中国西北地区人群高同型半胱氨酸血症、亚甲基四氢叶酸还原酶多态性与缺血性脑卒中的关系

背景：血浆中总同型半胱氨酸水平增高是缺血性脑卒中的一项危险因素，5，10-亚甲基四氢叶酸还原酶是同型半胱氨酸代谢途径中的关键酶。关于5，10-亚甲基四氢叶酸还原酶与缺血性脑卒中的关系还存在争议。 目的：通过检测中国西北地区汉族人群中缺血性脑卒中患者血浆中总同型半胱氨酸水平和5，10-亚甲基四氢叶酸还原酶基因两个位点C677T和A1298C的基因表型，探讨三者之间的关联性。 设计：病例一对照实验。 单位：吉林大学第一附属医院神经内科，解放军第四军医大学西京医院神经内科。 对象：病例组：随机选取2001-11／2002-05解放军第四军医大学西京医院神经内科经CT或磁共振确诊的缺血性脑卒中患者97例，男71例，女26例。对照组：94例，无脑卒中病史，其中男58例，女36例。以上两组受试者有脑出血，癌症，肾功能障碍及服用维生素和雌激素的排除在外。 方法：血浆总同型半胱氨酸水平用全自动荧光偏振免疫分析法检测，5，10-亚甲基四氢叶酸还原酶基因两个位点C677T和A1298C的基因表型用聚合酶链式反应-限制性片段多态性分析法检测。 主要观察指标：脑卒中患者C677T和A1298C的基因型频率，血浆总同型半胱氨酸水平。 结果：677T等位基因在病例组的分布明显高于对照组（59．3％，44．7％，P=0．006），但是1298C等位基因的频率在两组间较接近（22．7％，19．7％，P〉0．05）。6777T纯合子与高同型半胱氨酸血症显著相关（P〈0．01）。Logistic分析表明，C677T突变及高同型半胱氨酸血症者患缺血性脑卒中的OR值分别是1．87和1．03（P〈0．05）。 结论：高同型半胱氨酸血症是缺血性脑卒中的危险因素。C677T基因突变与缺血性脑卒中的发生相关，显著影响血浆总同型半胱氨酸水平，可能是缺血性脑卒中的一个独立的遗传危险因素。     

新疆维汉民族亚甲基四氢叶酸还原酶基因多态性及血浆同型半胱氨酸与冠状动脉粥样硬化性心脏病的关系

目的:分析新疆维汉民族亚甲基四氢叶酸还原酶基因C677T多态性及其与同型半胱氨酸水平、冠状动脉粥样硬化性心脏病之间的关系,以期为冠心病的预防和优化康复治疗提供理论依据。方法:收集2004-09/2005-10在新疆医科大学第一附属医院心内科住院并行冠状动脉造影术的320例维汉民族患者,按冠状动脉造影结果分为冠状动脉粥样硬化性心脏病组(n=189)与对照组(n=131),应用聚合酶链反应-限制性内切酶长度多态性方法检测亚甲基四氢叶酸还原酶基因C677T多态性,用荧光偏振免疫分析法测定血浆同型半胱氨酸水平,并分析同型半胱氨酸及亚甲基四氢叶酸还原酶基因C677T多态性与冠心病的关联性。结果:320例全部进入结果分析。①维汉民族冠状动脉粥样硬化性心脏病组和对照组亚甲基四氢叶酸还原酶C677TCC、CT、TT3种基因型分布(维吾尔族,χ2=9.561,P=0.008;汉族,χ2=10.618,P=0.005)和等位基因频率分布(维吾尔族,χ2=4.857,P=0.028;汉族,χ2=5.158,P=0.023)差异有统计学意义;但冠状动脉粥样硬化性心脏病组和对照组内维汉不同民族基因型分布和等位基因频率分布差异无统计学意义(P>0.05)。②维汉民族冠状动脉粥样硬化性心脏病组和对照组中,亚甲基四氢叶酸还原酶C677T各基因型之间血浆同型半胱氨酸水平的差异均有统计学意义(P<0.05)。其中TT基因型的血浆同型半胱氨酸水平均高于同组同民族CT和CC型者;CT基因型与CC基因型之间血浆同型半胱氨酸水平的差异无统计学意义P>0.05)。③经多因素非条件Logistic回归分析显示,亚甲基四氢叶酸还原酶C677T基因突变(OR=1.478)、同型半胱氨酸(OR=1.057)等因素是冠状动脉粥样硬化性心脏病的危险因素。结论:①同型半胱氨酸代谢关键酶基因亚甲基四氢叶酸还原酶C677T存在多态性,无民族差异。②亚甲基四氢叶酸还原酶C677T可导致血浆同型半胱氨酸明显增高。③亚甲基四氢叶酸还原酶C677T多态性和同型半胱氨酸是新疆维汉民族冠状动脉粥样硬化性心脏病发病的独立危险因素。     

