Gene polymorphisms of homocysteine metabolism-related enzymes in Chinese patients with occlusive coronary artery or cerebral vascular diseases.

The mutations in homocysteine (Hcy) metabolism-related enzyme genes including methylenetetrahydrofolate reductase (MTHFR) C677T, cystathionine beta-synthase (CBS) 844ins68, and methionine synthase (MS) A2756G have been identified as genetic risk factors for thromboembolic events. It has been noticed that these gene mutations have heterogeneous distributions among different ethnic groups or geographic areas. The data on the prevalence of the gene mutations in Chinese population is not yet available. In the present study, we have investigated the frequency of the MTHFR C677T, CBS 844ins68, and MS A2756G mutations in 102 patients with ischemic stroke (IS), 73 patients with myocardial infarction (MI) and 100 healthy controls. The distributive frequencies of the gene variations are as follows: In the IS, MI and control groups, the mutant homozygote for MTHFR C677T is 15 (14.7%), 8 (11.7%) and 16 (16.0%), respectively, and the T allele frequency is 37.7%, 33.6% and 39.5%, respectively; the heterozygote for CBS 844ins68 is 1 (1.0%), 1 (1.4%) and 5 (5.0%), respectively; the heterozygote for MS A2756G is 18 (17.6%), 14 (19.2%) and 17 (17.0%), and the G allele frequency is 8.8%, 11.0% and 9.5%, respectively. The carrier of both MS A2756G and MTHFR C677T (combined mutations) is 14 (12.7%), 8(11.0%) and 12(12.0%), respectively. There is no statistically significant difference between the patient groups and the control group in the frequencies of these single mutation or combined mutations. The heterozygosity of CBS 844ins68 yields an odds ratio (OR) of 0.19 (95% confidence interval (CI) 0.02-1.43) for IS and 0.26 (95% CI 0.03-2.31) for MI. The T allele of MTHFR C677T yields an OR of 0.93 for IS (95% CI 0.62-1.39) and 0.77 for MI (95% CI 0.50-1.21). The G allele of MS A2756G yields an OR of 0.92(95% CI 0.47-1.81) for IS and 1.17 (95% CI 0.58-2.37) for MI. Our results suggest that neither single mutation nor combined mutations in MTHFR C677T, CBS 844ins68 and MS A2756G represent an independent risk factor for increasing IS and coronary artery disease risks in Chinese population. However, CBS 844ins68 may be a protective factor against vascular thromboembolic disease. The prevalence of CBS 844ins68 and MS A2756G in Chinese population is obviously lower than in Western Caucasian population.     

Mutations in the genes regulating methylene tetrahydrofolate reductase (MTHFR C-->T677) and cystathione beta-synthase (CBS G-->A919, CBS T-->c833) are not associated with myocardial infarction in African Americans.

Moderate hyperhomocysteinemia is a putative risk factor for cardiovascular disease. Molecular studies have demonstrated increased plasma homocysteine levels in the presence of DNA mutations in either the methylenetetrahydrofolate reductase (MTHFR) enzyme found in the remethylation pathway or the enzyme cystathione beta-synthase (CBS) of the transsulfuration pathway. To determine whether the mutation C-->T677 in the MTHFR gene or the T-->C833/844ins68 and G-->A919 mutations in the CBS gene are associated with myocardial infarction (MI) in African Americans, DNA was analyzed from samples obtained from a case-control study conducted at a large, inner-city hospital. One-hundred ten African American subjects with a diagnosis of MI and 185 race- and age-matched controls were recruited. Our results demonstrated that 15% of the MI cases were heterozygous for the C-->T677 (MTHFR) mutation, while 1.8% were homozygous. When compared to the controls in which 15% were heterozygous and 2.1% were homozygous, no significant association with MI was observed. In addition, 34% of the cases were heterozygous for the T-->C833 (CBS) mutation while 6% were homozygous. This is compared to 32% and 5% of the controls having the heterozygous and homozygous genotype, respectively. No significant association was observed for the T-->C833 (CBS) mutation among the cases and controls. Although this mutation has no significant association with MI, the prevalence of the heterozygous state was higher than what has been reported for whites (12%). No mutations for G-->A919 (CBS) were detected in the cases or controls. The racial differences of the CBS T-->C833 polymorphism suggest that further investigation into the other areas of the CBS gene is needed.     

