Association of MTHFR gene polymorphism C677T with susceptibility to late-onset alzheimer’s disease

Increased total plasma homocysteine (t-Hcy) levels are found to be associated with Alzheimer's disease (AD). Because the methylenetetrahydrofolate reductase (MTHFR) gene encodes a key enzyme that influences the metabolism of homocysteine, it has been considered as a possible genetic risk factor for AD. Although the MTHFR gene C677T polymorphism has a significant impact on reducing enzyme activity and increasing t-Hcy concentrations, the association between the C677T polymorphism and AD remains inconclusive. To determine whether the MTHFR gene C677T polymorphism contributes to the risk for late-onset AD (LOAD) in Chinese, we have investigated 104 sporadic LOAD patients and 130 healthy controls. The strong associations of the TT genotype and T-allele with LOAD (p 0.001, OR 5.73 95% CI 1.85-17.72, and p 0.002, OR 1.89 95% CI 1.25-2.86) were found. After stratifying by apolipoprotein E allele 4 (APOE epsilon4) status, increased LOAD risks associated with the TT genotype only in the APOE epsilon4 noncarriers (chi2=8.92, df=1, p=0.003) and with the T-allele in either group (chi2=5.18, df=1, p=0.023 and chi2=5.53, df=1, p=0.019) were seen. These results suggest that as an APOE epsilon4 allele-dependent risk factor, the MTHFR gene C677T polymorphism is involved in developing LOAD in Chinese.     

Evaluation of the interactions of common genetic mutations in stroke subtypes

Objective: Ischemic stroke is a frequent heterogeneous multifactorial disease that is affected by several genetic mutations and environmental factors. We hypothesised the clinical importance of the co-occurrence of common, unfavorable genetic mutations in the development of different stroke subtypes. Method and material: The Factor V Leiden G1691A (Leiden V), the prothrombin G20210A and the methylenetetrahydrofolate reductase C677T (MTHFR C677T) mutations and the angiotensin-converting enzyme I/D (ACE I/D) and apolipoprotein E (APOE) genotypes were examined by the PCR technique in 689 ischemic stroke patients and 652 stroke-free controls. Logistic regression models were used to estimate the relative risks of different stroke subtypes for different genotype combination patterns. Results: The ACE D/D genotype alone or in combination with the MTHFR 677T or the APOE 4 allele or with both was highly specific for small-vessel infarction. The Leiden V mutation alone or in different combination patterns with the ACE D, APOE 4 and MTHFR 677T alleles was specifically predisposed to large-vessel infarction. The APOE 4 allele alone was calculated to be a general, minor genetic risk factor for ischemic stroke. The MTHFR 677T allele alone was not a risk factor for any stroke subtype. In the different specific predisposition gene combinations, however, both the APOE 4 and MTHFR 677T alleles could increase the relative risk of the given stroke subgroup. Conclusions: Common mutations which alone are minor or non-significant risk factors for ischemic stroke can yield, in specific combination patterns, a highly significant, moderate genetic risk of specific stroke subtypes. Received: 5 February 2002, Received in revised form: 17 April 2002, Accepted: 22 April 2002 Correspondence to Dr. Z. Szolnoki, M. D.     

Gene-environment and gene-gene interaction in the determination of plasma homocysteine levels in healthy middle-aged men

Healthy middle-aged men (n = 1,470) from eight general practices across Britain were examined for plasma total homocysteine levels and genotyped for the A222V polymorphism in the methylene-tetrahydrofolate (MTHFR) gene, the 68 bp insertion polymorphism in exon 8 of the cystathionine b synthase (CBS) gene and the D919G polymorphism in the methionine synthase (MS) gene. The median value for plasma homocysteine was 11.90 micromol/l (25-75% Interquartile range 10.10-14.20) for the whole sample. Smokers had significantly higher homocysteine levels than non-smokers (12.90 vs 11.70 micromol/l and p < 0.00005) and levels significantly differed according to folate (p-value < 0.00005), with men in the lowest quartile of folate having the highest median homocysteine levels. Genotype at all three loci was associated with differences in plasma homocysteine level. Individuals homozygous for the MTHFR V222 allele had 1.6 micromol/l higher median homocysteine levels when compared to the other two genotypes (p < 0.00005), while for the CBS and MS genes, individuals carrying one or more of the rare alleles had lower median homocysteine than individuals homozygous for the common allele (0.80 micromol/l, p < 0.03, and 0.70 micromol/l, p < 0.04 respectively). The raising effect associated with homozygosity for the V222 allele was greater in men in the lowest quartile of folate (interaction between folate and genotype p = 0.02), but none of the genotype effects was significantly modulated by B12 levels. While the raising effects of V222 and MS D919 homozygosity on homocysteine level were essentially additive, the homocysteine lowering effect associated with the CBS 68bp allele was seen most strongly in men homozygous for the V222 allele (MTHFR-CBS genotype interaction p = 0.03) and the D919 allele (MS-CBS interaction p = 0.09). Age, folate, B12 and smoking explained 13.48% of the variance while the three genotypes combined and with interaction terms explained only an additional 2.63%. This interaction between CBS genotype and MTHFR and MS genotype points to a key role of the CBS transulphuration pathway in the metabolism of homocysteine that may be particularly important as a compensatory mechanism in subjects with low dietary folate.     