同型半胱氨酸及其代谢酶基因多态性与缺血性脑卒中的相关性研究进展

高同型半胱氨酸血症是缺血性脑卒中发病的独立危险因素之一。关于同型半胱氨酸代谢酶基因多态性研究,主要包括:5,10-亚甲基四氢叶酸还原酶基因、胱硫醚合成酶基因、甲硫氨酸合成酶基因和甲硫氨酸合成酶还原酶基因等。本文主要探讨同型半胱氨酸相关代谢酶的基因突变对缺血性脑卒中的影响。     

MTHFR C677T和CBS T833C G919A基因突变与青年缺血性脑卒中的关系

血浆中同型半胱氨酸(Hcy)水平增高是缺血性脑卒中的独立危险因素.有研究认为,轻中度Hcy浓度增高与脑卒中的发生密切相关.N5,N10-亚甲基四氢叶酸还原酶是Hcy代谢的关键酶,胱硫醚β合成酶是Hcy代谢的相关酶,本研究拟采用聚合酶链-限制性内切酶片段长度多态性分析(PCR-RFLP)和扩增阻滞突变体系法,对血浆同型半胱氨酸(HCY)代谢关键酶N5,N10-亚甲基四氢叶酸还原酶(MTHFR)基因C677T位点和相关酶胱硫醚-β-合酶(CBS)基因T833C、G919A位点碱基突变与青年缺血性脑卒中的关系进行研究.……     

青年缺血性脑血管疾病独立危险因子与N5及N10-亚甲基四氢叶酸还原酶基因突变的关系

背景:血浆同型半胱氨酸浓度升高是动脉粥样硬化性血栓性脑梗死的独立危险因素,同型半胱氨酸在转硫化和再甲基化过程中的代谢酶N5,N10-亚甲基四氢叶酸还原酶(methylenetetrahydrofolatereductase,MTHFR)基因突变可致血浆同型半胱氨酸浓度升高。目的:探讨同型半胱氨酸血症、同型半胱氨酸代谢关键酶MTHFR基因突变与青年缺血性脑血管疾病的关系。设计:病例-对照观察。单位:吉林大学中日联谊医院神经内科。对象:于2003-04/2004-12吉林大学中日联谊医院神经内科收治发病2d内住院的青年脑梗死患者100例,为病例组,男73例,女27例;年龄27～45岁,平均(42±5)岁。对照组100例为同期健康体检者,男70例,女30例;年龄18～45岁,平均(39±4)岁。方法:以高效液相色谱法测定受试者空腹血浆同型半胱氨酸,采用聚合酶链反应-限制性内切酶片段长度多态性分析和扩增阻滞突变体系法,对MTHFR基因C677T位点和A1298C位点进行检测。主要观察指标:MTHFRC677T和A1298C基因检测,血浆同型半胱氨酸浓度与MTHFR基因型的关系。结果:纳入患者100例和正常对照100例,均进入结果分析。①MTHFRC677T和A1298C基因检测:MTHFRC677T基因检测病例组和对照组基因型分布、纯合子频率和等位基因频率差异均显著(P<0.01)。而MTHFRA1298C基因检测病例组和对照组基因型分布、纯合子频率和等位基因频率差异均无显著性(P>0.05)。②血浆同型半胱氨酸浓度与MTHFR基因型的关系:MTHFRC677T和A1298C各基因型间血浆同型半胱氨酸浓度差异有显著性(P<0.001)。2个位点突变结果LSD-t检验显示纯合子与杂合子,纯合子与野生型血浆同型半胱氨酸浓度均数差有统计学意义(P<0.05)。MTHFRC677T和A1298C杂合子与野生型血浆同型半胱氨酸浓度均数差无统计学意义(P>0.05)。结论:MTHFRC677T和A1298C突变均导致血浆同型半胱氨酸浓度明显增高。MTHFRC677T多态性位点是青年缺血性脑血管疾病的独立危险因子。MTHFRA1298C基因突变与青年缺血性脑血管疾病发病无相关性。     

