亚甲基四氢叶酸还原酶基因多态性对同型半胱氨酸水平及脑梗死的影响

目的　探讨 5 ,10 亚甲基四氢叶酸还原酶 (MTHFR)基因多态性对同型半胱氨酸 (homocysteine,Hcy)水平的影响及与脑梗死发病的关系。方法　选取年龄、性别匹配的脑梗死患者 97例 (脑梗死组 ) ,对照组 94例 ,测定空腹血浆Hcy浓度 ,采用限制性内切片段多态性分析法检测MTHFR基因两个位点的基因表型。结果　Hcy水平在脑梗死组与对照组的分布有显著性差异 [( 2 7.4 2± 34.91) μmoL Lvs( 13.82± 12 .18) μmoL L ,P <0 .0 0 1]。C6 77T位点突变对Hcy有影响 ,其中以TT表型者Hcy水平最高 ,A12 98C位点突变对Hcy无影响 ;logistic回归分析表明 ,C6 77T突变者患脑梗死的OR =1.87。结论　MTHFR基因C6 77T位点多态性与脑梗死的发生相关 ,显著影响Hcy水平 ,可能是脑梗死的一项独立遗传危险因素     

脑梗死患者5,10-亚甲基四氢叶酸还原酶基因位点多态性的研究

目的　研究脑梗死患者同型半胱氨酸代谢相关酶亚甲基四氢叶酸还原酶两个常见位点的突变。方法　选取年龄、性别匹配的病例组 6 1人 ,对照组 86人 ,采用聚合酶链反应 限制片段长度多态性技术进行基因分型。结果　C6 77T位点突变中T等位基因在病例组的分布明显高于对照组 ;A12 98C位点突变中C等位基因的频率在两组间差异无显著性意义 ;具有 3个突变等位基因的杂合子 6 77TT 12 98AC在两组间分布差异有显著性意义。结论　发现C6 77T与A12 98C突变都与脑梗死的发生有关 ,尤其当两个突变叠加产生 6 77TT 12 98AC表型时 ,这种相关性更加明显。     

血浆叶酸、同型半胱氨酸水平及亚甲基四氢叶酸还原酶基因突变与静脉血栓栓塞症

目的 探讨血浆叶酸、同型半胱氨酸(Hcy)水平及亚甲基四氢叶酸还原酶(MTHFR)基因突变与静脉血栓栓塞症(VTE)的关系及MTHFR基因突变对血浆叶酸、Hcy水平的影响。方法 采用病例对照研究,对58例既往确诊为VTE(VTE组)的患者及与其性别、年龄相匹配的58例健康对照者(健康对照组)行流行病学调查,高效液相色谱分析法测血浆中Hcy、蛋氨酸和半胱氨酸水平,放射免疫法测血浆中叶酸水平,PCR-限制性片段长度多态性(RFLP)法测MTHFR C677T基因型。结果吸烟、高血压、糖尿病等危险因素均与VTE无关。血浆Hcy和叶酸浓度在2组间有明显差异(P<0.05)。多变量logistic回归分析显示,Hcy和叶酸浓度是影响VTE的独立因素(OR=1.5,95％CI为1.216～2.213;OR=0.396,95％CI为0.149-0.709)。MTHFR C667T基因突变在2组间差异无显著性(P>0.05)。血浆叶酸浓度与血浆Hcy浓度有明显关联(偏相关系数为-2.061,P<0.05)。MTHFR C667T。基因突变虽然与血浆Hcy浓度无关,但与血浆叶酸浓度相关(偏相关系数为0.5856,P<0.01)。结论 高同型半胱氨酸血症和叶酸缺乏是VTE独立的危险因素,叶酸缺乏是造成高同型半胱氨酸血症的原因之一,MTHFlR C667T基因突变可能是造成叶酸缺乏的遗传因素之一。     

Association of elevated homocysteine levels with a higher risk of recurrent coronary events and mortality in patients with acute myocardial infarction