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.     

Homocysteine,apolipoproteine E and methylenetetrahydrofolate reductase in Alzheimer's disease and mild cognitive impairment

BACKGROUND: Alzheimer's disease (AD) is the most common dementia disorder in elderly people. Currently, the only known genetic factor associated with the development of sporadic AD is the apolipoprotein E (ApoE) 4 allele. There is a need to identify other environmental and genetic risk factors that could modulate the risk of developing sporadic AD. OBJECTIVE: To analyse the correlation between the ApoE and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and plasma homocysteine levels and vitamins (B(12) and folic acid) concentrations in serum from patients with AD and mild cognitive impairment (MCI) as compared with control group. METHODS: The study was carried out in 99 AD patients, 98 subjects with MCI and 100 healthy subjects. Diagnosis of probable AD was made according to the NINCDS-ADRDA and DSM-IV criteria. The following factors were analysed: age, gender, duration of disease, concentration of plasma total homocysteine, folic acid and vitamin B(12) in the serum and the polymorphism of MTHRF and ApoE genes. The results obtained were analysed by multivariate analysis of regression. RESULTS: We found that plasma total homocysteine is increased in AD patients (p < 0.0001) and depended on the MTHFR T/T genotype in the presence of low folate levels (p < 0.05). The increased frequency of ApoE4 allele in the AD population was independent of homocysteine, folic acid and vitamin B(12) levels and MTHFR status. CONCLUSIONS: We conclude that the concentration of plasma total homocysteine is increased in AD patients. This may be associated with the T/T genotype in the MTHFR gene; however, the distribution of the MTHRF C677T polymorphism in the Polish population does not differ in AD and controls.     

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.     

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.     

Gene--nutrition interactions in coronary artery disease: correlation between the MTHFR C677T polymorphism and folate and homocysteine status in a Korean population

INTRODUCTION: Elevated plasma total homocysteine is a major risk for coronary artery disease (CAD). Methyltetrahydrofolate reductase (MTHFR) is a main regulatory enzyme in homocysteine metabolism; a common C677T mutation in the MTHFR gene results in decreased enzyme activity, and contributes to increased homocysteine levels and decreased folate levels. We investigated the frequency of MTHFR C677T alleles in a Korean population, determined the genotype-specific threshold levels of folate or vitamin B12, and investigated the relationship between the TT genotype and the risk of CAD. MATERIALS AND METHODS: We enrolled a study population of 163 CAD patients and 50 control subjects, and screened the MTHFR C677T polymorphism using real-time PCR with melting point analysis. Levels of plasma homocysteine, folate and vitamin B12 were also determined. We then defined the genotype-specific threshold values of folate and vitamin B12 required to keep homocysteine levels in a normal range for individuals of each MTHFR C677T genotype. RESULTS: The frequency of the TT genotype was 18% in control subjects and 26% in patients group (P>0.05). Individuals homozygous for the TT genotype had significantly elevated homocysteine levels (P<0.05). The genotype-specific folate threshold level was significantly higher in TT individuals than in the CC or CT genotypes. The OR of individuals with low folate status and the TT genotype to estimate the relative risk of CAD was 2.2 and the OR of those with high folate status and the TT genotype was 1.5 (95% CI, 0.5-9.6 and 0.7-3.2, respectively). CONCLUSION: We were able to define a gene-nutrient interaction that shows a higher risk for CAD based on specific threshold folate levels required by different MTHFR C677T genotypes in a Korean population.     

