MTHFR 677 CT/MTHFR 1298 CC genotypes are associated with increased risk of hypertension in Indians

The goals of our present study were to measure plasma homocysteine levels and determine their association with methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms (C677T and A1298C) in essential hypertensive subjects. Plasma total homocysteine and folic acid levels were measured in essential hypertensive patients (n = 153) before and after oral supplementation with either 5 mg folic acid tablet/day or 5 mg placebo/day for 4 weeks and compared with age and sex matched normotensive controls (n = 133). MTHFR gene polymorphisms (C677T and A1298C) were studied by restriction fragment length polymorphism and correlated with plasma homocysteine levels. Homocysteine levels were significantly higher in hypertensive patients as compared to controls and showed a negative correlation with plasma folate levels. Folic acid supplementation (5 mg/day) for 4 weeks resulted in a significant decrease in plasma homocysteine concentrations in these patients. Patients carrying MTHFR 677T allele (OR = 1.90; 95%CI: 1.14–3.19) or MTHFR 1298C (OR = 2.6, 95%CI: 1.55–4.40) allele were at increased risk of hypertension. The frequency of co-occurrence of MTHFR 677 CT/1298 CC genotypes was significantly higher in the patients compared to controls (P < 0.05) and was associated with increased risk of hypertension (OR = 3.54, 95%CI: 0.37–4.30). Subjects with MTHFR 1298 CC genotype had significantly higher homocysteine levels compared to those with MTHFR 1298 AA genotype (P < 0.05). Our results indicate that MTHFR 677T and 1298C alleles and co-occurrence of MTHFR 677 CT/MTHFR 1298 CC genotypes are associated with increased risk of hypertension and MTHFR 1298 CC genotype is associated with higher homocysteine levels in our subjects.     

Functional inference of the methylenetetrahydrofolate reductase 677 C > T and 1298A > C polymorphisms from a large-scale epidemiological study

Two functional single nucleotide polymorphisms, 677C > T and 1298A > C have been described for the methylenetetrahydrofolate (MTHFR) gene. Both are associated with reduced enzyme activity in vitro. For the 677T, but not the 1298C allele, significantly lower serum folate and higher plasma total homocysteine (tHcy) have been reported. We genotyped 10,034 middle-aged (50–64 years old) subjects and measured serum folate and tHcy. Within strata of 677 genotypes, 1,298 genotypes had significantly different serum folate and tHcy (P ≤ 0.03 for all comparisons). Each additional 1298C allele reduced mean serum folate and increased mean tHcy, by (on average) 4.5 and 3.0%, respectively. In comparison, within strata of 1,298 genotypes, the increase from no, to one 677T-allele reduced serum folate and increased tHcy by, 7.1 and 6.3%, respectively. Lowest serum folate and highest tHcy level was found for the 677TT/1298AA genotype. The difference in tHcy was significantly larger at low folate than at high folate when genotypes 677TT/1298AA and 677CT/1298AA, 677CT/1298AC and 677CC/1298AC, and genotypes 677CT/1298AC and 677CT/1298AA were compared. We interpreted these data in the context of a model of the MTHFR enzyme that describes the enzyme as a dimer that mainly exist in six different configurations. The model reconciled the observed phenotypic effects of the 677/1,298 combination genotypes with previous in vitro measurements, and identified enzyme configurations that are sensitive to low folate levels. In conclusion, this report demonstrates functional inference of the MTHFR 677 C > T and 1,298 A > C polymorphisms from a large-scale epidemiological study.     

5,10‐Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms: genotype frequency and association with homocysteine and folate levels in middle‐southern Italian adults.

