亚甲基四氢叶酸还原酶基因多态性与缺血性卒中

近年来的研究表明,高同型半胱氨酸血症通过多种机制造成血管内皮损伤,破坏机体凝血和纤溶系统,影响脂质代谢,是卒中的独立危险因素.亚甲基四氢叶酸还原酶(MTHFR)是体内同型半胱氨酸代谢途径的关键酶,该酶含量不足或活性下降将直接导致同型半胱氨酸在体内的蓄积,从而引起高同型半胱氨酸血症.虽然许多研究发现MTHFR基因突变是该酶缺乏或活性下降的主要原因,但是MTHFR基因突变与缺血性脑血管病的相关关系目前颇有争议.文章就MTHFR基因多态性与缺血性卒中的关系进行综述.     

N~5,N~(10)-亚甲四氢叶酸还原酶基因及胱硫酸-β-合酶基因突变与冠心病、脑卒中发病的关系

大量流行病学资料和临床观察发现,同型半胱氨酸与冠心病及脑卒中的发生密切相关。N5,N0-亚甲四氢叶酸还原酶（MTHFR）基因与胱硫酸-β-合酶（CBS）基因突变、MTHFR与CBS活性降低可能是高同型半胱氨酸血症的产生和诱发冠心病和脑卒中的一个重要原因。高同型半胱氨酸血症是一些心血管疾病的一个独立危险因素。     

高同型半胱氨酸血症致血管内皮功能障碍研究进展

高同型半胱氨酸血症已被许多研究证实是心血管疾病的独立危险因素。高同型半胱氨酸血症可造成血管内皮功能障碍,而内皮功能障碍与诸多心血管疾病的发生、发展有着密切联系。与同型半胱氨酸代谢相关的酶的基因突变及营养性B族维生素(叶酸、维生素B12、维生素B6)缺乏均可造成高同型半胱氨酸血症。B族维生素可通过降低血浆同型半胱氨酸水平改善内皮功能。     

N5,N10-亚甲四氢叶酸还原酶基因及胱硫醚-β-合酶基因突变与冠心病、脑卒中发病的关系

大量流行病学资料和临床观察发现,同型半胱氨酸与冠心病及脑卒中的发生密切相关.N5,N10-亚甲四氢叶酸还原酶(MTHFR)基因与胱硫醚-β-合酶(CBS)基因突变、MTHFR与CBS活性降低可能是高同型半胱氨酸血症的产生和诱发冠心病和脑卒中的一个重要原因.高同型半胱氨酸血症是一些心血管疾病的一个独立危险因素.     

高同型半胱氨酸血症的叶酸干预

高同型半胱氨酸（Hcy）血症作为独立心血管危险因素已被广泛认可。高Hcy与促血栓形成状态、氧化应激、炎性反应及血管内皮损伤等密切相关,从而导致动脉粥样硬化形成。北美一些国家采用叶酸强化饮食后心血管疾病发病风险明显下降,但近期发表的多个大规模临床研究没能证实心血管疾病患者从Hcy降低中获益。血浆Hcy是否可以作为心血管危险因素进行临床干预尚存在争议。该文对高Hcy血症叶酸干预与心血管疾病的研究进展作一综述。     

高同型半胱氨酸血症的叶酸干预

高同型半胱氨酸（Hcy）血症作为独立心血管危险因素已被广泛认可。高Hcy与促血栓形成状态、氧化应激、炎性反应及血管内皮损伤等密切相关,从而导致动脉粥样硬化形成。北美一些国家采用叶酸强化饮食后心血管疾病发病风险明显下降,但近期发表的多个大规模临床研究没能证实心血管疾病患者从Hcy降低中获益。血浆Hcy是否可以作为心血管危险因素进行临床干预尚存在争议。该文对高Hcy血症叶酸干预与心血管疾病的研究进展作一综述。     

MTHFR基因多态性及同型半胱氨酸与糖尿病微血管并发症

亚甲基四氢叶酸还原酶（MTHFR）C677T基因突变导致血同型半胱氨酸水平升高，而高同型胱氨酸血症是心，脑及外周血管疾病的危险因素。近来研究表明MTHFR基因多态性及同型半胱氨酸与糖尿病大血管并发症有关，但是对其与糖尿病微血管并发症的关系意见不一。     

