因的8个多态性，基因分型结果经测序进一步确证。用Generalized Muhifactor—Dimensionality Reduction（GMDR）方法检测基因与基因之间的交互作用。结果当个体同时携带Notch3 381TT、MTHFR 677TT和ALOX5AP 2354AA基因型时，携带者血栓性脑卒中的相对患病风险率增加至3．72倍（95％CI：1．235～11．209；P〈0．05）。结论Notch 3381TT、MTHFR 677TT和ALOX5AP 2354AA基因型的多位点联合交互作用显著增加血栓性脑卒中患病风险。对基因与基因之间的交互作用的分析，有助于更深入的研究复杂疾病的基因型和表型间的关系。     

亚甲基四氢叶酸还原酶基因多态性与结肠癌发生关系的荟萃分析

背景：亚甲基四氢叶酸还原酶（methylene tetrahydrofolate reductase，MTHFR）基因多态性与结肠癌发生密切相关，目前多数病例对照研究结果表明MTHFR TT型多态性对结肠癌发生具有保护作用．尤其是在叶酸充足和摄人低乙醇的个体。目的：探讨亚甲基四氢叶酸还原酶基因多态性与结肠癌的相关性。方法：通过文献检索收集肿瘤组和非肿瘤组的病例对照研究，剔除不符合要求的文献，在全面文献回顾的基础上进行荟萃分析。结果：共有12篇符合条件的文献纳入分析，荟萃分析结果表明，以野生型677CC的基因型为参照，携带TT基因型个体发生结肠癌的危险性明显下降，OR为0．84（95％CI：0．76～0．94）；1298CC型相对AA型发生结肠癌的危险性为0．85（95％CI：0．72～1．01）。携带677TT基因型同时摄人高叶酸的个体相对于CC／CT基因型伴摄人低叶酸者发生结肠癌的危险性明显下降，OR为0．76（95％CI：0．52～1．10）；摄人高叶酸的1298AA和AC／CC携带者相对于携带AA基因型伴摄人低叶酸者发生结肠癌的危险性显著降低，OR分别为0．78（95％CI：0．63～0．95）和0．78（95％CI：0．64～0．96）。携带677 TT基因型者不论乙醇摄人高低，发生结肠癌的危险性均为0．92，而CC／CT基因型同时摄人高乙醇者发生结肠癌的危险性为1.34（95％CI：0．92～1．95）；1298位点基因多态性与结肠癌危险性似乎同乙醇摄人无多大关联。结论：MTHFR多态性与结肠癌发生危险性有关．677 TT型和高叶酸摄人明显降低肿瘤发生危险性．而高乙醇摄人在677CC／CT基因型个体中有增加结肠癌发生的趋势。     

甲基四氢叶酸还原酶基因C677T多态性与大肠癌遗传易感性的相关性

目的 探讨亚甲基四氢叶酸还原酶(MTHFR)基因C677T多态性与大肠癌(CRC)遗传易感性的关系.方法 采用聚合酶链反应(PCR)和限制性片段长度多态性(RFLP)分析方法检测120例CRC患者和202例正常对照的MTHFR C677T的基因型分布及差异.结果 与对照组相比,CRC组677T等位基因频率显著降低(OR:0.57,95％ CI:0.40 ～0.81,P=0.002).与CC纯合子相比,TT纯合子的CRC风险显著降低至0.28倍(95％ CI:0.12～0.63,P=0.002) CT杂合子的CRC风险虽降低至0.64倍(95％ CI:0.37～ 1.08,P=0.094),差异无统计学意义.在CRC人群中,MTHFR C677T与肿瘤大小、位置、组织学类型、分化程度、淋巴结转移以及Dukes分期均无显著相关性(P＞0.05).结论 MTHFR 677TT基因型可降低CRC风险;MTHFR C677T基因型与CRC肿瘤特征无相关性.     