BACKGROUND: Despite the prothrombotic and proinflammatory effects associated with elevated homocysteine levels, only limited data exist regarding the effect of homocysteine levels on outcome of patients with acute myocardial infarction. METHODS: Homocysteine levels were determined within 24 hours of presentation in 157 consecutive patients with acute myocardial infarction. Patients were allocated to 2 groups: those with homocysteine levels of 2.7 mg/L (20 micro mol/L) or more (n = 22 [14%]) and those with homocysteine levels of less than 2.7 mg/L (n = 135 [86%]). RESULTS: Female and diabetic patients had significantly lower homocysteine levels than males (P<.01) and nondiabetic patients (P =.005), respectively, with no significant correlation with age (r = 0.07, P =.42) or other risk factors. Patients with homocysteine levels greater than or equal to 2.7 mg/L and less than 2.7 mg/L did not differ significantly regarding extent of coronary artery disease as reflected by prevalence of multivessel disease (54% vs 61%; P =.87), and their in-hospital course. However, in a mean +/-SD follow-up of 30 +/- 10 months, patients with homocysteine levels greater than or equal to 2.7 mg/L had a higher incidence of recurrent coronary events (36% vs 17%; P =.04) and death (18% vs 5%; P<.05). Homocysteine levels greater than or equal to 2.7 mg/L remain a significant determinant of recurrent coronary event and/or death after controlling for potential cofounders by multivariate analysis (odds ratio, 3.8; 95% confidence interval, 1.3-11.0). CONCLUSIONS: In patients with acute myocardial infarction, elevated homocysteine levels are associated with a higher risk of recurrent coronary events and death, independent of other risk factors and the extent of coronary artery disease.     

Association study of CD14 polymorphism with myocardial infarction in a Japanese population

There have been many studies investigating the association between gene polymorphisms and coronary artery disease (CAD) including myocardial infarction (MI), and some studies have shown that certain gene polymorphisms are associated with CAD/MI. However, the results of the association have sometimes been controversial. The reason may be that the contribution of genetic risk factors to CAD/MI varies depending on the ethnic, environmental, and habitual backgrounds, and differs between males and females. In this study, we analyzed 17 polymorphisms in 12 candidate genes for MI in 136 patients and 200 to 235 controls, and found that there is a significant association of MI with the polymorphisms in the genes for E-selectin and CD14 receptor. To further explore the association, we investigated the C-260 T polymorphism in the promoter region of the CD14 gene in 502 MI patients and 527 control subjects. The genotype distributions of the CD14 polymorphism were as follows: patients; T/T 32.5%, C/T 48.2%, C/C 19.3%, and controls; T/T 25.4%, C/T 52.8%, C/C 21.8%. The frequencies of the T/T homozygotes were significantly higher in the patients (OR = 1.41, P = 0.013) than in the control group, confirming the association of CD14 polymorphism with MI in Japanese. Stratification analyses further demonstrated that the association was more prominent in females and in patients with a relatively low body mass index, suggesting that the contribution of the CD14-linked genetic risk to MI differs with respect to gender and habitual background.     

Plasma level of homocysteine is correlated to extracranial carotid-artery atherosclerosis in non-hypertensive Japanese

BACKGROUND: Results of some epidemiologic studies in Western countries have clarified that hyperhomocysteinemia is a plausible risk factor for atherosclerotic vascular disease, but its role in Japanese communities is not known. DESIGN: A community-based cross-sectional design. METHODS: We performed a cross-sectional study of 474 elderly men aged 60-74 years in two Japanese rural communities (Noichi in southwestern Japan and Ikawa in northeastern Japan). We examined the association between plasma concentrations of homocysteine and the maximum intima-media thickness (assessed by ultrasonography). RESULTS: The prevalence of thickening was 10.7% for the lowest tertile of homocysteine level and 21.1% for the highest tertile. For the subjects without hypertension, the odds ratio for having carotid intima-media thickening was 5.8; it was significantly higher for the highest tertile of homocysteine level than it was for the lowest after adjusting for age, hypercholesterolemia, hypoalphalipoproteinemia, diabetes, and smoking by using a multiple logistic regression model. However, its correlation was not evident for those with hypertension. CONCLUSIONS: High levels of plasma homocysteine are correlated to extracranial carotid artery atherosclerosis in elderly men without hypertension in Japanese rural communities.     