Two genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene (C677T and A1298C) can influence the plasma homocysteine (Hcy) levels, especially in the presence of an inadequate folate status. The aim of this study was to evaluate the frequencies of C677T and of A1298C MTHFR polymorphisms and their correlation with Hcy and serum folate concentrations in a population of blood donors living in a region of middle‐southern Italy (the Molise Region). One hundred ninety seven blood donors were studied for total plasma Hcy, serum folate and C677T and A1298C MTHFR genotypes. The frequency of C677T genotypes was 20.8% (CC), 49.8% (CT) and 29.4% (TT); for the A1298C genotypes: 48.7% (AA), 43.7% (AC) and 7.6% (CC). Hcy and serum folate concentrations were significantly different among genotypes of the C677T polymorphism (CC versus CT versus TT: <0.0001 both for Hcy and folate), with Hcy values increasing, and serum folate decreasing, from CC to TT subjects. Regarding to A1298C polymorphism, the difference among genotypes (AA versus AC versus CC; p: 0.026 for Hcy and 0.014 for serum folate), showed an opposite trend for both parameters, with Hcy higher in the wild‐type and lower in the homozygotes and serum folate higher in CC than in AA subjects. In conclusion, we found a high frequency of MTHFR allele associated with high level of Hcy and low levels of folate in an Italian southern population. Copyright © 2013 John Wiley & Sons, Ltd.     

Methylenetetrahydrofolate reductase genotypes and haplotypes associated with susceptibility to colorectal cancer in an eastern Chinese Han population

Methylenetetrahydrofolate reductase (MTHFR) plays an important role in folate metabolism and is involved in DNA synthesis, DNA repair and DNA methylation. The two common functional polymorphisms of MTHFR, C677T and A1298C have been associated with several diseases, including cancer. We made a case-control study to analyze a possible association of MTHFR gene polymorphisms C677T and A1298C with risk for colorectal cancer in an eastern Chinese Han population of 137 patients with a confirmed histopathological diagnosis of CRC and 145 age- and gender-matched controls with no history of cancer. DNA was isolated from peripheral blood samples and the genotypes were determined by PCR-RFLP. The concentrations of folate in plasma were measured by chemiluminescence immunoassay. The MTHFR 677TT genotype had a protective effect against colorectal cancer, with an odds ratio (OR) = 0.467 (95% confidence interval (CI) = 0.225-0.966). The 1298CC genotype was significantly correlated with a reduced risk of colorectal cancer (OR = 0.192; 95%CI = 0.040-0.916). Compared with the MTHFR 677CC and MTHFR 1298 AA genotypes, for individuals who carried both MTHFR 677CC and 1298CC genotypes, the OR of colorectal cancer was 0.103 (95%CI = 0.012-0.900); among individuals who carried both MTHFR 677TT and 1298AC genotypes, the OR for risk of colorectal cancer was 0.169 (95%CI = 0.044-0.654). MTHFR 677TT+CT genotypes had a significantly lower plasma folate concentration than those with the MTHFR 677CC genotype. MTHFR 1298AC+CC genotypes had a lower plasma folate concentration than those with the MTHFR 1298AA genotype (P < 0.05). In conclusion, subjects with the MTHFR 677TT and MTHFR 1298CC genotypes appeared to have a significantly lower risk for colorectal cancer. MTHFR haplotypes 677CC/1298CC and 677TT/1298AC were less common in cases than in controls. These haplotypes, when compared to the most common haplotype 677CC/1298AA, were associated with a decreased risk for colorectal cancer. We conclude that plasma folate level is influenced by MTHFR genotypes.     

MTHFR C677T and A1298C gene polymorphisms and their relation to homocysteine level in Egyptian children with congenital heart diseases

Objective

To investigate the association of combined MTHFR C677T and A1298C gene polymorphisms with congenital heart diseases (CHD) in Egyptian children and their mothers and to determine their effect on homocysteine level in these children.

Material and methods

MTHFR C677T and A1298C polymorphisms were genotyped in 160 Egyptian children (80 patients with CHD and 80 healthy controls) and their mothers using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP), while, homocysteine (Hcy) level was measured optically by enzymatic method.