同型半胱氨酸与冠心病关系的研究进展

冠心病是一种常见的心血管疾病，因其严重危害人类健康、降低生活质量及缩短寿命长度，历来在世界范围内都是一个主要的公众健康难题；冠心病的预防及控制，也一直被视为公共卫生管理领域一久攻不下的难题。同型半胱氨酸目前已被认为是冠心病的一个新的独立危险因素，与冠心病的发生、发展密切相关。由于遗传、代谢等各种因素导致的高同型半胱氨酸血症会损伤血管内皮，介导炎症因子的释放，平滑肌增生等一系列病理改变；通过补充维生素、叶酸可以降低同型半胱氨酸水平，以达到降低心血管疾病发生率的效果。本文就同型半胱氨酸水平与冠心病的关系，同型半胱氨酸的代谢，影响同型半胱氨酸代谢的因素，血浆高同型半胱氨酸引起冠心病的可能机制及其治疗措施作一综述。     

亚甲基四氢叶酸还原酶基因多态性与心血管疾病的研究进展

<正>近年来,由于快速发展的社会经济和不断改变的人们的生活方式,心血管疾病的发病率和死亡率在中国也是越来越多。高同型半胱氨酸血症(HHcy)作为心血管疾病的危险因素,是由多个基因与环境因素共同作用的结果,这可能是遗传易感基因通过影响血管平滑肌或血管内皮细胞等方式在心血管疾病的病理生理中发挥重要作用。研究认为亚甲基四氢叶酸还原酶(MTHFR)基因突变使酶活性下降,导致血浆同型半胱氨酸(Hcy)水平升高,故该基因突     

MTHFR基因多态性及同型半胱氨酸与糖尿病微血管并发症

亚甲基四氢叶酸还原酶 (MTHFR)C6 77T基因突变导致血同型半胱氨酸水平升高 ,而高同型半胱氨酸血症是心、脑及外周血管疾病的危险因素。近来研究表明MTHFR基因多态性及同型半胱氨酸与糖尿病大血管并发症有关 ,但是对其与糖尿病微血管并发症的关系意见不一     

Low folate levels may be an atherogenic factor regardless of homocysteine levels in young healthy nonsmokers

Low folate and high homocysteine levels are emerging as important risk factors for atherosclerosis and predictors of early coronary heart disease. We evaluated folate and homocysteine levels, compared them with endothelial function, and analyzed their association with the methylenetetrahydrofolate reductase (MTHFR) and endothelial nitric oxide synthase genotypes. We recruited 71 young healthy male nonsmokers without overt cardiovascular or renal disease. Plasma homocysteine levels were enhanced 2-fold in the subjects with the MTHFR 677T/T compared with the others (P = .0001) and also enhanced in the subjects with the endothelial nitric oxide synthase −786C allele (P = .031). Homocysteine levels were independently predicted only by the MTHFR genotype. A relationship between folate and homocysteine levels was not significant. Plasma folate levels were associated independently either with high-density lipoprotein cholesterol levels or with endothelial function in the brachial artery. These results suggest that low folate levels may be a risk factor for cardiovascular diseases regardless of homocysteine levels and that the subjects with lower folate levels should be recommended for dietary folic acid supplementation to elevate endothelial function and probably increase high-density lipoprotein cholesterol levels.     