Influence of a methionine synthase (D919G) polymorphism on plasma homocysteine and folate levels and relation to risk of myocardial infarction

Methionine synthase (MS) encodes an enzyme that catalyzes the remethylation of homocysteine to methionine using a methyl group donated by 5-methyltetrahydrofolate, which is the major circulating form of folate in the body. Functional genetic variants of the MS may alter total homocysteine (tHcy) as well as folate levels which are independent risk factors for vascular disease. The influence of a common genetic polymorphism (2756A-->G, D919G) of the MS gene on plasma tHcy and folate levels and its relation to the risk of myocardial infarction (MI) in a prospective study of male physicians in the US was investigated. A nested case-control study was conducted within the Physicians' Health Study which was originally designed as a double-blind trial of aspirin and beta-carotene among 22071 US male physicians, aged 40-84 years in 1982. Sixty-eight percent of participants also donated a blood sample. The study included 387 incident MI case and 767 controls matched on age, smoking status, and time from randomization in 6-month intervals. Individuals with GG genotype had a non-significant reduction of MI risk (RR 0.51, 95% CI 0.17-1.16) compared to individuals with DD genotype after adjusting for MI risk factors. The MS polymorphism was associated with decreased tHcy (10.55, 9.87 and 9.57 nmol/ml for DD, DG and GG genotypes, respectively) and increased folate levels (3.95, 3.78, 7.31 ng/ml for DD, DG and GG genotypes, respectively) only among controls but not cases. It was concluded that influence of the MS (D919G) polymorphism on the plasma tHcy and folate levels is at most moderate, but should be further investigated in other large prospective studies.     

Lipoprotein lipase gene HindIII polymorphism and risk of myocardial infarction in South Indian population

IntroductionStudies have reported an association between lipoprotein lipase (LPL) gene and myocardial infarction in some populations. Therefore, the present study aimed to investigate the association of the HindIII polymorphism of the (LPL) gene with myocardial infarction and to explore its potential role in susceptibility in a South Indian population.Subjects and methodsWe included a total of 412 subjects (202 myocardial infarction patients and 210 age- and sex-matched controls). Demographic and clinical characteristics were collected. Lipid profiles were estimated. DNA was isolated and the LPL gene HindIII polymorphism was determined by polymerase chain reaction.ResultsComparison of the lipid profiles between patients and controls showed that patients had statistically high significant values (p = 0.0001). The H⁺ H⁺ genotype of the LPL gene is associated with myocardial infarction. H⁺ H⁺ vs. H^? H^? was χ2 = 19.4, OR 3.1, CI 95% 1.8–5.2, p < 0.0001.ConclusionOur study strongly suggests that the LPL gene HindIII Hþ Hþ genotype is an independent risk factor for first MI.     

Does the polymorphism 677C-T of the 5,10-methylenetetrahydrofolate reductase gene contribute to homocysteine-related vascular disease?

Whether the 677C-T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene acts as a risk factor for homocysteine-related vascular disease remains a matter of debate. Testing for the 677C-T nucleotide substitution and assay of plasma homocysteine were carried out simultaneously in 69 controls and 113 vascular disease patients from the Paris area. The variant gene frequency as well as the variant homozygous genotype frequency were very similar in controls and patients. Conversely, plasma homocysteine levels were substantially higher in patients than in controls. A slight interaction between the 677C-T MTHFR polymorphism and homocysteinaemia was observed in the patient group only, while a negative correlation between fasting homocysteine and plasma folate levels was found in all individuals homozygous for the 677C-T MTHFR genotype, irrespective of vascular disease. These data suggest that the 677C-T MTHFR polymorphism is not a major determinant of the vascular disease but contributes to increased plasma homocysteine concentration in conjunction with low plasma folate levels.     