Results

We found that MTHFR 677TT genotype, T allele, 1298CC genotype, and C allele were associated with 2.61, 2.0, 2.91 and 1.99 fold increased risk of CHD in Egyptian children respectively. Furthermore, the frequencies of MTHFR 1298AC and CC genotypes and C allele significantly increased in mothers with CHD affected children. The homocysteine levels were significantly increased in MTHFR 677TT and 1298CC genotypes in children with CHD.

Conclusions

Our study demonstrated an association of MTHFR A1298C polymorphisms with CHD in Egyptian children and their mothers, while, MTHFR C677T polymorphisms were significantly associated with the risk of CHD in the children only. An association between combined MTHFR A1298C and C677T polymorphisms and CHD was recorded in the children and their mothers. Also, homocysteine levels were significantly increased with both MTHFR 677TT and 1298CC genotypes in Egyptian children with CHD.     

Oxidative stress mediates cardiac fibrosis by enhancing transforming growth factor-beta1 in hypertensive rats

The methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism has been shown to be associated with cardiovascular disease and in patients with end-stage renal disease (ESRD). However, the relationship between MTHFR polymorphisms and cardiovascular disease (CVD) in patients on hemodialysis has not been examined. The aim of this study was to assess the association of polymorphisms of MTHFR gene with homocysteine (Hcy) and intimal medial thickness (IMT) in patients on hemodialysis. We performed case-control study involving107 patients with ESRD and 103 healthy controls. Plasma Hcy was measured in all the subjects and these subjects were genotyped for three MTHFR polymorphisms (C677T, A1298C, and G1793A). We observed significantly higher Hcy levels in patients as compared to controls. The frequency of MTHFR 1298CC genotype was significantly higher in ESRD patients than in controls (21.4% vs. 2.9%); the frequency of the MTHFR C677T genotypes did not differ between groups (26.1% vs. 17.4%). Compound heterozygous MTHFR 677CT/1298AC genotypes showed maximum association with the risk of ESRD (OR: 12.8; 5%CI: 1.64–10.01, P < 0.05). Concurrent occurrence of MTHFR 677CC wild genotype with either 1298CC or 1793GA significantly increased the risk of disease (OR: 7.20; 95%CI: 2.06–2.51, P < 0.001 and OR: 7.60; 95%CI: 1.68–34.35; P < 0.05, respectively). MTHFR 1298CC genotype was associated with higher Hcy levels. IMT was also significantly higher in patients with the 1298CC genotype (P < 0.05). Thus, A1298C polymorphism of MTHFR gene appears to be associated with the severity of carotid atherosclerosis and co-occurrence of MTHFR polymorphisms may be a risk factor for CVD in patients on hemodialysis.     

MTHFR C677T、A1298C基因多态性与老年单纯收缩期高血压患者Hcy、血脂水平的关系研究

摘要 目的：研究5,10-亚甲基四氢叶酸还原酶（MTHFR）C677T、A1298C基因多态性与老年单纯收缩期高血压（ISH）患者同型半胱氨酸（Hcy）、血脂水平的关系。方法：选取2019年3月至2021年3月期间中南大学湘雅医学院附属海口医院全科医学科收治的212例老年ISH患者作为ISH组,以同期体检无高血压老年人120例为对照组。检测两组MTHFR C677T、A1298C基因多态性。收集两组一般资料及血浆Hcy及血脂检查结果。观察MTHFR C677T、A1298C不同基因型的血浆Hcy、血脂水平差异。采用多因素Logistic回归分析老年ISH发生的影响因素。结果：相比于对照组,ISH组MTHFR C677T位点T等位基因频率较高,C等位基因频率较低;ISH组CC基因型频率较低,CT、TT基因型频率较高（P<0.05）。相比于对照组,ISH组A1298C位点C等位基因频率较高,A等位基因频率较低;ISH组A1298C位点AA基因型频率较低,CC、AC基因型频率较高（P<0.05）。MTHFR基因C677T位点不同基因型血浆Hcy、总胆固醇（TC）水平差异具有显著性（P<0.05）。MTHFR基因A1298C位点不同基因型血浆Hcy、TC水平明显差异具有显著性（P<0.05）。血浆Hcy、MTHFR C677T及A1298C基因多态性是老年ISH发生的影响因素（均P<0.05）。结论：MTHFR C677T、A1298C基因多态性与老年ISH患者血浆TC、Hcy水平有关,血浆Hcy、MTHFR C677T及A1298C基因多态性是老年ISH发生的影响因素。     