Prion protein gene M129 allele is a risk factor for Alzheimer’s disease

Summary. Prion protein gene polymorphism M129V represents a known risk factor for Creutzfeldt-Jakob disease. Recently, the meta-analysis revealed that homozygosity at codon 129 is connected with increased risk of Alzheimer’s disease (AD). To determine whether M129V polymorphism is a risk factor for AD we analyzed a group of early-onset, and late-onset Polish AD patients. We observed that in LOAD patients there is a statistically significant increase of MM (p = 0.0028) and decrease of MV (p = 0.0006) genotype frequency, as compared to controls. When both groups were stratified according to APOE4 status, increase of MM and decrease of MV genotype frequency were significant in the LOAD subgroup with no APOE4 (p = 0.017, and p = 0.018, respectively). In the subgroup with APOE4 allele, only MV genotype frequency was significantly lower, as com pared to controls (p = 0.035). However, no interaction was found between APOE4 status and M129V polymorphism. We conclude that MM genotype increases LOAD risk in Polish population independently from the APOE4 status.     

Methylenetetrahydrofolate reductase gene and risk of Alzheimer's disease in Koreans

BACKGROUND: The association between methylenetetrahydrofolate reductase (MTHFR) c.677C>T (A222V) polymorphism and Alzheimer's disease (AD) is controversial. The objectives of the study were to investigate the association between MTHFR c.677C>T polymorphism and AD in Korean elders and to the extent to which it is modified by the major components of one-carbon metabolism and apolipoprotein E (APOE) genotype. METHODS: Seven hundred and thirty-two community residents aged 65 or over were clinically assessed for AD. Genotyping was performed for MTHFR c.677C>T and APOE; serum levels of folate, vitamin B(12), and homocysteine were assayed. Age, gender and education were included as covariates. RESULTS: A trend of association between TT genotype of MTHFR c.677C>T and AD was found [adjusted OR (95% CI): 1.73 (0.80-3.74)]. The association was significant in the presence of below-median vitamin B(12) level [3.66 (1.14-11.71)] and in APOE e4 non-carriers [2.97 (1.00-8.55)] with significant interaction terms, and bordered on significance in the presence of above-median homocysteine level [2.73 (0.94-7.90)]. CONCLUSIONS: These findings suggest gene-environment and gene-gene interactions on the risk of AD in Koreans.     

Association Between Alzheimer’s Disease and the <Emphasis Type="Italic">NOS3</Emphasis> gene Glu298Asp Polymorphism in Chinese

The oxidative stress caused by nitric oxide (NO) in the brain has been proposed as a pathogenic mechanism in Alzheimer’s disease. Endothelial NO synthase (ecNOS) produces the majority of circulating NO. The biological functional and genetic association studies suggested that the Glu298Asp polymorphism of the ecNOS gene (NOS3) may be a genetic risk factor for late-onset Alzheimer’s disease (LOAD). To investigate an association between the NOS31 Glu298Asp polymorphism and sporadic LOAD in Chinese, we examined 338 LOAD patients and 378 healthy controls. The associations of the Glu/Glu genotype and Glu allele with LOAD (χ ² = 9.12, df = 1, P = 0.003 by genotype; χ ² = 8.37, df = 1, P = 0.038 by allele) were found. After stratifying by apolipoprotein E allele 4 (APOE ɛ4) status, increased LOAD risks associated with the Glu/Glu genotype and Glu allele only in the APOE ɛ4 noncarriers (χ ² = 6.28, df = 1, P = 0.012 by genotype; χ ² = 5.62, df = 1, P = 0.018 by allele) were seen. These results suggest that the NOS3 gene Glu298Asp polymorphism might be a risk factor for LOAD and dependent on APOE ɛ4 status in Chinese. Binbin Wang and Sainan Tan contributed equally to the work.     

α1-Antichymotrypsin as a risk modifier for late-onset Alzheimer's disease in Japanese apolipoprotein E ε4 allele carriers

In the Japanese population, sporadic late-onset Alzheimer's disease (LOAD) cases had significantly higher frequencies of the A allele of α₁?antichymotrypsin (ACT) gene as well as the $4 allele of apolipoprotein E (APOE) gene than controls. The odds ratio for LOAD in APOE4 carriers with the ACT-A allele was more than six times that in APOE4 carriers without the ACT-A allele (21.1 vs 3.2). These results indicate that the ACT-A allele is a risk modifier for LOAD in APOE4 carriers.     