类风湿关节炎合并心血管病变患者血清同型半胱氨酸水平及其与亚甲基四氢叶酸还原酶基因多态性的关系

目的检测类风湿关节炎（RA）患者血清同型半胱氨酸水平和亚甲基四氢叶酸还原酶（MTHFR）基因单核苷酸多态性,分析其在RA合并心血管病变患者中的作用。方法收集183例RA患者,分为合并心血管病变组和无心血管病变组,同时选取50名我院健康体检者作为对照组。采用实时荧光定量聚合酶链反应方法测定RA患者和对照组的MTHFR基因rs1801133C／T（677）和rs1801131A／C（1298）2个位点的基因单核苷酸多态性;ELISA法检测3组受试者血清同型半胱氨酸水平。结果①183例RA患者心血管病变发生率约为29．0％,其中合并心血管病变组同型半胱氨酸水平明显高于无心血管病变组（P〈0．001）。②677TT基因型组血清同型半胱氨酸水平高于CC及CT组（P〈0．05）。③RA患者血清同型半胱氨酸水平与心血管事件呈正相关。结论RA合并心血管病变患者血清同型半胱氨酸水平明显高于RA无心血病变组及正常对照组,其水平增高可能与MTHFR677C／T基因多态性有关。血清同型半胱氨酸水平升高可作为RA患者发生心血管事件的预测指标。     

The methylenetetrahydrofolate reductase gene polymorphism in Koreans with coronary artery disease

Hyperhomocysteinemia is a known risk factor of cardiovascular diseases. Methylenetetrahydrofolate reductase (MTHFR), involved in folate-dependant metabolism, is associated with homocysteine levels. We studied the associations among MTHFR genotypes, coronary artery disease (CAD), and homocysteine levels in 85 patients with CAD and 152 healthy subjects. The MTHFR genotypes and plasma homocysteine levels were determined. No significant difference in mutation of the MTHFR gene between two groups was observed (P>0.05). While the homozygous mutant genotype (V/V) had the highest homocysteine levels compared to wild (A/A) and heterozygous mutant (A/V) genotypes, there were no significant differences in homocysteine levels among the MTHFR genotype groups. Homocysteine was significantly and inversely related to folate levels, the significant association in V/V genotype (beta coefficient=-1.954, P=0.04). Our data suggested that MTHFR polymorphism was not associated with homocysteine levels, implying no association between gene polymorphism and CAD in Koreans.     

Methylene tetrahydrofolate reductase (MTHFR) and nitric oxide synthase (ecNOS) genes and risks of peripheral arterial disease and coronary heart disease: Edinburgh Artery Study

Hyperhomocysteinaemia and reduced nitric oxide synthesis may each result in endothelial dysfunction predisposing to atherogenesis. Genetic variants of methylene tetrahydrofolate reductase (MTHFR) and endothelial nitric oxide synthase (ecNOS) influence homocysteine metabolism and nitric oxide synthesis, respectively and might thus be determinants of the risk of atherosclerotic disease. The aim of our study was to identify, in a general population sample, the risks of peripheral arterial disease and of coronary heart disease related to MTHFR (175;198) and ecNOS (4;5) polymorphisms. In the Edinburgh Artery Study, which is a population based cohort study, 940 men and women aged 60-79 years, who had previously been selected at random from the general population, had DNA extracted from a venous blood sample. Based on a clinical examination at baseline and follow up investigations, three groups of subjects were identified: those with peripheral arterial disease (n=80), those with coronary heart disease (n=137), and healthy controls who had no evidence of cardiovascular disease (n=300). The distributions of the ecNOS and MTHFR genotypes did not differ significantly between the groups with and without cardiovascular disease. However, the ecNOS-4 allele (frequency 0.13) was related to the occurrence of coronary heart disease in non smokers, OR=2.47 (95% CI [1.42, 4.34], P=0.02). No association was found with peripheral arterial disease. The MTHFR-175 allele (frequency 0.31) was not related to coronary heart disease, but was associated with a reduced risk of peripheral arterial disease, OR=0.54 (95% CI [0.32, 0.90], P=0.02). Neither the ecNOS-4 allele or MTHFR-175 allele was related to the ankle brachial pressure index in the whole study population. In conclusion, the ecNOS-4 allele was associated with a slightly increased risk of coronary heart disease in non-smokers, but otherwise the MTHFR and ecNOS genotypes appeared to have little influence on the risks of peripheral arterial disease and coronary heart disease in this older population.     