亚甲基四氢叶酸还原酶基因C677T多态与肝细胞癌遗传易感性的相关性研究

目的探讨亚甲基四氢叶酸还原酶（MTHFR）基因C677T多态与中国人肝细胞癌（Hcc）遗传易感性的关系。方法采用聚合酶链反应一限制性片段长度多态性（PCR—RFLP）方法，检测508例Hcc与543例对照的MTHFR C677T基因型分布及其差异。结果HCc和对照两组人群的MTHFR C677T基因型分布差异无统计学意义。但与C等位基因携带者（C／C和C／T基因型）相比，T／T基因型携带者患HCC的风险增加0．66倍（95％可信区间为1．08～2．54，P〈0．05）。性别因素分层分析结果显示：T／T基因型女性携带者其HCC的风险是C等位基因女性携带者的2．64倍（95％可信区间为1．19～5．88，P〈0．05）；而男性T／T基因型与C等位基因携带者其HCC的风险差异无统计学意义。结论MTHFR基因C677T多态可能是中国女性患HCC的一个遗传易感因素，而男性HCC发病风险与该多态无明显关系。     

花生四烯酸5-脂氧合酶激活蛋白基因多态性与急性冠状动脉综合征的易感性

目的探讨花生四烯酸5脂氧合酶激活蛋白(ALOX5AP)基因SG1 3S114T/A多态性与急性冠状动脉综合征(ACS)的易感性。方法选择住院的胸痛患者714例,将确诊为ACS的患者377例作为ACS组,非ACS患者337例作为对照组,采用聚合酶链反应限制性片段长度多态性方法检测ALOX5AP基因SG13S114T/A多态性,并进行logistic回归分析。结果 ACS组患者AA、AT和TT基因型频率分别为1 3.79%、50.93%和35.28%,对照组患者分别为12.76%、38.58%和48.66%,2组AT和TT基因型频率差异有统计学意义(P=0.041,0.020);ACS组男性AT基因型频率高于对照组(P=0.040),女性TT基因型频率低于对照组(P=0.013)。SG13S114T/A位点AT和TT基因型以及T等位基因是所有ACS(P=0.004、0.001和0.013)和男性ACS(P=0.014、0.005和0.020)发病的危险因素。结论 ALOX5AP基因SG1 3S114T/A多态性AT和TT基因型以及T等位基因可能与老年人,特别是老年男性ACS的易感性相关。     

汉族脑卒中与N5,N10亚甲基四氢叶酸还原酶基因多态性的相关性研究

目的　探讨人体 N5,N1 0亚甲基四氢叶酸还原酶 (MTHFR)的基因多态性与脑卒中的遗传相关性。方法　采用限制性内切酶片段长度多态性方法 (PCR- RFLP) ,对 67例脑卒中病人和 78例健康人 MTHFR基因 C677T多态性位点进行检测。结果　病例组 MTHFR基因 T、C等位基因频率分别为 53%、47%,对照组为 39.7%、60 .3%,两组显著性差异 (χ2 =5.0 9,P<0 .0 5)。 TT型携带者较 CC型携带者罹患脑卒中的相对风险度为 2 .35(95%CI1 .0 2～ 5.43)。 T等位基因携带者较 C等位基因携带者罹患脑卒中的相对风险度为 1 .71 (95%CI1 .0 7～ 2 .74)。出血性卒中与缺血性卒中之间等位基因及等位基因型频率无明显差异。结论　脑卒中汉族人群 MTHFR基因 C677T位点多态性与脑卒中有相关性 ,MTHFR基因可能是脑卒中的一个易感基因。     

血清白三烯B4水平与AMI发病风险和ALOX5AP基因SG13S114T/A多态性的相关性

目的:探讨中国苏南地区汉族人群血清白三烯(LT)B4水平与急性心肌梗死(AMI)发病风险和花生四烯酸5-脂氧合酶激活蛋白(ALOX5AP)基因SG13S114T/A多态性的相关性。方法:采用酶联免疫吸附试验和聚合酶链反应-限制性片段长度多态性方法对262例AMI患者(AMI组)和132例非冠心病者(对照组)分别检测血清LTB4水平(M/IQR)和ALOX5AP基因SG13S114T/A多态性。结果:AMI组和对照组均存在ALOX5AP基因SG13S114T/A多态性。血清LTB4水平在AMI组(477.97/370.52ng·L-1)明显高于对照组(200.57/236.65ng·L-1)(P0.01),与吸烟呈正相关(P0.01,R2=0.039),与性别、年龄、高血压、糖尿病和血脂异常均无关。AMI组ALOX5AP基因SG13S114位点AA、AT和TT任何基因型之间的血清LTB4水平均无显著差异(517.98/392.00ng·L-1∶492.31/427.55ng·L-1∶495.29/398.54ng·L-1),在同性别AMI亚组中亦无明显差异。结论:中国苏南地区汉族人群血清LTB4水平明显升高,并与AMI发病风险相关,但与ALOX5AP基因SG13S114多态性无相关性。     