Genetic determinants of folate status in Central Bohemia

Although several genetic factors have been implicated as determinants of blood folate concentration in various populations, their effect on folate status in the Czech population has not yet been examined. We explored whether blood folate concentrations in healthy Czech population are associated with polymorphisms in 5,10-methylenetetrahydrofolate reductase (MTHFR), folate hydrolase 1 (FOLH1), reduced folate carrier (RFC), and folate receptor (FOLR1) genes. In a cross-sectional study of 591 control subjects we determined genotypes by PCR-RFLP or ARMS-PCR methods, and plasma and erythrocyte folates by MEIA. The effect of different genotypes on folate status was examined by non-parametric tests and by regression analysis. The prevalence of the MTHFR 677C>T, MTHFR 1298A>C, FOLH1 1561C>T, RFC 80G>A and FOLR1 480G>C variant alleles was 0.34, 0.33, 0.05, 0.44 and 0.00, respectively. Only the MTHFR 677C>T variant was significantly associated with plasma folate concentrations (median 14.7, 14.0 and 12.2 nmol/l for the CC, CT and TT genotypes, respectively). Our study showed that among the five studied allelic variants, only the 677C>T polymorphism in the MTHFR gene is a significant genetic determinant of plasma folate concentrations in Czech population.     

Association study between methylenetetrahydrofolate reductase gene polymorphisms and Graves' disease

5,10‐Methylenetetrahydrofolate reductase (MTHFR) catalyzes the metabolism of folate and nucleotides, which are essential for DNA synthesis and methylation. It is highly polymorphic, and its variant genotypes result in lower enzymatic activity and higher plasma homocysteine. Previous studies have provided evidence that a high prevalence of MTHFR gene polymorphisms is frequently detected in patients with autoimmune disease, suggesting a novel genetic association with autoimmune disorders. However, the genetic association between MTHFR and Graves' disease (GD), one of the most common autoimmune diseases, has not been studied. Here, we designed a clinic‐based case–control study including 199 GD cases and 235 healthy controls to examine the associations between three common MTHFR polymorphisms (i.e., C677T, A1298C, and G1793A) and GD. Surprisingly, logistic regression analysis shows MTHFR 677CT + TT genotypes are associated with an approximately 42% reduction in the risk of GD in women (adjusted OR = 0.58, 95% CI = 0.3–0.9), compared to the CC genotype, indicating a significant protective effect of 677CT + TT genotypes. Our result provides epidemiological evidence that MTHFR mutation (C677T) protects women from GD. The protective effect, possibly obtained by influencing DNA methylation, should be confirmed in a large number of cohorts. Copyright © 2010 John Wiley & Sons, Ltd.     

Gene–environment and gene–gene interactions of specific MTHFR,MTR and CBS gene variants in relation to homocysteine in black South Africans