Contribution of the cystathionine beta-synthase gene (844ins68) polymorphism to the risk of early-onset venous and arterial occlusive disease and of fasting hyperhomocysteinemia

The frequency of the heterozygous 844ins68 mutation of the cystathionine beta-synthase (CBS) gene and of its association with the homozygous C677T transition of the methylenetetrahydrofolate reductase (MTHFR) gene, plasma fasting tHcy, folate and vitamin B12 levels were evaluated in 309 consecutive patients with objectively diagnosed early-onset venous (n = 200) or arterial thromboembolic disease (n = 109) recruited over 25 months in Milan (North Italy) and Naples (South Italy). The above gene polymorphisms were also evaluated in a population of 787 unmatched controls, 204 of whom--similar to patients for age- and sex-distribution--had fasting tHcy, vitamins and activated protein C resistance measured in their plasma. Moderate fasting hyperhomocysteinemia was detected in 15.5% of patients and in 5.9% of 204 controls (Mantel-Haenszel OR after stratification for type of occlusive disease and gender: 2.88; 1.48-5.32). The frequencies of the 677TT mutation of the MTHFR gene and of the heterozygous 844ins68 insertion of the CBS gene were not significantly different in the patient (19.4% and 6.9%) and the control population (16.5% and 7.8%), but the association of the two gene polymorphisms found in 3.9% of patients and in 1.1% of controls - was significantly associated with an increased risk of venous or arterial occlusive diseases (RR = 3.63; 1.48-8.91). The MTHFR 677TT mutation (RR: 6.92; 3.86-12.4) and its association with the 844ins68 insertion (RR: 21.9; 8.35-57.4), but not the isolated insertion (RR: 0.71), were more frequent in patients and controls with fasting hyperhomocysteinemia than in normohomocysteinemic subjects, irrespective of the type of occlusive disease (venous or arterial). When adjusted for determinants of hyperhomocysteinemia in the patient and the control populations (generalized linear model), fasting tHcy levels were significantly higher in subjects with association of the two gene abnormalities (24.2+/-3.8 micromol/L) than in subjects with the MTHFR 677TT mutation only (14.0+/-5.8 micromol/L, p = 0.004). Activated protein C resistance was significantly more prevalent in venous patients (9.9%) than in controls (3.9%, OR = 2.69; 1.08-6.88). Six of 21 venous patients with APC-resistance also had hyperhomocysteinemia (RR = 5.04; 0.68-37.6), but isolated fasting hyperhomocysteinemia retained statistical significance for the association with venous occlusive disease (RR = 2.84; 1.34-6.01). Heterozygosity for the 844ins68 mutation of the CBS gene is not per se a risk factor for premature arterial and/or venous occlusive diseases. However, when detected in combination with thermolabile MTHFR, it increases by almost 4-fold the risk of occlusive diseases (arterial and/or venous), by increasing the risk and the degree of fasting hyperhomocysteinemia.     

CBS 844ins68, MTHFR TT677 and EPCR 4031ins23 genotypes in patients with deep-vein thrombosis

The role of methylenetetrahydrofolate reductase (MTHFR) TT677 genotype, cystathionine beta-synthase (CBS) 844ins68 mutation and endothelial cell protein C receptor (EPCR) 4031ins23 in the development of deep-vein thrombosis (DVT) was investigated in 300 consecutive DVT patients and 410 healthy blood donors. MTHFR TT677 was found in 40 (13.3%) patients and in 59 (14.4%) controls (OR 0.92; 95% C.I. 0.54-1.41); CBS 844ins68 in 20 (6.7%) patients and in 56 (13.7%) control subjects (OR 0.45; 95% C.I. 0.27-0.77); and the combination of MTHFR TT677 with CBS 844ins68 in 4 (1.3%) patients and in 7 (1.7%) controls (OR 0.78; 95% C.I. 0.23-2.68). Logistic regression analysis did not show a further increase of risk for MTHFR TT677 or CBS 844ins68 in combination with the factor V Leiden or the prothrombin gene G20210A mutations. The EPCR 4031ins23 was observed in 2 patients (0.66%) and none of the controls. In conclusion, MTHFR TT677 does not appear to be an important risk factor for DVT, EPCR 403ins23 seems to be very rare, its role in the development of DVT unclear. A putative protective effect of CBS 844ins68 should be further investigated.     