青年缺血性脑血管疾病独立危险因子与N5及N10-亚甲基四氢叶酸还原酶基因突变的关系

背景：血浆同型半胱氨酸浓度升高是动脉粥样硬化性血栓性脑梗死的独立危险因素，同型半胱氨酸在转硫化和再甲基化过程中的代谢酶Ns，N10-亚甲基四氢叶酸还原酶（methylene tetrahydrofolate reduetase，MTHFR）基因突变可致血浆同型半胱氨酸浓度升高。 目的：探讨同型半胱氨酸血症、同型半胱氨酸代谢关键酶MTHFR基因突变与青年缺血性脑血管疾病的关系。 设计：病例-对照观察。 单位：吉林大学中丑联谊医院神经内科。 对象：于2003-04／2004-12吉林大学中丑联谊医院神经内科收治发病2d内住院的青年脑梗死患者100例，为病例组，男73例，女27例；年龄27-45岁，平均（42&;#177;5）岁。对照组100例为同期健康体检者：男70例，女30例；年龄18～45岁，平均（39&;#177;4）岁。 方法：以高效液相色谱法测定受试者空腹血浆同型半胱氨酸，采用聚合酶链反应-限制性内切酶片段长度多态性分析和扩增阻滞突变体系法，对MTHFR基因C677T位点和A1298C位点进行检测。 主要观察指标：MTHFRC677T和A1298C基因检测，血浆同型半胱氨酸浓度与MTHFR基因型的关系。 结果：纳入患者100例和正常对照100例，均进入结果分析。④MTHFRC677T和A1298C基因检测：MTHFR C677T基因检测病例组和对照组基因型分布、纯合子频率和等位基因频率差异均显著（P〈0．01）。而MTHFR A1298C基因检测病例组和对照组基因型分布、纯合子频率和等位基因频率差异均无显著性（P〉0．05）。②血浆同型半胱氨酸浓度与MTHFR基因型的关系：MTHFR C677T和A1298C各基因型问血浆同型半胱氨酸浓度差异有显著性（P〈0．001）。2个位点突变结果LSD-t检验显示纯合子与杂合子，纯合子与野生型血浆同型半胱氨酸浓度均数差有统计学意义（P〈0．05）。MTHFR C677T和A1298C杂合子与野生型血浆同型半胱氨酸浓度均数差无统计学意义（P〉0．05）。 结论：MTHFR C677T和A1298C突变均导致血浆同型半胱氨酸浓度明显增高。MTHFR C677T多态性位点是青年缺血性脑血管疾病的独立危险因子。MTHFR A1298C基因突变与青年缺血性脑血管疾病发病无相关性。     

新疆哈萨克族人群同型半胱氨酸及其代谢酶基因多态性与原发性高血压的关系

背景:新疆哈萨克族人群高血压的发病率居全国前列,但其发病机制至今未明.有报道证实同型半胱氨酸与许多心血管疾病的发病有关,但同型半胱氨酸水平及代谢酶基因多态性与新疆哈萨克族人群原发性高血压是否存在关系尚无报道.目的:探讨同型半胱氨酸水平及亚甲基四氢叶酸还原酶A1298C、甲硫氨酸合酶A2756G多态性与新疆哈萨克族人群原发性高血压的关系.方法:纳入408例哈萨克族受试者,分成两组,高血压组195例,其中男性93例,女性102例,平均年龄(49.44±9.71)岁;对照组213例,其中男性95例,女性118例,平均年龄(40.82±8.87)岁.应用特异引物PCR及聚合酶链反应限制性片断长度多态性(PCR-RFLP)方法,检测两组亚甲基四氢叶酸还原酶基因A1298C、甲硫氨酸合酶A2756G多态位点的基因型;采用酶标免疫吸附法检测血浆同型半胱氨酸水平.结果与结论:高血压组血浆同型半胱氨酸水平明显高于正常对照组(P＜0.05),且血浆同型半胱氨酸水平有性别差异,男性血浆同型半胱氨酸水平明显高于女性(P＜0.05).两组间亚甲基四氢叶酸还原酶A1298C、甲硫氨酸合酶A2756G各多态位点及联合基因的基因型和等位基因频率分布无明显差异(P＞0.05).亚甲基四氢叶酸还原酶A1298C、甲硫氨酸合酶A2756G各基因型和各联合基因型之间的血浆同型半胱氨酸水平比较无明显差异(P＞0.05).结果表明新疆哈萨克族人群亚甲基四氢叶酸还原酶基因A1298C、甲硫氨酸合酶基因A2756G位点多态性与新疆哈萨克族人群原发性高血压的发生无明显的相关性.血浆同型半胱氨酸水平可能是新疆哈萨克族人群高血压发生的危险因素,但不是独立的危险因素.     

