MTHFR (methylenetetrahydrofolate reductase) C677T polymorphism and psoriasis

The aim of the study was to evaluate possible association of MTHFR C677T gene polymorphism (NM_005957) with psoriasis. Genotypes of MTHFR C677T gene polymorphism were determined in a sample of 654 Caucasian (Czech) subjects. Case group (n = 410) included patients with psoriasis (plaque psoriasis diagnosed in 285 patients, other subtypes of psoriasis were observed in 125 patients). Control group (n = 244) consisted of healthy subjects without individual history of psoriasis, with similar age and gender characteristics. The MTHFR C677T polymorphism genotypes were determined by a polymerase chain reaction and a subsequent restriction analysis with HinfI. The genotypes of C(677)T methylenetetrahydrofolate reductase (MTHFR) gene polymorphism were determined in a sample of 654 Caucasian (Czech) subjects. We proved a significant difference in genotype distribution (P _g = 0.03) and allelic frequency (P _a = 0.02) between psoriatic and control subjects (Table 3). The CC (the thermostabile) genotype was significantly more frequent in psoriatic patients compared to controls [OR = 1.55, 95% confidential interval (CI) = 1.12–2.15, P = 0.004814, P _corr = 0.01]. But, a significant increase of T allele in MTHFR gene was observed in patients with positive family history of diabetes (P _a = 0.02) and in those with a frequent tonsillitis/tonsillectomy (P _a = 0.04). No difference was observed between patients with and without positive family history of psoriasis (P _a = 0.251). But, when psoriatic patients were described for FHDM, FH-Ps, and PH-T simultaneously, The highest incidence of CT + TT genotypes was calculated for psoriasis patients with positive history of psoriasis and diabetes mellitus together with personal history of repeated tonsillitis/tonsillectomy compared to patients without all these three phenotypes (odds ratio = 3.17, 95% CI 1.33–7.56, P _corr = 0.04). In conclusion, MTHFR C677T polymorphism is marginally associated with psoriasis. The T allele (thermolabile) appears to be more frequent in psoriasis patients with positive history of psoriasis and diabetes mellitus together with personal history of repeated tonsillitis/tonsillectomy. This could reflect an inborn predisposition in complex regulation in one-carbon moieties transport in psoriatic patients and therefore, MTHFR genotype can be a part of genetic background of psoriasis.     

No association of the C677T methylenetetrahydrofolate reductase polymorphism with schizophrenia

Some serological and genetic studies have suggested that alterations in folate metabolism are associated with increased vulnerability to schizophrenia. In particular, these findings are most striking for the role of a putatively functional variant (C677T) in the methylenetetrahydrofolate reductase (MTHFR) gene. To test the hypothesis that the T allele and the TT genotype are risk factors for psychosis, we genotyped the C677T polymorphism in 206 participants with schizophrenia or schizoaffective disorder and 359 participants from a population control sample. Neither the T allele nor the TT genotype was associated with increased risk for schizophrenia. These results do not support a role for the C677T MTHFR variant in schizophrenia.     

A1298C methylenetetrahydrofolate reductase mutation and coronary artery disease: relationships with C677T polymorphism and homocysteine/folate metabolism

5, 10-Methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme in homocysteine/methionine metabolism. The most-studied C677T polymorphism in the MTHFR gene results in a thermolabile variant with reduced activity, and is associated with increased levels of total plasma homocysteine, a risk factor for coronary artery disease. A new mutation in the MTHFR gene (A1298C) has also been reported to lower enzyme activity. Whether A1298C is a risk factor for coronary artery disease, separately or in combination with C677T, and/or relative to total plasma homocysteine and folate status, is unclear to date. We evaluated this hypothesis in 470 angiographically characterized subjects, 302 with coronary artery disease, and 168 with normal coronary arteries. The frequency of the 1298C allele was 0.33 and that of combined heterozygosity 0.315. No difference was found in the frequency of the genotypes or when analyzed for combined heterozygosity between patients with coronary artery disease and normals. Independent of folate status, the 1298C allele was not associated with increased total plasma homocysteine. No additional effect of A1298C on total plasma homocysteine was observed in 148 combined heterozygotes compared with 98 heterozygotes for the C677T alone. These findings do not support a major role for the A1298C mutation in homocysteine metabolism and emphasize the hypothesis that MTHFR genotypes may interfere with coronary artery disease risk only when an unbalanced nutritional status leads to raised total plasma homocysteine levels.     