Cystathionine beta synthase as a risk factor for Alzheimer disease

One of the known risk factors for developing Alzheimer disease (AD) is hyperhomocysteinemia. The latter may result from mutations of the genes coding for three key enzymes involved in homocysteine metabolism (methylenetetrahydrofolate reductase [MTHFR], methionine synthase [MS], and cystathionine beta-synthase [CBS]). Although MTHFR and MS polymorphisms have been shown to be positively associated with AD in some populations, the relationship of the CBS gene with AD remains undefined. In order to evaluate whether AD is associated with CBS gene changes leading to decreased CBS activity and homocysteine accumulation, we genotyped the CBS 844ins68 mutation and VNTR polymorphisms of the CBS gene in 206 AD patients and 186 age-matched controls. A slight increase in both 844ins68 mutation and VNTR allele 19 frequencies was detected in the whole AD patient group, compared with controls. The division of AD patients and controls into three age-at-onset/age dependent subgroups (<65 years, 65-74 years, > 75 years) revealed that the 844ins68 mutation and VNTR allele 19 are independent risk factors for AD development in subjects aged 75 years or more.     

Genetic determinants of fasting and post-methionine hyperhomocysteinemia in patients with retinal vein occlusion

INTRODUCTION: Moderate hyperhomocysteinemia is considered a risk factor for both venous and arterial thrombosis. A prevalence of up to 30% of fasting hyperhomocysteinemia has been recently reported in patients with retinal vein occlusion (RVO) whereas conflicting data exist on the role of C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene as a risk factor for RVO. No report has been published on cystathionine beta-synthase (CBS) 844ins68 polymorphism (another genetic determinant of blood Hcy levels) in RVO patients. Moreover, scarce information is available on the usefulness of measuring homocysteine also after methionine loading to increase the diagnostic efficacy of hyperhomocysteinemia in RVO patients. MATERIALS AND METHODS: In 55 consecutive patients with diagnosis of RVO and 65 matched controls, plasma fasting total homocysteine (Hcy) levels and CBS and MTHFR polymorphisms were evaluated. In patients with normal fasting Hcy levels, post-methionine Hcy levels were determined. RESULTS: Moderate fasting hyperhomocysteinemia was detected in 18/55 patients (32.7%). In the remaining 37 patients, Hcy was measured again post-methionine loading (PML). Only 3/37 (8.1%) patients had PML hyperhomocysteinemia. Thus, the total prevalence of moderate hyperhomocysteinemia in this cohort of RVO patients was 21/55 (38.2%). The prevalence of homozygosity for C677T MTHFR genotype, but not that of heterozygosity for CBS844ins68, was significantly higher in RVO patients than in controls. CONCLUSIONS: Differently from what has been reported for arterial and/or venous thrombosis, a single fasting Hcy measurement is able to detect most of RVO patients (85.7%) with moderate hyperhomocysteinemia. C677T MTHFR, but not CBS 844ins68, genotype may play a role as risk factor for RVO.     