PCR熔解曲线法检测MTHFR 677T基因多态性在H型高血压诊治中的应用

高同型半胱氨酸血症是指血浆同型半胱氨酸（homocysteine,Hcy）水平的异常升高（Hcy≥10μmol/L）。亚甲基四氢叶酸还原酶（methylenetetrahydrofolate reductase,MTHFR）是同型半胱氨酸代谢过程中较为重要的关键酶,MTHFR677C/T多态性可引起血浆Hcy水平的增高,研究发现MTHFR677C/T突变是中国人患有高同型半胱氨酸血症的重要原因之一。     

MTHFR基因多态性及血浆同型半胱氨酸水平与心脑血管疾病的相关性分析

正亚甲基四氢叶酸还原酶(methylenetetra hydrofolate reductase,MTHFR)在叶酸代谢中发挥了重要作用,MTHFR可以催化5,10-亚甲基四氢叶酸转化还原为5-甲基四氢叶酸,该转化过程也为同型半胱氨酸(homocysteine,Hcy)的甲基化提供甲基,从而可以快速调节血浆Hcy浓度[1]。1995年,FROSST等[2]确定了MTHFR基因在677位点C→T的变异会导致肽链上222位的     

亚甲基四氢叶酸还原酶基因多态性和疾病易感性之间的关系

亚甲基四氢叶酸还原酶(5,10-methylenetetrahydrofolate reductase,MTHFR)是叶酸和同型半胱氨酸代谢途径的关键酶。MTHFR基因677C>T和1298A>C单核苷酸多态性(single nucleotide polymorphism,SNP)和多种疾病相关,例如会加速动脉粥样硬化和血栓栓塞事件发生,引发心血管疾病;影响同型半胱氨酸的排泄,引起高胱氨酸尿症;减低循环中叶酸水平,升高同型半胱氨酸水平,引起神经毒性和血管毒性作用;影响孕妇叶酸的有效摄入,增加先天性神经管缺陷发生风险等。本文就MTHFR基因SNP和疾病发生之间的易感性,以及在药物基因组学中的研究进展进行综述。     

5,10-Methylenetetrahydrofolate reductase 677C-->T and 1298A-->C mutations are genetic determinants of elevated homocysteine

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) is one of the main regulatory enzymes of homocysteine metabolism. Elevated plasma total homocysteine (tHcy) is a major risk for cardiovascular disease. A common 677C-->T mutation in the MTHFR gene results in decreased enzymic activity, and contributes to increased plasma tHcy, in association with low plasma folate. A recently described 1298A-->C mutation in the MTHFR gene clearly reduces MTHFR activity (although to a lesser extent than the 677C-->T) but its effect on plasma tHcy levels is not yet clear. AIM: To investigate the frequency of these two MTHFR polymorphisms in a Portuguese population, and to correlate the MTHFR genotype with the biochemical phenotype at the level of homocysteine and folate concentrations. DESIGN: Prospective population survey. METHODS: We studied 117 healthy volunteers (71 females, 46 males). The 677C-->T and 1298A-->C mutations were screened by PCR-RFLP. Levels of plasma tHcy and folate, and red blood cell folate, were determined. RESULTS: The allele frequencies of the 677C-->T and 1298A-->C mutations were 0.33 and 0.28, respectively. Homozygotes for the 677C-->T mutation had significantly elevated plasma tHcy and RBC folate levels and significantly lowered plasma folate concentrations than subjects without the mutation. The 1298A-->C mutation showed a significant effect on plasma tHcy, but not on plasma folate or RBC folate levels. DISCUSSION: The observed 677T allele frequency is not consistent with the idea of a north-south gradient as previously suggested. The 1298A-->C mutation is common in Portugal. Both MTHFR mutations showed effects on plasma tHcy levels.     