Effect of MTHFR Polymorphisms on Hyperhomocysteinemia in Levodopa-treated Parkinsonian Patients

High plasma homocysteine levels have been observed in Parkinson’s disease (PD) patients treated with levodopa. In this study, we investigated the effects of C677T and A1298C MTHFR polymorphisms, in association with l-DOPA daily dose and vitamin status, on hyperhomocysteinemia development in PD patients. Plasma homocysteine and folate/vitamin B12 levels were assayed in 49 l-DOPA-treated PD patients, and compared with those of 86 healthy subjects. Genotyping for MTHFR polymorphisms was carried out by DG-DGGE. Homocysteine levels were significantly higher in patients than in controls (16.3 ± 5.7 vs. 11.7 ± 2.7 μmol/l, P < 0.01). No significant differences were found between patients and controls with regard to folate/vitamin B12 levels, and MTHFR allele distribution. The TT+AA genotype was significantly more frequent in PD patients than in controls (32.5% vs. 17.4%, P < 0.05), but not associated with an increased risk for PD (OR = 2.3, CI = 1.0–5.2). Further, patients carrier of this genotype exhibited a mild hyperhomocysteinemia (22.1 ± 4.9 μmol/l), while a protective effect was observed in patients having the CC+AA genotype (11.2 ± 1.6 μmol/l; OR = 0.19, CI = 0.06–0.59). Interestingly, homocysteine levels were also moderately increased in patients with CT heterozygous genotype, in the context of either AA or AC (14.5 ± 3.6 μmol/l), in comparison to subjects with the CC + AA genotype. Finally, we did not find any significant association of combined C677T and A1298C MTHFR polymorphisms with an increased risk for hyperhomocysteinemia in PD patients. A better understanding of the role of homocysteine and MTHFR genotypes in PD is needed to reveal novel approaches for disease management.     

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.     

The 894G > T (Glu298Asp) Variant in the Endothelial NOS Gene and MTHFR Polymorphisms Influence Homocysteine Levels in Patients with Cognitive Decline

The presence and severity of cerebrovascular pathological findings have been shown to increase the risk and stage of cognitive decline observed in Alzheimer’s disease and vascular dementia. Thus, the modification of vascular risk factors seems useful to reduce the risk of dementia regardless of type. Hyperhomocysteinemia has long been known as a major independent risk factor for vascular dysfunction. In this study, we evaluated the relationships between plasma homocysteine levels and genetic risk factors for hyperhomocysteinemia, i.e., the presence of gene variants for methylenetetrahydrofolate reductase (MTHFR) and endothelial nitric oxide synthase (eNOS) in patients with cognitive impairment. Genotyping for MTHFR C677T and eNOS 894G > T polymorphisms was carried out in 69 patients with probable diagnosis of AD and anamnestic mild cognitive impairment, matched for age and gender with 69 healthy volunteers. Patients with MTHFR TT677 genotype showed higher plasma Hcy levels than controls, even after adjustment for folate levels (P < 0.05). Moreover, Hcy plasma levels were higher in cases than controls for any given eNOS genotype. In particular, the presence of eNOS TT894 genotype in patients with cognitive decline resulted significantly associated with increased plasma Hcy levels when compared with controls having the same genotype or patients having other eNOS genotypes (P = 0.02). These data suggest that both MTHFR C677T and eNOS G894T variants should be regarded as genetic risk factors for hyperhomocysteinemia in patients with cognitive decline.     

SIRT2 polymorphism rs10410544 is associated with Alzheimer's disease in a Han Chinese population

Sirtuin 2 (SIRT2) is a strong protein deacetylase, which is highly expressed in central nervous system. Recently, an association between SIRT2 rs10410544 polymorphism and late-onset Alzheimer's disease (LOAD) was found in the APOEε4-negative Caucasian population. To investigate the potential association between the rs10410544 C/T polymorphism of SIRT2 and the risk of LOAD, we conducted an independent replication case–control study in a Northern Han Chinese population comprising 1133 cases and 1159 healthy controls being matched for age and gender. The results revealed that there were significant differences in genotype and allele frequencies between LOAD cases and controls (genotype P = 0.008, allele P = 0.009). When compared with the C allele, the T allele of rs10410544 demonstrated a 1.709-fold risk for developing LOAD. After stratification by apolipoprotein E (APOE) ε4-carrying status, only APOEε4 noncarriers (P = 0.035, adjusted OR = 1.656, 95% CI: 1.036–2.647) showed the relation between LOAD and SIRT2 rs10410544 T allele. This study provides the evidence that the rs10410544 C/T polymorphism of SIRT2 was associated with genetic susceptibility to LOAD in a Northern Han Chinese population.     