The methylenetetrahydrofolate reductase (MTHFR), cystathione-β-synthase (CBS) and methionine synthase (MTR) genes interact with each other and the environment. These interactions could influence homocysteine (Hcy) and diseases contingent thereon. We determined single nucleotide polymorphisms (SNPs) within these genes, their relationships and interactions with total Hcy concentrations within black South Africans to address the increased prevalence of diseases associated with Hcy. The MTHFR 677 TT and MTR 2756 AA genotypes were associated with higher Hcy concentrations (16.6 and 10.1 μmol/L; p < 0.05) compared to subjects harboring the MTHFR 677 CT/CC and the MTR 2756 AG genotypes (10.5, 9.7 and 9.5 μmol/L, respectively). The investigated CBS genotypes did not influence Hcy. We demonstrated interactions between the area of residence and the CBS T833C/844ins68 genotypes (p = 0.005) so that when harboring the wildtype allele, rural subjects had significantly higher Hcy than their urban counterparts, but when hosting the variant allele the environment made no difference to Hcy. Between the CBS T833C/844ins68 or G9276A and MTHFR C677T genotypes, there were two-way interactions (p = 0.003 and = 0.004, respectively), with regard to Hcy. Subjects harboring the MTHFR 677 TT genotype in combination with the CBS 833 TT/homozygous 844 non-insert or the MTHFR 677 TT genotype in combination with the CBS 9276 GA/GG displayed higher Hcy concentrations.     

年轻母亲叶酸代谢基因多态性与唐氏综合征发生的关系

为探讨年轻母亲叶酸代谢相关基因MTHFR 677C>T、MTRR 66A>G、RFC-1 80G>A和MTR 2756A>G多态性与唐氏综合征(Down syndrome, DS)发生的关系, 采用随机病例-对照研究设计, 应用PCR-RFLP方法检测60例DS患儿的母亲与68例正常生育女性的基因型。经χ² 检验, MTHFR基因T等位基因频率在病例组和对照组中差异有统计学意义(P<0.05), 而MTRR、MTR和 RFC-1等位基因频率差异无统计学意义。Logistic回归分析显示: 携带MTHFR TT基因型的母亲孕育DS患儿的风险显著增加(OR=3.51, 95% CI=1.30~9.46, P<0.05), 而杂合子CT以及CT合并TT基因型与DS发生风险无显著关联; 携带MTRR GG基因型的母亲孕育DS患儿的风险增加3.16倍(OR=3.16, 95% CI=1.20~8.35, P<0.05), 而RFC-1和MTR突变基因型与DS发生风险无显著关联; MTHFR(CT+TT)/MTRR GG、MTHFR (CT+TT)/ RFC-1 AA、MTHFR CC / MTR (AG +GG)、 MTHFR (CT+TT)/MTR AA、MTRR GG/MTR AA和RFC-1 AA / MTR AA联合基因型与DS发生风险显著相关。结果表明, 年轻女性MTHFR 677C>T、MTRR 66A>G位点变异是孕育DS患儿的独立风险因子, 尚不能认为RFC-1 80G>A、MTR 2756A>G多态性与DS发生相关, 而基因与基因多态位点之间存在交互和修饰效应。     

MTHFR 677T is a strong determinant of the degree of hearing loss among Polish males with postlingual sensorineural hearing impairment

Hearing impairment (HI) is the most common sensory handicap. Congenital HI often has a genetic basis, whereas the etiology of nonsyndromic postlingual HI (npHI) usually remains unidentified. Our purpose was to test whether the MTHFR C677T (rs1801133) polymorphism affecting folate metabolism is associated with the occurrence or severity of npHI. We studied rs1801133 genotypes in 647 npHI patients (age <40, sudden sensorineural loss excluded, HI characterized as mean of better ear hearing thresholds for 0.5-8 kHz) and 3273 adult controls from the background population. Genotype distribution among patients and controls was similar, but among male cases (n = 302) we found a dose-dependent correlation of MTHFR 677T with the degree of HI (mean thresholds in dB: 38.8, 44.9, and 53.3, for CC, CT, and TT genotypes, respectively; p = 0.0013, p(cor.) = 0.017). Among male patients rs1801133 TT significantly increased the risk of severe/profound HI (odds ratio = 4.88, p = 0.001). Among controls the known effect of MTHFR 677T on plasma total homocysteine was more pronounced in men than in women (p<0.00004 for genotype-sex interaction) suggesting that in Poland folate deficiency is more prevalent in males. In conclusion, we report a novel strong effect of MTHFR 677T among males with npHI. The functional significance of rs1801133 suggests that these patients may benefit from folate supplementation-an intervention which is simple, cheap, and devoid of side effects.     