亚甲基四氢叶酸还原酶基因C677T多态与结直肠癌遗传易感性的相关性

目的:探讨亚甲基四氢叶酸还原酶基因(MTHFR)C677T多态与结直肠癌(CRC)遗传易感性的关系.方法:采用TaqMan方法检测CRC 449例与对照672例的MTHFR C677T的基因型分布及差异.以非条件Logistic回归法计算表示相对危险度的比值比(OR)及其95%可信区间(CI).OR值均经性别、年龄、吸烟、饮酒、体质量指数和一级亲属CRC家族史等因素校正.结果:CRC组677T等位基因频率显著低于对照组,其为CRC发生的保护因素(OR:0.70,95%CI:0.58-0.83,P<0.01).与CC纯合子相比,CT杂合子的CRC风险显著降低至0.73倍(95%CI:0.56-0.95,P<0.05),而TT纯合子的CRC风险进一步降至0.47倍(95%CI:0.33-0.68,P<0.01).在非饮酒人群中,C677T的CRC风险保护效应略有增强;而在饮酒人群中,CT和TT基因型携带者的CRC发病风险虽仍低于CC基因型携带者,但差异无统计学意义.在CRC人群中,荷大肿瘤(最大直径>4cm)者携带TT基因型的比例高于荷小肿瘤者(16.3% vs 8.3%,P<0.05);荷黏液腺癌者携带TT基因型的比例高于荷乳头状腺癌及管状腺癌者(22.2% vs 17.1%,10.3%,P=0.084).结论:MTHFR C677T降低CRC发病风险,饮酒可能削弱该多态的CRC风险保护效应.TT基因型可能与CRC肿瘤进展有关.     

亚甲基四氢叶酸还原酶基因C677T、A1298C和G1793A多态性与血液透析患者血浆Hcy水平的关系

目的探讨亚甲基四氢叶酸还原酶(MTHFR)基因C677T、A1298C和G1793A多态性与血液透析患者血浆同型半胱氨酸(Hcy)水平的关系。方法接受血液透析的慢性肾衰竭患者(疾病组)88例的外周血标本,采用直接测序法对MTHFR基因3个标签(C677T、A1298C和G1793A)单核苷酸多态性(SNPs)进行基因分型,选取同期92例健康体检者的外周血作对比(对照组),比较两组以上SNPs位点基因型和等位基因的分布差异,采用酶联免疫吸附法检测血浆Hcy水平并比较疾病组MTHFR基因SNPs位点各基因型的血浆Hcy水平,以比值比(OR)及其95%置信区间(CI)评价以上SNPs发生Hcy升高的风险情况。结果两组C677T和G1793A基因型和等位基因分布差异有统计学意义(P0.05),其中疾病组C677T TT基因型和T等位基因的比例及G1793A AA基因型和A等位基因的比例明显高于对照组(P0.05)。疾病组血浆Hcy水平为(38.25±4.67)μmol/L,显著高于对照组的(19.36±2.59)μmol/L(P0.05)。疾病组C677T TT型的血浆Hcy水平高于CC、CT型,CT型高于CC型,G1793A AA型的血浆Hcy水平高于GG、GA型,GA型高于GG型,差异均有统计学意义(均P0.05)。C677T TT基因型较CC型血浆Hcy水平升高的风险升高至3.429倍(P0.05),而GA、GA+AA型血浆Hcy水平升高的风险未改变(P0.05);以C等位基因为参照,携带T等位基因者Hcy水平升高的风险升高至2.050倍(P0.05)。A1298C、G1793A位点血浆Hcy水平升高的风险均未改变(P0.05)。结论MTHFR C677T和G1793A携带突变基因者的血浆Hcy水平升高,其中C677TT等位基因的血浆Hcy水平升高的风险升高,在预测血液透析患者血浆Hcy水平异常上有一定价值。     