Metabolic effects of C677T and A1298C mutations at the MTHFR gene in Brazilian children with neural tube defects

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) deficiency leads to impairment in folate metabolism and is implicated as a risk factor for neural tube defects (NTDs). Both C677T and A1298C MTHFR mutations are associated with NTDs, in some populations. METHODS: The frequencies of the C677T and A1298C MTHFR mutations were determined in 25 children with NTDs, case mothers and 75 healthy individuals from Sao Paulo City. Both C677T and A1298C mutations were analyzed by PCR-FLRP. The effects of MTHFR mutations on folate, vitamin B12 and homocysteine concentrations were also evaluated. RESULTS: C677T and A1298C allele frequencies in NTDs children and mothers were similar to that found in controls. Eleven in 23 NTDs patients and 10 in 21 NTDs mothers had folate or vitamin B12 concentrations in the lower end of the normal range. In NTDs children, C677T MTHFR genotypes did not affect vitamins and homocysteine concentrations, but plasma homocysteine was higher (p=0.028) in patients with 1298AA MTHFR genotype. Moreover, 677CT/1298AA haplotype was associated with lower vitamin B12 concentrations (p<0.05) in NTDs children. CONCLUSIONS: MTHFR gene mutations may affect vitamin B12 and homocysteine metabolism in Brazilian children with NTDs.     

Low frequency of mutated methylenetetrahydrofolate reductase 677C-->T and 1298A-->C genetics single nucleotide polymorphisms (SNPs) in Sub-Saharan populations.

5,10-Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) are two of the key enzymes in the folate/vitamin B12-dependent remethylation of homocysteine to methionine. The frequencies of MTHFR single nucleotide polymorphisms (SNPs), 677C-->T, 1298A-->C, 1317T-->C and of MTR, 2756A-->G, have been widely studied in Caucasians, but they have never been reported simultaneously in a large population from Sub-Saharan Africa. Presently, we report the prevalence of these SNPs and their relationship to homocysteine in 240 subjects recruited in West Africa. The frequencies of the mutant genotypes 677TT (0.8%) and 1298CC (2%) were lower than that usually observed in Caucasians, while the frequency of the mutant 1317CC was higher (16%). We formed a systematic association of the mutated MTHFR 677C-->T SNP with a 1298A/1317T common haplotype. The MTHFR mutant genotype 677TT was associated with an intermediate hyperhomocysteinemia (92.4 +/- 6.0 micromol/l) higher than that described in Caucasians. The 2756A-->G SNP in the MTR was similarly distributed in Africans compared to Caucasians. In conclusion, the MTHFR 677TTor 1298CC genotypes are much rarer in Africans than in Caucasians. The 677TT low frequency may be related to the high effect of this mutation on homocysteine metabolism in the environmental conditions of this African region.     

Metabolic and genetic risk factors for migraine in children

Migraine can induce ischaemic stroke, and is considered an independent risk factor for stroke in the young. To date, the nature of the link between migraine and stroke is essentially unknown. Forty-five children were studied. Homocysteine levels (fasting and post methionine load), vitamin B12 and plasma folate levels, factor V Leiden, factor II G20210A, methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C mutations were examined. Compared with controls, patients with migraine had higher levels of post-methionine load homocysteine values (19.5 +/- 4.9 vs. 16.9 +/- 1.9; P = 0.025) and significantly lower folate levels (5.8 +/- 2.6 vs. 7.5 +/- 2.1; P = 0.002). We found a trend toward an increased risk of migraine in subjects carrying a homozygous mutant genotype for MTHFR C677T and MTHFR A1298C polymorphisms. Genetic prothrombotic conditions do not seem to be related to migraine in the young, whereas the biochemical differences between migrainous patients and controls are an appealing topic for further investigation.     