同型半胱氨酸与冠状动脉粥样硬化性心脏病关系的研究进展

同型半胱氨酸(Hcy)参与动脉粥样硬化的发生和发展,是心血管疾病的独立危险因素,主要作用机制与损伤血管内皮细胞、增加炎症及氧化应激反应等相关。本文综述了Hcy与冠状动脉粥样硬化性心脏病关系的研究进展,希望可以为冠心病的预防、早期诊断及预后评估提供参考。     

Optimization of dietary folate or low-dose folic acid supplements lower homocysteine but do not enhance endothelial function in healthy adults, irrespective of the methylenetetrahydrofolate reductase (C677T) genotype

OBJECTIVES

We sought to study the effect of low-dose folic acid supplementation or optimization of dietary folate intake on plasma homocysteine and endothelial function in healthy adults.

BACKGROUND

Elevated homocysteine is associated with cardiovascular disease, but it is not known whether this relationship is causal. Individuals homozygous (TT) for the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene (12% of the population) have increased homocysteine levels, particularly in association with suboptimal folate intake.

METHODS

Healthy subjects (n = 126; 42 of each MTHFR genotype) were included in this cross-over study of three interventions of four months each: 1) placebo plus natural diet; 2) daily 400-μg folic acid supplement plus natural diet; and 3) increased dietary folate intake to 400 μg/day.

RESULTS

At baseline, homocysteine was inversely related to plasma folate and was higher in TT homozygotes. For the whole group, plasma folate increased by 46% after dietary folate and by 79% after supplementation, with reductions of homocysteine of 14% and 16%, respectively. Within the genotype, TT homozygotes exhibited the most marked changes in these variables. Brachial artery endothelial function, as determined by a change in end-diastolic diameter in response to increased flow, was not changed by increased folate intake (98 ± 73 μm at baseline, 110 ± 69 μm after a high-folate diet, 114 ± 59 μm after supplementation and 118 ± 68 μm after placebo). Plasma von Willebrand factor antigen was unaltered.

CONCLUSIONS

Optimization of dietary folate or low-dose folic acid supplementation reduces plasma homocysteine but does not enhance endothelial function, irrespective of the MTHFR (C667T) genotype.     

An association between the methylenetetrahydrofolate reductase (MTHFR) C677T mutation and inflammation markers related to cardiovascular disease

BACKGROUND: Prospective studies have identified many markers of systemic inflammation that are powerful predictors of future cardiovascular events. The methylenetetrahydrofolate reductase (MTHFR) C677T genotype, a common polymorphism that induces hyperhomocysteinaemia, has been proposed as a genetic risk factor for cardiovascular disease. In this work, we evaluated the relationship between the levels of inflammation markers and MTHFR genotype among cardiovascular disease free subjects of the ATTICA study. METHODS: During 2001-2002, we randomly enrolled for genetic evaluation 574 subjects from Attica region, Greece. In this work, we investigated demographic, lifestyle, clinical, biochemical and genetic information from 322 men (46+/-13 years) and 252 women (45+/-14 years). Among other characteristics, we measured various inflammatory markers levels in relation to C677T MTHFR genotype distribution. RESULTS: The MTHFR genotypes distribution was: homozygous normal (CC) genotype, 41%; heterozygous (CT), 48%; and homozygous mutant (TT) genotype, 11%. C-reactive protein (CRA), fibrinogen, white blood cell (WBC) counts and amyloid-a levels were higher in TT compared to CC and CT genotypes (p<0.01), in both genders, even after controlling for various potential confounders. CONCLUSION: The observed association between markers of systemic inflammation with MTHFR genotype may state a hypothesis for a common pathobiological mechanism between inflammation process and MTHFR, which is a key enzyme in homocysteine (Hcy) metabolism.     

亚甲基四氢叶酸还原酶基因多态性与原发性高血压患者合并冠心病的相关性研究

目的探讨N5,10-亚甲基四氢叶酸还原酶(MTHFR)C677T位点突变与河南豫北地区原发性高血压及其合并冠心病发病的关系。方法选择原发性高血压患者405例为高血压组,高血压合并冠心病患者400例为冠心病组,健康体检者400例为对照组。对3组MTHFR基因C677T多态性进行基因分型。结果冠心病组T等位基因频率和TT基因型频率明显高于高血压组和对照组(P<0.05)。冠心病组TT基因型患者TC和血浆同型半胱氨酸水平明显高于CC+CT基因型(P<0.05)。结论 MTHFR基因C677T多态性与原发性高血压患者冠心病的发生相关。