Two MTHFR polymorphisms, maternal B-vitamin intake, and CHDs

BACKGROUND: The methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms are associated with complex congenital malformations. Whether these polymorphisms are associated with CHDs is not clear. We studied both MTHFR polymorphisms, folate and vitamin B2 by maternal food intake and supplements, and CHD risk. METHODS: A case‐control family study was conducted in a European population in the Netherlands including 230 case and 251 control children with both parents. Approximately 17 months after the index pregnancy, mothers filled out standardized questionnaires on periconception use of folic acid supplements and a validated food frequency questionnaire on current dietary folate and vitamin B2 intake. All subjects were genotyped for the MTHFR C677T and A1298C polymorphisms. Data were analyzed by logistic regression analysis and ORs and 95% CIs were calculated. For the interaction analysis the dominant model was used. RESULTS: The risk estimates for the MTHFR 677 CT genotypes were 1.4 (0.9–2.0) in mothers, 1.1 (0.8–1.6) in fathers, and 1.2 (0.8–1.7) in children, and for the MTHFR 677 TT genotypes 0.9 (0.6–1.2), 1.4 (1.0–1.9), and 1.0 (0.7–1.3), respectively. The MTHFR 1298 CC genotype in fathers and the MTHFR 1298 AC genotype in children significantly reduced CHD risk, 0.6 (0.5–0.9) and 0.6 (0.4–0.9), respectively. Of interest is the significant interaction (p = .008) towards a nearly twofold increased risk in mothers carrying the MTHFR 1298C allele and using a periconception folic acid supplement. CONCLUSIONS: The MTHFR C677T and A1298C polymorphisms are not strong risk factors for CHDs. Birth Defects Research (Part A), 2008. © 2008 Wiley‐Liss, Inc.     

Plasma total homocysteine level and methylenetetrahydrofolate reductase 677C>T genetic polymorphism in Japanese patients with rheumatoid arthritis

Hyperhomocysteinemia is a known risk factor of cardiovascular disease. Homocysteine has been also linked to inflammation in rheumatoid arthritis (RA). In this study, we investigated the relationship between plasma homocysteine levels and single nucleotide polymorphism (SNP) of the gene coding for methylenetetrahydrofolate reductase (MTHFR), an enzyme involved in the biosynthesis of homocysteine, and the correlation between the plasma homocysteine levels and generally used inflammatory markers (C-reactive protein, erythrocyte sedimentation rate and matrix metalloproteinase-3) in 96 Japanese patients with RA. Plasma homocysteine levels in patients with the MTHFR 677TT genotype were significantly higher than in those with the 677CC genotype (p < 0.05). In addition, plasma homocysteine levels were increased along with the elevation of general inflammatory markers. Therefore, we conclude that homocysteine might affect the inflammatory status of patients, and the MTHFR 677C>T SNP could be a predictive factor of hyperhomocysteinemia in patients with RA.     

Modulator effects of the methylenetetrahydrofolate reductase C677T polymorphism on response to vitamin B12 therapy and homocysteine metabolism

In this study, our aim was to investigate the association of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism on the vitamin B12 therapy response in 95 patients with vitamin B12 deficiency and 92 healthy control subjects using vitamin B12, plasma total homocysteine (tHcy), and folate as the main measure of outcome. MTHFR C677T genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism techniques. There were no differences in the distribution of MTHFR genotypes in the cases versus the controls. Mean concentrations of plasma tHcy and B12 vitamin were 18.84 μM and 142.47 pg/mL in patients with TT (10.5%) genotypes. Furthermore, mean concentrations of B12 vitamin after cobalamin therapy were 697.62, 656.64, and 488.76 pg/mL in patients with the CC, CT, and TT genotypes, respectively. The MTHFR 677 TT genotype has decreasing effect in B12 vitamin and increasing effect in tHcy. In comparison with the patients having CC and CT genotypes, patients with the TT genotype had a lower response to vitamin B12 therapy.     