叶酸代谢基因及血浆同型半胱氨酸在老年脑卒中患者中的表达及相关性

目的 探讨四氢叶酸还原酶(MTHFR)C677T位点、甲硫氨酸合成酶还原酶(MTRR A66G位点及血浆同型半胱氨酸(Hcy)在老年脑卒中患者中的表达及相关性。方法 选取2018年1月到2019年6月西宁市第二人民医院收治的80例老年脑卒中患者作为脑卒中组,另选择我院同期体检的73例健康人员作为对照组。采用PCR-RELP法检测患者MTHFR C677T位点和MTRR A66G位点基因多态性,采用全自动生化仪检测血浆Hcy水平,分析不同MTHER、MTRR基因型、血浆Hcy水平与脑卒中关系。结果 脑卒中组TT型、GG型基因频率均高于对照组,CC型、AA型基因频率低于对照组(t=12.771、4.408、4.912、3.921,P 0.05)。脑卒中组各基因型Hcy水平均高于对照组,差异具有统计学意义(t=6.477、10.663、4.227、2.685、2.949、3.929,P 0.05),两组MTHFR C677T的TT型患者Hcy水平均高于CT型、CC型,差异具有统计学意义(P 0.05);两组MTRR A66G位点GG型患者Hcy水平均高于AG型、AA型,差异具有统计学意义(P 0.05)。Spearman相关性分析显示,MTHFR C677T位点、MTRR A66G位点各基因型频率均与Hcy水平呈正相关(r=0.779、0.684、0.716、0.806、0.758、0.818,P 0.05);Logistic回归分析显示,MTHFR C677T位点TT型、Hcy水平是影响脑卒中发生的危险因素[OR (95%CI)=3.167(1.421～5.385)、2.822(1.652～4.770),P 0.05]。结论 老年脑卒中患者MTHFR C677T位点TT型、MTRR的A66G位点GG型基因频率、血浆Hcy水平高于健康人群,其中MTHFR C677T位点TT型基因频率、血浆Hcy水平是影响脑卒中发生的重要因素。     

Hyperhomocysteinemia increases the risk of venous thrombosis independent of the C677T mutation of the methylenetetrahydrofolate reductase gene in selected Brazilian patients.

Fasting total homocysteine (tHcy) and the methylenetetrahydrofolate reductase (MTHFR) C677T mutation were evaluated in 91 patients with venous thromboembolism and without acquired thrombophilia, and in 91 age-matched and sex-matched controls. Hyperhomocysteinemia was detected in 11 patients (12.1%) and in two controls (2.2%), yielding an odds ratio (OR) for venous thrombosis of 6.1 [95% confidence interval (CI), 1.3-28.4]. After excluding 21 patients and four controls with other known genetic risk factors for venous thrombosis, the OR was not substantially changed (7.0; 95% CI, 1.5-33.1). The prevalence of the MTHFR 677TT genotype was not significantly different in patients (9.9%) and in controls (5.5%), with an OR for venous thrombosis of 1.8 (95% CI, 0.6-5.8). Subjects with the MTHFR 677TT genotype showed higher levels of tHcy compared with the 677CC genotype in patients (P = 0.010) and in controls (P = 0.030). In conclusion, we found that fasting hyperhomocysteinemia is a risk factor for venous thrombosis in patients without known acquired thrombophilia and other genetic risk factors for venous thrombosis. Although tHcy levels are significantly higher in those homozygous for the MTHFR C677T mutation, this genotype does not increase the thrombotic risk in our study population.     