胱硫醚-β-合成酶基因突变与有家族聚集现象脑血管病关系探讨

目的:探讨胱硫醚-β-合成酶(CBS)基因突变与有家族聚集现象脑血管病的关系,从而探讨不同群体对脑血管病的易感性的差异。方法:采用聚合酶链式反应-单链构象多态性分析法(PCR—SSCP)分析25个有家族聚集现象的脑血管病家系成员CBS基因C699T、C1080T突变;扩增阻滞突变系统分析法(AMRS)分析CBS基因T833C突变。结果:①、脑血管病组(包括有家族聚集现象的脑血管病组)的CBS基因C699T突变频率均高于对照组。②、有家族聚集现象的脑血管病组的CBS基因T833C突变频率较散发性脑血管病组有增高的趋势,有家族聚集现象的脑梗死组中患者和Ⅰ级亲属的CBS基因T833C突变频率高于Ⅱ、Ⅲ级亲属;脑血管病组(包括有家族聚集现象的脑血管病组)的CBS基因T833C突变频率均高于对照组。③、有家族聚集现象的脑血管病组的CBS基因C1080T突变频率高于散发性脑血管病组,有家族聚集现象的脑血管病组中患者和Ⅰ级亲属的CBS基因C1080T突变频率高于Ⅱ＼Ⅲ级亲属;脑血管病组(包括有家族聚集现象的脑血管病组)的CBS基因C1080T突变频率均高于对照组。结论:有家族聚集现象的脑血管病可能与CBSC699T、CBSC1080T、CBST833C基因突变有关。     

Intermediate and severe hyperhomocysteinemia with thrombosis: a study of genetic determinants

Hyperhomocysteinemia is an independent risk factor for cardiovascular disease. In search of genetic factors causing elevated levels of total homocysteine in plasma (tHcy), we investigated a cohort of consecutively identified, unrelated thrombosis patients (n = 28) having intermediate or severe hyperhomocysteinemia (30 micromol/l 100 micromol/l, respectively). The methylene-tetrahydrofolate reductase (MTHFR) 677C-->T genotype, and the complete cystathionine beta-synthase (CBS) genotype was determined in all patients. We found that the MTHFR T/T genotype was strongly correlated with intermediate hyperhomocysteinemia, being present in 73.9% of those cases (17 of 23). In three of five patients with severe hyperhomocysteinemia, compound heterozygosity for CBS mutations was detected. Among the mutations, two novel missense mutations: 1265C-->T (S422L) and 1397C-->T (S466L) were detected. The phenotype in those patients was quite mild, thromboembolism apart. This indicates that a search for CBS mutations in patients with severe hyperhomocysteinemia is important to ensure the detection of a possible CBS deficiency, thus enabling treatment. Co-existence of the MTHFR T/T genotype and the common CBS 844ins68 variant was significantly higher among patients (10.7%) as compared to controls (1.2%), indicating that this genotype combination is a thrombotic risk factor (P <0.05). In a few patients, hyperhomocysteinemia could not be explained by this genetic approach, suggesting that other genetic risk factors were implicated.     

Cystathionine β-synthase T833C/844INS68 polymorphism: a family-based study on mentally retarded children

Background  

Cystathionine β-synthase (CBS) mediates conversion of homocysteine to cystathionine and deficiency in enzyme activity may lead to hyperhomocysteinemia/homocystinuria, which are often associated with mental retardation (MR). A large number of polymorphisms have been reported in the CBS gene, some of which impair its activity and among these, a T833C polymorphism in cis with a 68 bp insertion at 844 in the exon 8 is found to be associated with mild hyperhomocysteinemia in different ethnic groups.     

Polymorphisms of genes controlling homocysteine/folate metabolism and cognitive function

Elevated concentrations of the amino acid homocysteine and/or folate deficiency have been reported to affect neural development/function in both human patients and animal models. We have investigated the distribution of functional polymorphisms in genes involved in homocysteine/folate metabolism in children with high IQ and in children with average IQ. No differences in the frequencies of genetic variants in the methionine synthase or methylenetetrahydrofolate reductase genes were found. However, the cystathionine beta-synthase (CBS) 844ins68 allele was significantly underrepresented in children with high IQ. The mechanism by which a functional genetic variant in the CBS gene may influence cognitive function remains to be determined.     