出血性卒中与MTHFR C677T基因多态性的相关性研究

摘要 目的：探讨与分析出血性卒中与亚甲基四氢叶酸还原酶（MTHFR）C677T基因多态性的相关性。方法：2020年2月到2021年4月选择在本地区诊治的H型高血压患者220例作为研究对象,检测所有患者的MTHFR C677T基因多态性状况,检测血清同型半胱氨酸、叶酸、维生素B12含量。随访判定患者的出血性卒中状况并进行相关性分析。结果：随访调查1年,220例患者中出现出血性卒中20例（出血性卒中组）,占比9.1 %。出血性卒中组的血清同型半胱氨酸含量明显高于非出血性卒中组,血清维生素B12、叶酸明显低于非出血性卒中组（P<0.05）。两组的MTHFR C677T基因型分布均符合Hardy-Weinberg遗传平衡,出血性卒中组的TT基因型、等位基因T占比分别为70.0 %、80.0 %,都显著高于非出血性卒中组的24.0 %、35.0 %（P<0.05）。Spearman相关系数分析显示H型高血压患者的血清同型半胱氨酸、叶酸、维生素B12含量、TT基因型、等位基因T都与出血性卒中存在相关性（P<0.05）。多元回归分析显示血清同型半胱氨酸、叶酸、维生素B12含量、TT基因型、等位基因T都为导致H型高血压患者出血性卒中发生的重要因素（P<0.05）。结论：H型高血压在随访过程中容易发生出血性卒中,也伴随有血清同型半胱氨酸、维生素B12、叶酸含量异常,MTHFR C677T的T基因型、等位基因T与出血性卒中存在相关性,也是导致出血性卒中发生的重要危险因素。     

Methylenetetrahydrofolate reductase gene polymorphism in diabetes and obesity

Methylenetetrahydrofolate reductase (MTHFR) polymorphism may play an important role in the pathophysiology of obesity and diabetes accompanied by obesity due to its influence on plasma homocysteine levels. There are significant and sometimes very strong relationship between levels of homocysteine and several multi-system diseases including CHD and CVA. To examine the association between MTHFR gene C677T polymorphism in diabetes and obesity with serum homocysteine levels. A total of 682 subjects were recruited in four groups (Normal, obese, diabetic and obese and diabetics). MTHFR gene C677T polymorphism was detected using PCR-RFLP technique. Serum homocysteine levels were measured using HPLC. There was a significant increase in the mean serum homocysteine levels in subjects carrying TT genotype (34.6 ± 26.5) compared to subjects carrying CC (15.1 ± 8) or CT genotype (16.4 ± 7.8) (P < 0.000). We found no significant differences for MTHFR allele and genotype frequencies between different groups. Our data have confirmed the association between serum homocysteine levels and MTHFR C677T genotype reported in other populations.     

Additional food folate derived exclusively from natural sources improves folate status in young women with the MTHFR 677 CC or TT genotype

The effectiveness of additional food folate in improving folate status in humans is uncertain particularly in people with the common genetic variant (677 C-->T) in the methylenetetrahydrofolate reductase (MTHFR) gene. To examine the effect of a doubling of food folate consumption on folate status response variables, women (n=32; 18-46 years) with the MTHFR 677 CC or TT genotype consumed either 400 (n=15; 7 CC and 8 TT) or 800 (n=17; 8 CC and 9 TT) microg/day of dietary folate equivalents (DFE) derived exclusively from naturally occurring food folate for 12 weeks. A repeated measures two-factor ANOVA was used to examine the effect of the dietary treatment, the MTHFR C677T genotype and their interactions on serum folate, RBC folate and plasma total homocysteine (tHcy) during the last 3 weeks of the study. Consumption of 800 microg DFE/day resulted in serum folate concentrations that were 67% (P=.005) higher than consumption of 400 microg DFE/day (18.6+/-2.9 vs. 31.0+/-2.7 nmol/L, respectively) and RBC folate concentrations that were 33% (P=.001) higher (1172+/-75 vs. 1559+/-70 nmol/L, respectively). Serum folate (P=.065) and RBC folate (P=.022) concentrations were lower and plasma tHcy was higher (P=.039) in women with the MTHFR 677 TT genotype relative to the CC genotype. However, no genotype by dietary treatment interaction was detected. These data suggest that a doubling of food folate intake will lead to marked improvements in folate status in women with the MTHFR 677 CC or TT genotype.     