亚甲基四氢叶酸还原酶基因 C677 T多态性与中国山东地区汉族人群缺血性卒中、高尿酸血症的相关性

目的：探讨亚甲基四氢叶酸还原酶（methylenetetrahydrofolatereductase,MTHFR）基因C677 T 多态性与中国山东地区汉族人群缺血性卒中、高尿酸血症的相关性。方法纳入山东地区汉族急性缺血性卒中患者和年龄、性别相匹配的对照者。采用聚合酶链反应扩增和芯片杂交显色技术检测MTHFR基因C677T 多态性,并测定血清尿酸浓度。结果共纳入山东地区汉族急性缺血性卒中患者145例和年龄、性别相匹配的对照者145名。缺血性卒中组糖尿病构成比（26.90％对6.89％;χ2=20.653,P<0.001）以及空腹血糖[（5.56±1.57）mmol/L对（5.01±1.11）mmol/L;t=－3.390, P=0.001]、高半胱氨酸[中位数,四分位数间距：18.2（16.30~22.55）μmol/L对15.20（12.10~17.85）μmol/L;Z=－6.323,P<0.001]和尿酸[43.0（361.60~490.45）μmol/L对285.9（267.00~346.25）μm o l/L;Z=－10.360, P<0.001]水平均显著高于对照组;缺血性卒中组 T T 基因型（42.07％对15.17％;χ2=25.673, P<0.001）和 T 等位基因（58.28％对34.48％;χ2=33.008, P<0.001）分布频率均显著高于对照组。多变量logistic回归分析显示,尿酸[优势比（ odds ratio, OR）1.018,95％可信区间（confidence interval, CI）1.013~1.024;P<0.001]、TT 基因型（对CT 基因型, OR 6.774,95％CI 1.779~25.507;P=0.005）、高血压（ OR 1.919,95％CI 1.013~3.636;P=0.045）、高半胱氨酸（ OR 1.153,95％CI 1.059~1.258;P=0.001）为缺血性卒中的独立危险因素。将缺血性卒中组与对照组合并,共101例存在高尿酸血症,189例尿酸正常。高尿酸血症组糖尿病患者构成比（32.67％对11.64％;χ2=23.749, P<0.001）以及总胆固醇[（5.67±1.56）mmol/L对（5.10±1.33）mmol/L;t=－3.255,P<0.001]和高半胱氨酸[19.50（17.10~24.70）μmol/L对15.40（12.60~18.05）μmol/L;Z=－7.236,P<0.001]水平显著高于尿酸正常组,TT 基因型（55.45％对13.76％;χ2=56.409,P<0.001）和T等位基因（71.79％对32.54％;χ2=79.561,P<0.001）分布频率显著高于尿酸正常组。多变量logistic回归分析显示,TT 基因型（对CC 基因型,OR 6.434,95％CI 2.334~17.736;P<0.001）、CT 基因型（对CC基因型,OR 2.234,95％CI 1.019~4.898;P=0.045）、高半胱氨酸（OR 1.081,95％CI 1.010~1.157;P=0.024）、总胆固醇（OR 1.363,95％CI 1.123~1.653;P=0.002）为高尿酸血症的独立危险因素。结论 MTHFR基因C677T TT 基因型和血清尿酸水平是中国山东地区汉族人群缺血性卒中的独立危险因素,MTHFR基因C677T TT 基因型亦为该人群高尿酸血症的独立危险因素,调整饮食习惯可能对山东地区汉族人群缺血性卒中的预防具有积极意义。     

Methylenetetrahydrofolate reductase 677 C-->T mutation and coronary heart disease risk in UK Indian Asians

Plasma homocysteine concentrations are elevated in UK Indian Asians and may contribute to twice as many coronary heart disease (CHD) deaths in this group compared with European whites. The mechanisms underlying elevated homocysteine concentrations among Indian Asians are not well understood. In this study, we have investigated the extent to which the methylenetetrahydrofolate reductase (MTHFR) 677 C-->T mutation accounts for elevated plasma homocysteine and increased CHD risk in Indian Asians compared with European whites. We investigated 454 male cases (with myocardial infarction or angiographically proven CHD: 224 Indian Asians, 230 European whites) and 805 healthy male controls (381 Indian Asians, 424 European whites). Fasting homocysteine concentrations, MTHFR 677 C-->T genotype, and conventional CHD risk factors were measured. The prevalence of homozygous MTHFR 677T in Indian Asian controls was less than one third that in European white controls (3.1% versus 9. 7%, P<0.001). In Indian Asians, the TT MTHFR genotype was not associated with homocysteine concentrations and was not present in any of the Asian controls with hyperhomocysteinemia (>15 micromol/L). In contrast, among European whites, the TT MTHFR genotype was strongly related to elevated plasma homocysteine concentrations and was found in 27% of the European controls with hyperhomocysteinemia. Elevated homocysteine in Indian Asian compared with European white controls was accounted for by their reduced levels of B vitamins but not by the MTHFR 677T genotype. However, neither the TT MTHFR genotype nor B vitamin levels explained the elevated homocysteine concentrations in CHD cases compared with controls. TT MTHFR was not a risk factor for early-onset CHD in Indian Asians (odds ratio, 0.5; 95% confidence interval, 0.1 to 2.4; P=0.39), unlike in European whites (odds ratio, 2.1; 95% confidence interval, 1.1 to 4. 1; P=0.02). We conclude that the MTHFR 677T: mutation does not contribute to elevated plasma homocysteine concentrations or increased CHD risk in Indian Asians compared with European whites. Our results suggest that novel genetic defects and/or environmental factors influence homocysteine metabolism in Indian Asians residing in the United Kingdom.     