Plasma homocysteine, MTHFR C677T, CBS 844ins68bp, and MTHFD1 G1958A polymorphisms in spontaneous cervical artery dissections

Abstract. Mild hyperhomocysteinemia is a probable risk factor for atherosclerotic diseases and stroke. Recently, associations of elevated plasma homocysteine concentrations in the acute phase and of MTHFR 677 TT genotype with spontaneous cervical artery dissections (sCAD) have been reported. The purpose of this study was to test this hypothesis in the currently largest sample of patients with sCAD, taking into account known factors influencing plasma homocysteine levels. Ninety-five patients with past sCAD were compared with 95 age- and sex-matched healthy individuals. Homocysteine, vitamin B6, B12, folate, and polymorphisms of methylenetetrahydrofolate reductase (MTHFR C677T), cystathionine -synthase (CBS 844ins68bp) and methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase (MTHFD1 G1958A) were assessed and any associations were analysed using multivariate statistics. The occurrence of sCAD was associated with elevated homocysteine levels with an odds ratio of 1.327 per 20 % percentile. Homocysteine levels were influenced by gender, smoking status, occurrence of hypertension, vitamin B12 and folate levels, and by the MTHFR TT genotype. MTHFR, CBS 844ins68bp, and MTHFD1 G1958A genotype were not independently associated with the occurrence of sCAD. These data suggest that elevated homocysteine is associated with the occurrence of sCAD. The MTHFR C677T polymorphism is associated with the homocysteine level.     

胱硫醚β合酶基因T833C多态及血浆同型半胱氨酸水平与缺血性脑血管病的相关性

目的 探讨血浆同型半胱氨酸(Hcy)水平、胱硫醚β合酶(CBS)基因T833C多态与缺血性脑血管病(ICVD)的相关性.方法 应用高效液相色谱仪-FD法和扩增阻滞突变体系法(ARMS)检测360例ICVD患者和210名健康体检者的血浆Hcy水平和CBS T833C基因型,并进行相关分析.结果 ICVD组和对照组空腹血浆Hcy浓度分别为(17.6±4.8)μmol/L和(13.3±4.3)μmol/L,差异有统计学意义(t=10.716,P<0.05).ICVD组CBS基因第833位点T/T、T/C、C/C和基因型频率与对照组比较差异无统计学意义(χ2=o.785,P>0.05),C等位基因频率与对照组差异也无统计学意义(χ2=0.941,P>0.05).ICVD组各亚组CBS基因第833位点T/T和T/C+C/C基因型频率比较差异无统计学意义(χ2=1.691,P>0.05),C等位基因频率比较差异也无统计学意义(χ2=1.617,P>0.05).CBS T833C不同基因型之间血浆Hcy水平不同(F=6.56,P<0.05),TC、CC基因型组血浆Hcy水平明显高于TT基因型组,TC、CC基因型组间血浆Hcy水平差异无统计学意义.结论 血浆Hcy水平升高可能为ICVD的危险因素,CBS T833C基因多态可能不是ICVD的独立危险因子.     

FXII (46C-->T) polymorphism and in vivo generation of FXII activity--gene frequencies and relationship in patients with coronary artery disease.

Increased Factor XIIa concentrations have been found in association with coronary artery disease. Recently, a common 46 C to T point mutation in exon I of the factor XII gene has been described which is associated with lower FXII clotting activity and lower zymogen levels in relation to possession of the T allele. It is not known whether this polymorphism relates to the phenotypes of FXIIa in vivo or to coronary artery disease. The aim of the study was to investigate the interaction of this polymorphism with FXIIa plasma levels and to study the prevalence of the polymorphism in 266 patients with suspected coronary artery disease characterised by angiography and in 185 healthy controls. FXIIa levels were strongly associated with FXII genotype with lower levels with increasing numbers of T alleles (p <0.0001). There was no difference between the prevalence of this polymorphism in patients with M1 compared to those without MI and controls and between all patients and controls (p > or =0.2, chi-square test). There was no association between extent of coronary artery disease (0, 1, 2, and 3 vessel disease) and FXII genotype. In conclusion, the common 46 C to T point mutation is strongly associated with FXIIa but the present study did not show an association with coronary artery disease. The role of this polymorphism in other thrombotic disorders such as ischemic stroke and venous thrombosis and its clinical significance in FXII deficient states remains to be investigated.     