Methylenetetrahydrofolate reductase (MTHFR) c677t gene variant modulates the homocysteine folate correlation in a mild folate-deficient population

Background: A large body of evidence links plasma concentrations of homocysteine and cardiovascular disease. Several genetic and environmental variables may modulate such relationship. We investigated the influence of methylenetetrahydrofolate reductase (MTHFR) gene variants C677T, A1298C, and T1317C on homocysteine, folate, and cobalamin concentrations in a sample of individuals from a mild folate deficiency population to better clarify the complex interactions existing among these variables. Methods: In the present study, 209 individuals belonging to an admixed urban population characterized by mild folate deficiency were investigated. MTHFR gene variants C677T, A1298C, and T1317C were genotyped and homocysteine-, folate-, and cobalamin-determined for each individual. Results: Univariate analyses showed a significant association between the C677T variant with homocysteine (P<0.001) and cobalamin (P=0.005) as well as a significant relationship between the T allele and serum folate concentrations (P<0.05). The TT genotype of the C677T polymorphism remained significantly associated with log-transformed homocysteine even after adjustment for age, sex, smoking status, ethnicity, folate, and cobalamin concentrations (P<0.01). Both univariate and multivariate analysis have failed to show any effect of the A1298C and T1317C genetic variants in homocysteine concentrations in this population. Finally, a significant interaction between folate and C677T polymorphism in the determination of homocysteine was also disclosed (P<0.005). Conclusions: Taken together, these results demonstrate a significant interaction between serum folate and MTHFR genotype in predicting homocysteine concentrations. One may consider that a differential response of homocysteine to folic acid supplementation may depend on MTHFR genotype which may have important implications when attempting to lower homocysteine concentrations in populations with mild folate deficiency.     

Prevalence of methylenetetrahydrofolate reductase mutations in patients with venous thrombosis.

BACKGROUND: The objectives of this study are to examine the prevalence of combined methylenetetrahydrofolate reductase (MTHFR) 677C-->T and 1298A-->C mutations in patients with venous thrombosis (VT) and healthy volunteers and to determine if these mutations are in Hardy-Weinberg equilibrium. METHODS AND RESULTS: Sixty-five patients with VT and 64 healthy volunteers were assessed for MTHFR 677T and 1298C alleles using polymerase chain reaction and restriction fragment length polymorphism. Observed MTHFR genotype frequencies were compared with expected genotype combinations, and their odds ratios were determined. MTHFR allele frequency did not differ between VT and control groups; however, differences were observed for MTHFR genotype distribution. MTHFR 677T and 1298C alleles occurred in cis in our population, and therefore mutation crossover has occurred. There was deviation from the Hardy-Weinberg equilibrium for combined MTHFR genotypes, although this may at least partly be attributable to linkage disequilibrium. MTHFR 677CT/1298CC and 677TT/1298CC genotypes (P<.05) were not observed in either group. CONCLUSIONS: The absence of MTHFR 677CT/1298CC and 677TT/1298CC genotypes in both groups suggests that certain MTHFR genotypes may carry a selective advantage. Our discovery of a substantial number of MTHFR mutations in cis configuration suggests that any MTHFR allele linkage disequilibrium present is incomplete.     

Genetic and nongenetic factors influencing plasma homocysteine levels in patients with ischemic cerebrovascular disease and in healthy control subjects.

Moderately elevated plasma homocysteine levels have been established as an independent risk factor for atherosclerosis and its complications, including cerebrovascular disease. A common mutation (C677T) in the gene encoding for the enzyme methylenetetrahydrofolate reductase (MTHFR) has been linked to increased plasma homocysteine levels in homozygous carriers, particularly in the presence of low folate levels. However, the results of most of the previous studies suggest that the C677T MTHFR mutation is not a significant risk factor for arterial disease. This discrepancy might, at least partly, be due to the fact that plasma homocysteine levels are influenced by several other factors, including age, gender, renal function, and vitamin status. We investigated the relation between plasma homocysteine levels, the C677T MTHFR mutation, and these other factors in a population of 96 patients with transient ischemic attacks or minor strokes and in 96 age- and sex-matched healthy control subjects. We further tested the value of a multivariate model for the prediction of plasma homocysteine levels under particular consideration of the MTHFR mutation status. In the patients, plasma homocysteine levels were significantly higher than in the healthy control subjects. With regard to the MTHFR mutation, the distribution of the C/C, C/T, and T/T genotypes was not significantly different between patients and healthy control subjects. Univariate (linear regression) analysis revealed significant (positive) correlations between plasma homocysteine levels on the one hand and age and creatinine on the other, the latter particularly in subjects with creatinine levels in the upper quartile. Significant (negative) correlations were found between plasma homocysteine levels, vitamin B12, and folate levels. However, these relations could much better be expressed by means of a multiplicative regression model. T/T subjects exhibited slightly higher homocysteine levels than C/C and C/T subjects; however, the differences between the 3 genotypes were not significant. Multivariate (stepwise regression) analysis revealed age, vitamin B12 levels, folate levels, and creatinine levels as significant independent variables influencing plasma homocysteine levels, whereas the MTHFR mutation status and gender were removed from the model. Considering all 192 subjects, only 28.8% of the variance of plasma homocysteine levels could be accounted for by the model. However, in homozygous carriers of the MTHFR mutation, the predictive power of the model is very high, explaining 76.1% of the variance of plasma homocysteine levels. According to our results, the C677T mutation does not constitute a major risk factor for transient ischemic attack or minor stroke, even under consideration of other possibly confounding factors that are known to affect plasma homocysteine levels. However, it is possible to predict plasma homocysteine levels in homozygous carriers of the mutation with high accuracy. The knowledge of the MTHFR mutation status may therefore help to identify subjects at high risk for hyperhomocysteinemia.     