The 5,10-methylenetetrahydrofolate reductase C677T polymorphism interacts with smoking to increase homocysteine

Elevated homocysteine is a risk marker for several human pathologies. Risk factors for elevated homocysteine include low folate and homozygosity for the T allele of the 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism. Because nitric oxide may inhibit folate catabolism and endothelial nitric oxide synthase activity is reduced in smokers, we postulated that smoking status might modify the impact of the MTHFR C677T polymorphism on homocysteine (tHcy) concentrations. We tested this hypothesis in a healthy young adult population for which MTHFR C677T genotypes and tHcy concentrations were previously reported. The MTHFR 677TT genotype was significantly associated with elevated tHcy concentrations in smokers (P = 0.001) but not in non-smokers (P = 0.36). Among smokers, the MTHFR 677TT genotype was significantly associated with high tHcy in heavy smokers (P = 0.003) but not light smokers (P = 0.09), in men (P = 0.003) but not women (P = 0.11), and in subjects from the lowest serum folate quartile (P = 0.49) but not from folate quartiles 2-4 (P = 0.49). After adjustment for nutritional variables, interactions between MTHFR C677T genotype and NOS3 G894T genotype, and between MTHFR genotype, smoking status and gender were statistically significant. We propose that hyperhomocysteinemia in MTHFR 677TT homozygote smokers is the consequence of mild intracellular folate deficiency caused by a smoking-related reduction of NOS3 activity that is exacerbated when serum folate is low.     

Contribution of the glycoprotein Ia 807TT, methylene tetrahydrofolate reductase 677TT and prothrombin 20210GA genotypes to prothrombotic risk among factor V 1691GA (Leiden) carriers

The cooperative effects of the GPIa 807TT, MTHFR 677TT and prothrombin 20210GA genotypes with the FV Leiden 1691GA (FVL) genotype were evaluated by comparing these genotype frequencies in 77 asymptomatic and 156 symptomatic heterozygous FVL carriers. The GPIa 807TT and MTHFR 677TT genotypes did not segregate within the symptomatic FVL carrier group and did not contribute to venous thrombotic risk in this patient cohort. There was no difference in the prothrombin 20210GA genotype frequency between asymptomatic FVL carriers and a random Caucasian control group; however, the prothrombin 20210GA genotype was nearly 5 times as prevalent (19/156 v 2/77; P < 0.02) in the symptomatic FVL carriers (odds ratio 5.21; 95% confidence interval 1.20-47.62), demonstrating that this important prothrombotic risk factor acts synergistically with FVL.     

Methylenetetrahydrofolate reductase gene polymorphisms in essential hypertension relation: with the development of hypertensive end-stage renal disease

BACKGROUND: The pathogenesis of hypertensive nephropathy is multifactoral and in addition to BP, other factors contribute to the development of this renal pathology and its progression to end-stage renal disease. These include genetic predisposition and increased pleasure level of homocysteine-intermediate protein catabolism product known to induce kidney injury. The 677C --> T polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene is associated with elevated homocysteine level in the general population, and therefore it has been hypothesized to be a risk factor for the development of renal failure in the course of essential hypertension. METHODS: In this case-control, cross-sectional study the frequency of the MTHFR 677C --> T and the 1298A --> C polymorphism was compared between patients with hypertension-related chronic renal failure (n = 90), patients with essential hypertension without kidney injury (n = 90), and healthy individuals (n = 90) who were matched for age and gender. In addition, the influence of these polymorphisms on homocysteine concentration in individuals with essential hypertension was examined. RESULTS: The frequency of the MTHFR 677 TT genotype did not differ between groups (4.5%, 12.3%, and 11.1%, respectively). Patients with hypertension and the 677TT genotype showed significantly higher homocysteine levels as compared to individuals having CC and CT. In the multivariate correlation analysis the MTHFR 677TT genotype (P < .01; beta = 0.27), age (P < .001; beta = 0.33), and body mass index (P < .01; beta = 0.3) were independent predictors for total homocysteine level. CONCLUSIONS: Plasma homocysteine levels in individuals with essential hypertension is affected by the MTHFR 677C --> T polymorphism. However, we did not prove the hypothesis that MTHFR 677C --> T influences the risk of development of renal failure in the course of hypertension.     