Sequence variations within the genes related to hemostatic imbalance and their impact on coronary artery disease in Turkish population

Coronary artery disease (CAD) is reported to be associated with some genetic risk factors. Since identification of genetic risk factors for CAD in different ethnic groups is important for the development of new intervention and prevention programs, we investigated the association between the R353Q and -323ins10 polymorphisms in Factor VII gene, C677T mutation in MTHFR, Factor V Leiden and PT G20210A mutations and CAD in Turkish population. The promoter region of the PAI-1 gene was also screened by SSCA (single-stranded conformation analysis) using specifically designed primers. 137 CAD patients with early onset documented by coronary angiography and 41 individuals who had no significant coronary stenosis by angiography as control group were screened for the identification of the polymorphisms. In conclusion, Factor V Leiden was found to be an independent genetic risk factor for CAD in Turkish population. Combined risk assessment indicated that the coexistence of two other inherited thrombophilia markers, namely MTHFR C677T and PT G20210A with Factor V Leiden may increase the risk of the development of the disease in this population. The results of the present study show that there is no statistically significant association between the two polymorphisms in Factor VII gene, MTHFR C677T polymorphism, PT G20210A polymorphism, 4G/5G polymorphism of PAI-1 and CAD in Turkish population.     

Hyperhomocysteinemia

Despite the increasing incidence of cervical artery dissection (CAD) due to chiropractic manipulation of the cervical spine, risk factors predisposing to vascular damage are still unknown. In the present study we measured fasting total plasma homocysteine (tHcy) concentration in 4 subjects with manipulation-related CAD selected from a larger series of patients with spontaneous dissection of the neck arteries (sCAD) and in a group of 36 control subjects. C677T MTHFR genotypes and 844ins68bp CBS genotypes were also determined. Median tHcy levels were significantly (P = 0.002) higher in patients with manipulation-related CAD (18.2 micromol/l, range 14.3 to 30.0) compared with controls (8.9 micromol/l, range 5 to 17.3) and not significantly different (P = 0.129) from those observed in patients with sCAD (13.9 micromol/l, range 7 to 32.8). No significant difference in the distribution of genotypes was observed in the three groups. Hyperhomocysteinemia may represent a potential risk factor for manipulation-related CAD, leading to structural abnormalities of the arterial wall and increasing the susceptibility to mechanical stress.     

胱硫醚β合酶基因突变在脑梗死患者轻度血管性认知功能障碍中的相关性研究

目的研究同型半胱氨酸(homocystine,Hcy)代谢基因胱硫醚β合酶(cystathionineβsynthase,CBS)基因T833C突变在急性脑梗死后轻度血管性认知功能障碍(vascular cognitve impairment,VCI)中的价值研究。方法采用扩增阻滞突变体系法检测CBS T833C基因型,对急性脑梗死分别行入院时、14 d、30 d和90 d时蒙特利尔认知评估量表(Montreal Cognitive Assessment,Mo CA)和简易精神状态量表(Mini-Mental State Examination,MMSE)评分。结果 Logistic回归分析显示Hcy可能是轻度VCI的独立危险因素(OR为1.274;95%CI 1.027~1.264,P=0.018);空腹高同型半胱氨酸血症(Hhcy)组14 d、30 d和90 d MMSE和Mo CA评分分别低于Hcy水平正常组(P0.01或0.05);各基因型入院时MMSE和Mo CA评分无差别(P0.05),而入院14 d时,C/C型MMSE和Mo CA评分低于T/T型(P0.05),随访30 d和90 d时,C/C型MMSE和Mo CA评分趋势是低于C/T和T/T型(P0.01或0.05),C/T型低于T/T型(P0.01或0.05)。结论 CBS T833C基因突变可能是引起Hhcy,间接促进了脑梗死患者VCI事件的出现,可能是VCI的遗传易感因素。     

Influence of endothelial nitric oxide synthase gene polymorphisms (-786T>C, 4a4b, 894G>T) in Korean patients with coronary artery disease