Association of acute ischemic stroke with the MTHFR C677T polymorphism but not with NOS3 gene polymorphisms in a Singapore population

Background and purpose: The association of polymorphisms in the nitric oxide synthase 3 (NOS3) gene (T‐786C, variable number tandem repeats 4A/B/C, and G894T) and in the methylenetetrahydrofolate reductase (MTHFR) gene (C677T) with acute ischemic stroke have been reported. Methods: First‐time onset acute ischemic stroke patients (n = 120) and controls (n = 207) with no past history of stroke were compared. Allele specific gene amplification and restriction fragment length polymorphism (RFLP) analysis were used to determine the genotype and allelic frequencies in both groups. Plasma homocysteine (Hcy) and nitrite levels were measured. Results: No significant association of NOS3 polymorphisms with ischemic stroke was noted. The TT genotype of the MTHFR C677T polymorphism was significantly associated with ischemic stroke (P = 0.004). Elevated plasma Hcy levels were also significantly associated with ischemic stroke (P = 0.001). Conclusions: The TT genotype of C677T polymorphism in the MTHFR gene contributes to genetic susceptibility of acute ischemic stroke in a Singapore population.     

Homocysteine is not associated with global motor or cognitive measures in nondemented older Parkinson's disease patients

Levodopa (L ‐dopa) treatment of Parkinson's disease (PD) is associated with elevated homocysteine (Hcy). To examine the relationship between Hcy, methylenetetrahydrofolate reductase polymorphisms (MTHFR: 677C/T; 1298A/C), and B‐vitamins in older PD patients and whether Hcy or MTHFR polymorphisms were associated with clinical measures. MTHFR polymorphisms, B‐vitamin intake, and blood concentrations of Hcy, vitamin B12 and folate, and creatinine were determined and compared between groups (PD and controls). The relationship of Hcy to clinical measures was examined in PD. Among 51 patients [30M/21F, mean age (SD): 71.5 (4.7)] and 50 controls [29M/21F, 71.5 (4.8)], Hcy was higher in PD [13.6 (3.8); controls: 10.5 (2.5), P < 0.0005]. Hcy was associated with B‐vitamin intake [F = 21.7, P < 0.0005], folate level (R = 0.31, P = 0.035), and the interaction of intake with MTHFR 677T (F = 5.2, P = 0.007), but not MTHFR 1298C genotype. Hcy did not correlate with global measures of cognition, mood, or parkinsonism in PD or with dyskinesias, fluctuations, or freezing. Higher vitamin B12 levels were associated with lower dyskinesia risk. Hcy was influenced by PD, MTHFR 677 genotype, and vitamin use, but not by the MTHFR 1298 genotype. There was no clear association with motor or cognitive measures, but dyskinesias were less likely with higher B12. © 2008 Movement Disorder Society     

MTHFR基因多态性及同型半胱氨酸与青年脑血管病的关系

目的:研究Ns,N10-亚甲基四氢叶酸还原酶(MTHFR)基因多态性及血浆同型半胱氨酸(Hcy)水平与青年脑血管病的关系。方法:研究对比40例青年脑血管病患者(首次发病年龄≤50岁)及32例健康青年人的MTHFR基因多态性及血浆Hcy水平。结果:(1)对照组及病例组T/T纯合子率分别为37.5％和22.5％;T等位基因频率分别为60.9％和51.3％,差异均无显著统计意义(均P>0.05)。(2)病例组血浆Hcy几何均值(11.0±2.3μmol/L)显著高于对照组(8.0±1.4μmol/L,P<0.05)。(3)所有受试者中T/T组Hcy值高于C/C组(10.4μmol/L和7.6μmol/L),但差异无显著性(P>0.05)。结合叶酸考虑,进一步将所有受试者按叶酸中位数水平分组。叶酸中位数以下组中,T/T组Hcy值显著高于C/C组(P<0.05);而叶酸中位数以上组中,T/T组Hcy值与C/C组无显著差异。(4)血浆Hcy与叶酸、维生素B12呈显著负相关,与肌酐呈显著正相关。吸烟者血浆Hcy水平显著高于不吸烟者(P<0.05)。结论:(1)本组人群MTHFR基因C677T突变的纯合子在低叶酸状态下可引起血浆Hcy水平显著增高,但与青年脑血管病无显著关系。MTHFR基因677TT纯合突变可能为健康青年人脑血管的保护因素。(2)血浆Hcy水平与青年脑血管病的发生密切相关。(3)叶酸、维生素B12肌酐、吸烟是Hcy的非遗传影响因素。