Correlation of methylenetetrahydrofolate reductase polymorphisms with homocysteine metabolism in healthy Lebanese adults

Hyperhomocysteinemia is associated with several vascular and teratogenic conditions. Determinants of total homocysteine concentrations include genetic and nutritional factors. This study assesses the relation between homocysteine concentrations and MTHFR gene polymorphisms at two common alleles (C677T (rs1801133) and A1298C (rs1801131)) as well as other predictors of homocysteine (folate, vitamin B(12), body mass index (BMI), age, and gender) in a group of healthy Lebanese: 109 males and 124 females aged 17-55years. We used serum for the determination of homocysteine, folate and vitamin B(12) levels and blood drawn in EDTA tubes for molecular analysis of MTHFR polymorphisms. Hyperhomocysteinemia was present in 59/233 (25.3%) of the subjects, with male/female ratio of 1.95. Multivariable regression analysis showed that homocysteine levels were negatively related to folate and vitamin B(12) and positively related to male gender and C677T homozygosity; but not A1298C polymorphism, BMI or age. The prevalence of wild, heterozygous, and homozygous C677T genotypes was 45.0%, 43.3% and 11.6%, respectively; with a carrier frequency of 54.9% and allelic frequency of 33.3%. The A1298C genotypic prevalence was 39.5%, 30.9%, and 29.6% respectively; with a carrier frequency of 60.5% and allelic frequency of 45.1%. C677T/A1289C compound heterozygosity was present in 47/233 (20.2%) of volunteers. In this first pilot study, gender, folate, vitamin B(12) and C677T mutational status could explain around 32% of homocysteine variations. Future larger studies are recommended to investigate other predictors of homocysteine variation and combine them with markers explored in this and other studies, in order to evaluate their impact on vascular and/or congenital diseases.     

C677T mutation of methylenetetrahydrofolate reductase gene and serum homocysteine levels in Turkish patients with coronary artery disease

Elevated levels of homocysteine is a risk factor for coronary artery disease. The C677T transition in methylenetetrahydrofolate reductase (MTHFR) is associated with increased homocysteine levels in the general population. We analysed the association between the MTHFR C677T polymorphism and serum homocysteine concentrations in patients with coronary artery disease (CAD). Allele frequencies for the 'C' (wild-type) and 'T' alleles were 0.71 and 0.29 in CAD patients and 0.70 and 0.30 in controls, respectively. There was no difference in the distribution of MTHFR genotypes between patients with CAD and control subjects (p > 0.05). In the patient group, homocysteine levels were higher than controls but not significantly (13.99 +/- 7.44 vs. 11.77 +/- 5.18 micromol l(-1); p > 0.05). Serum homocysteine concentration was significantly higher in the TT genotype with respect to CC and CT genotypes in both the control group (p < 0.01) and patient group (p < 0.01). Systolic and diastolic blood pressures in subjects with different MTHFR genotypes did not differ significantly. In conclusion, MTHFR C677T mutation was significantly related to hyperhomocysteinemia. In spite of the clear effect of the MTHFR polymorphism on elevated homocysteine levels, we did not observe any associations among the MTHFR genotypes with a the risk of CAD in the Turkish population.