INTRODUCTION: Endothelium-derived nitric oxide (NO) is synthesized from l-arginine by endothelial nitric oxide synthase (eNOS) encoded by the eNOS3 gene on chromosome 7. The effects of the eNOS polymorphisms with the risk of coronary artery disease are conflicting. In this study, we investigated the association of the eNOS genotypes with coronary artery disease in Koreans. MATERIALS AND METHODS: A case-control study was performed to evaluate the association between the eNOS -786T>C, 4a4b, or 894G>T polymorphism and coronary artery disease. 147 consecutive patients with coronary artery disease and 222 healthy controls were recruited. The genotypes of eNOS -786T>C and 894G>T polymorphisms were determined by the polymerase chain reaction-restriction fragment length polymorphism analysis. The genotypes of a 27 bp insertion/deletion in intron 4 (eNOS 4a4b) were determined by the banding pattern on gel electrophoresis. RESULTS: The eNOS -786T>C (odds ratio [OR]; 1.61, 95% confidence interval [CI]; 0.97-2.69), 894G>T (OR; 1.12, 95% CI; 0.65-1.92) and 4a4b (OR; 1.44, 95% CI; 0.87-2.39) polymorphisms were not an independent predisposition factor to coronary artery disease. However, a subgroup analysis adjusted with various cardiovascular risk factors confirmed positive association of the -786T>C polymorphism in CAD patients with hypertension and a smoking history and also a significant association of the intron 4 genotypes with a smoking history, but no significance has been found in the eNOS polymorphisms of 894G>T upon any risk adjustment. In this study we also found that the distribution of heterozygotes (-786TC, 894GT, and 4a4b) and variant homozygotes for the -786C, 894T, and intron 4a alleles of eNOS in Koreans were significantly lower than in Caucasian populations. CONCLUSIONS: The present study demonstrates that polymorphisms of the eNOS -786T>C and 4a4b are associated with coronary artery disease with adjustments for cardiovascular risk factors in the Koreans.     

High prevalence of the I278T mutation of the human cystathionine beta-synthase detected by a novel screening application.

Classical homocystinuria due to cystathionine beta-synthase deficiency is one of the disorders revealing a high risk of thromboembolic events and vascular disease. This autosomal-recessively inherited metabolic disorder is considered to be rare with an estimated prevalence of 1:130,000 in the German population. In this study, we developed a novel multiplex PCR generating allele specific fragment lengths to analyse individual genotypes of the two most frequent cystathionine beta-synthase alterations, the I278T mutation, which is worldwide found on up to the half of homocystinuric alleles, and the adjacent polymorphism 844ins68. Screening of 200 unrelated German control subjects revealed a frequency of heterozygosity of 1.5% for 1278T corresponding to a calculated frequency of homozygosity of 1:17.800. Our data indicate that homocystinuria due to cystathionine beta-synthase deficiency is a frequently unrecognized disorder resulting in a high risk of thromboembolic events.     

Prevalence of three common polymorphisms in the A-subunit gene of factor XIII in patients with coronary artery disease

Activated blood coagulation factor XIII has an important role in the final stage of the clotting cascade by the covalent crosslinking of alpha- and gamma-fibrin chains. We have recently shown that a functional polymorphism in exon 2. codon 34 of the FXIII A-subunit gene is protective against myocardial infarction. To investigate the prevalence of three other common point mutations in the A-subunit gene (codon 564, C to T, 650 G to A and 651 G to C) and their association with FXIII activity and antigen levels, 275 patients with coronary artery disease and 196 controls were studied. There was no difference in the prevalence of the polymorphisms between patients and controls or between patients with or without MI. Only genotype at codon 564 was associated with FXIII activity with lower activities in subjects possessing the T allele. There was evidence of linkage disequilibrium between codon 34 and codon 564. These results suggest that FXIIIVal34Leu is the only common polymorphism in the coding region of the A-subunit gene of FXIII associated with coronary artery disease.     

MTHFR、CBS基因多态性与脑血管病的相关性研究

目的 研究MTHFR、CBS基因多态性与脑血管病的遗传相关性。方法采用限制性内切酶片段长度多态性方法，对54例脑梗死、27例脑出血及96例健康人MTHFR基因C677T、CBS基因T27796C多态性位点进行检测。结果MTHFR C677T位点与脑梗死及脑出血均有显著相关，两组与对照组之间T／C等位基因频率存在差异。TT型携带者较CC型患脑血管病的风险高。CBS T27796C位点与脑血管病无明显相关。结论 MTHFR基因可能是脑血管病的一个易感基因。CBS基因T27796C多态性位点与脑血管病无明显相关。