Lipoprotein lipase gene polymorphism, cholesterol subfractions and myocardial infarction in large samples of the general population

OBJECTIVE: Genetic variants of the lipoprotein lipase gene have been associated with dyslipidemia and coronary artery disease. However, data have been inconsistent and are mainly based on selected predominantly male patient groups. METHODS: We evaluated the influence of the HindIII restriction fragment length polymorphism on lipid levels in the general population (1361 participants of a large population-based survey from Augsburg, Germany; 50% women) as well as the association of this polymorphism with the risk of myocardial infarction (MI; genotype frequencies in 1159 patients with documented MI under 60 years of age). RESULTS: In the population-based survey, a highly significant association between the frequent H2H2 genotype and unfavorable cholesterol subfraction levels was observed in men and in postmenopausal women whereas no significant association was observed in premenopausal women (uni- and multivariate analysis). Such unfavorable lipid levels in homozygotes for the H2 allele may be expected to be associated with a 19-25% increased risk to suffer from myocardial infarction (MI). Nevertheless, genotype and allele frequencies in the general population were not different from those in patients with previous MI (H2H2 genotype frequency 51.3% vs. 53.2%, respectively; P=0.63). CONCLUSION: This large study shows that the H2H2 genotype of the lipoprotein lipase gene polymorphism is associated with unfavorable lipid levels. Estrogen status may modulate this association in women. The effects of the genotype on lipid levels were apparently not strong enough to reveal a significant association with MI.     

Association of elevated plasma homocysteine levels with impaired ST-segment resolution after fibrinolytic therapy in acute ST-elevation myocardial infarction

OBJECTIVE: Elevated plasma homocysteine levels are associated with increased intracoronary thrombus burden in acute coronary syndromes. The relationship between plasma homocysteine levels and ST-segment resolution (STR) after fibrinolytic therapy has, however, not been investigated. We sought to investigate this issue. METHODS: Forty-nine patients who were administered fibrinolytic therapy for ST-segment elevation myocardial infarction (STEMI) were included in this study. Maximum STR was measured after 90 min of fibrinolytic therapy. Patients with a maximum STR of less than 50% were included in group 1. Patients with a maximum STR >or=50% were included in group 2. Blood samples were collected from the antecubital vein upon arrival to the hospital. The plasma was separated and kept at -70 degrees C until the time of analysis. Total plasma homocysteine level was determined by the high-performance liquid chromatography method with fluorescence detection. RESULTS: Fifteen patients in group 1 and 34 patients in group 2 were present. Baseline characteristics were similar in both groups. The plasma homocysteine levels were 22.5+/-10 micromol/l in group 1 and 14.1+/-4 micromol/l in group 2 (P<0.001). CONCLUSION: Elevated plasma homocysteine levels are associated with impaired STR after fibrinolytic therapy in acute STEMI.     

Mutations C677T and A1298C of the 5,10-methylenetetrahydrofolate reductase gene and fasting plasma homocysteine levels are not associated with the increased risk of venous thromboembolic disease.

Mild hyperhomocysteinemia is associated with homozygosity for the thermolabile variant of 5,10-methylenetetrahydrofolate reductase (MTHFR) and could increase the risk of venous thromboembolic disease (VTD). Recently, the second A1298C mutation of the MTHFR gene was described. The present study aimed to analyze both mutations of the MTHFR gene and plasma homocysteine levels in subjects with VTD. The study groups comprised 146 patients with VTD and 100 healthy subjects. There were no statistical differences in carrier frequency and allelic frequency for both A1298C and C677T mutations, nor were there any differences encountered between subjects with VTD and controls in either plasma homocysteine levels or according to C677T or A1298C genotypes of MTHFR. In our VTD patients and controls, neither MTHFR 677CT/1298CC nor MTHFR 677TT/1298CC combined genotypes were observed; double heterozygotes (A1298C/C677T) were represented only in 11% of VTD patients, and in 15% of the controls. In conclusion, the polymorphisms C677T and A1298C of MTHFR and fasting plasma homocysteine levels do not seem to be significant risk factors for venous thromboembolic disease.