Portal vein thrombosis in Egyptian patients with liver cirrhosis: Role of methylenetetrahydrofolate reductase C677T gene mutation

Aim: The pathogenesis of non‐malignant portal vein thrombosis (PVT) in cirrhotic patients is not clearly defined. This case‐control study aimed to investigate the role of methylenetetrahydrofolate reductase (MTHFR) C677T gene mutation in the pathogenesis of PVT in Egyptian cirrhotic patients. Methods: Plasma homocysteine was measured and MTHFR C677T gene mutation was detected in 76 cirrhotic patients (21 with PVT, 55 without PVT) and 20 healthy controls. Results: The frequency of CC genotype (wide type) in cirrhotic patients with PVT was lower than controls and cirrhotics without PVT. However, the frequency of TT genotype (homozygous mutation) was elevated in cirrhotic patients with PVT as compared to controls and those without PVT. Cirrhotic patients with PVT had significantly higher homocysteine than those without PVT. Cirrhotic patients with TT genotype are at a significant risk for PVT (odds ratio = 7.7, 95% confidence interval, 1.50–42.81) when compared with CC genotype. Moreover, subjects carrying TT genotype had a higher homocysteine than those carrying CC genotype. Conclusions: The TT genotype of MTHFR is associated with an increased risk of PVT in Egyptian cirrhotic patients. Hyperhomocysteinemia could be considered as a relatively new risk factor for PVT in cirrhotic patients and plasma homocysteine should be investigated particularly in patients with PVT of unexplained etiology. The important clinical implication is that the readily available therapy of folate, vitamin B6 and B12 supplementation may reduce homocysteine and prevent further thrombotic complications in cirrhotic patients carrying the TT genotype.     

Methylenetetrahydrofolate reductase genotypes and predisposition to atherothrombotic disease; evidence that all three MTHFR C677T genotypes confer different levels of risk.

AIMS: Elevated plasma homocysteine is an independent risk factor for atherothrombotic disease. Individuals homozygous for the methylenetetrahydrofolate reductase (MTHFR) 677C allele exclusively accumulate 5methyltetrahydrofolate, the methyl donor for homocysteine remethylation, in their red blood cells; this contrasts with 677 TT homozygotes who also accumulate significant levels of non-methylated folate derivatives. Those with the MTHFR 677 TT, CT and CC genotypes may therefore differ qualitatively with respect to folate utilization and hence their capacity to remethylate homocysteine. This study was consequently designed to establish whether all three genotypes confer different levels of atherothrombotic risk. METHODS AND RESULTS: The risk of atherothrombotic disease conferred by the MTHFR 677 CT and 677 CC genotypes was assessed using a 'restricted' meta-analysis approach applied to subjects from the first ten studies reporting a significantly increased risk conferred by the 677 TT genotype. The defined risk of the TT genotype in each of these ten studies was judged by us to denote 'genetic vulnerability' in the populations from which subjects were drawn. After proportional adjustment for the greater number of case TT homozygotes, the CT and CC frequencies observed in cases were compared with expectations based on the frequencies of these genotypes in controls. The observed CT frequency among cases was higher than expected in eight of the ten studies. In the meta-analysis, which included 1857 cases and 2942 controls, 847 (45.6%) cases, instead of the 777 (41.8%) expected, had the MTHFR CT genotype (P=0.010). CONCLUSIONS: Our findings suggest that the three MTHFR C677T genotypes confer different levels of atherothrombotic risk in 'genetically vulnerable' populations: CT heterozygotes have an elevated risk over CC homozygotes. One explanation is that the CT genotype actively confers atherothrombotic risk. An alternative interpretation however, for which a biologically plausible mechanism is proposed, is that CC is a protective genotype.