缺血性心脑血管病患者血浆同型半胱氨酸水平及其代谢相关酶基因多态性分析

目的　了解缺血性心脑血管病患者血浆同型半胱氨酸 (Hcy)水平的变化 ,分析该变化与Hcy代谢相关酶基因变异的相关性。方法　用高效液相色谱结合荧光检测法测定 80名正常人 ,86例脑梗死 ,6 6例心肌梗死患者血浆总同型半胱氨酸 (tHcy)浓度 ,分析血浆tHcy水平与缺血性心脑血管疾病与胱硫醚 β 合成酶 (CBS)基因 844ins6 8、甲硫氨酸合成酶 (MS)基因A2 75 6G、亚甲基四氢叶酸还原酶(MTHFR)基因C6 77T三种Hcy代谢相关酶基因突变之间的相关性。结果　缺血性心脑血管病患者血浆tHcy水平 [脑梗死组 (19.5 9± 10 .6 5 ) μmol/L ,心肌梗死组 (2 1.13± 9.5 7) μmol/L]较正常对照组[(13.73± 4.78) μmol/L]显著升高 (P <0 .0 5 ) ;MTHFRC6 77T纯合突变者血浆tHcy水平无论在正常对照组或患者组均较野生型及杂合突变者明显升高 (P <0 .0 5 )。MSA2 75 6G ,CBS 844ins6 8基因突变者血浆tHcy水平差异无显著性。结论　高Hcy血症是缺血性心脑血管病的重要危险因子 ,MTHFRC6 77T纯合突变可能是导致血浆Hcy水平轻、中度增高的遗传决定簇。     

α-转化生长因子及其受体在人肝脏组织硬化过程中的表达特征

背景:α-转化生长因子及表皮生长因子受体在不同病变中的表达和意义不尽相同。目的:观察α-转化生长因子及表皮生长因子受体在人类肝硬变组织中的表达。设计:非随机对照实验。材料:实验于2003-03/2004-05在解放军第四军医大学西京医院病理科完成。63份人类肝硬变组织选自解放军第四军医大学西京医院外科手术标本(患者知情同意),5份正常人类肝脏组织取自第四军医大学病理学教研室尸检组织(排除有肝脏疾病)。方法:运用免疫组织化学和原位杂交的方法对63份人类肝硬变组织及5份正常人类肝脏组织进行研究,计算α-转化生长因子及表皮生长因子受体阳性率并进行统计学处理。主要观察指标:免疫组织化学染色方法和原位杂交染色检测肝硬变组织中α-转化生长因子及表皮生长因子受体的表达。结果:免疫组织化学方法检测α-转化生长因子与表皮生长因子受体在63份肝硬变组织中的阳性率分别为84%(53/63)及52%(33/63),阳性产物为棕黄色颗粒,主要弥漫分布于肝细胞浆内,α-转化生长因子与表皮生长因子受体的表达在肝硬变组织中呈显著正相关(r=0.32,P<0.05),5份正常肝组织中α-转化生长因子与表皮生长因子受体表达为阴性;α-转化生长因子与表皮生长因子受体的原位杂交阳性率(86%,54%)略高于其免疫组织化学结果,两种检测方法之间差异无显著性(P>0.05)。结论:在肝脏组织硬变形成过程中可能存在α-转化生长因子/表皮生长因子受体自分泌循环,而α-转化生长因子、表皮生长因子受体高水平表达是促使肝脏组织硬变形成的重要因素之一。