Thermolabile methylenetetrahydrofolate reductase C677T polymorphism and homocysteine are risk factors for coronary artery disease in Moroccan population

Increased plasma total homocysteine (tHcy) levels have been shown to be a risk factor for coronary artery disease (CAD). The common methylenetetrahydrofolate reductase C677T (MTHFR C677T) polymorphism has been reported to be a strong predictor of mild hyperhomocysteinaemia (HHcy). We assessed whether this mutation was associated with increased risk of CAD and plasma levels of tHcy. We also evaluated interactions between this polymorphism, mild elevated tHcy levels and conventional risk factors of CAD. Method. Using PCR-RFLP analysis, we studied the frequency of the C677T genotypes and its effect on CAD and on tHcy concentrations in 400 subjects without and with CAD angiographically confirmed. There were 210 subjects with CAD and 190 subjects without CAD. Results. The frequencies of the C677T genotypes were 53% (59.5% in controls versus 48.1% in cases), 34.8% (32.1 in controls versus 37.1 in cases), and 11.8% (8.4% in controls versus 14.8% in cases), respectively, for 677CC, 677CT, and 677TT. The genotype frequencies were significantly different between case and control groups (P < .05). The 677T allele enhances the risk of CAD associated to HHcy (P < .01). In multivariate analysis models, MTHFR C677T polymorphism effect on CAD was masked by other risk factors. HHcy was only and independently influenced by MTHFR polymorphism and smoking habits, and it is a strong predictor of CAD independently of conventional risk factors. Conclusion. Our data suggest that HHcy is strongly and independently associated to CAD risk increase; and MTHFR C677T polymorphism and smoking habits were the main predictors of tHcy levels. The CAD risk increase is mainly associated with mild HHcy in 677TT, whereas in 677CT and 677CC it is mainly associated with the conventional risk factors.     

Meta-analysis of the methylenetetrahydrofolate reductase C677T polymorphism and susceptibility to Alzheimer's disease

No clear consensus has been reached at the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and Alzheimer's disease (AD) risk. Thus in this meta-analysis, a total of 19 case–control studies was assessed to evaluate the possible association. The data demonstrated that the frequency of T677 allele (T vs. C) was significantly associated with susceptibility to AD in all subjects (OR = 1.15, 95% CI = 1.06–1.26) and in East Asians (OR = 1.22, 95% CI = 1.08–1.39). There was statistical difference between AD patients and the controls under recessive genetic mode (CT + TT vs. CC) and homozygote comparison (TT vs. CC) in all subjects and in East Asians as well. Despite a small effect of the polymorphism on late-onset AD (LOAD) risk, MTHFR C677T polymorphism was not a major risk factor for LOAD in East Asians and Caucasians. A subgroup analysis in the subjects without APOE ?4 alleles showed T677 allele significantly increased risk of AD in all subjects (OR = 1.21, 95% CI: 1.04–1.42) and in East Asians (OR = 1.28, 95% CI: 1.06–1.55). However, no association was found in Caucasians. In conclusion, this meta-analysis supports that MTHFR C677T polymorphism is capable of causing AD susceptibility in East Asians, not in Caucasians.     

甲叉四氢叶酸还原酶C677T与精神分裂症的连锁不平衡研究

目的 通过对甲叉四氢叶酸还原酶（methylenetetrahydrofolate reductase,MTHFR)C677T错义突变与精神分裂症的连锁不平衡研究，探讨该突变与精神分裂症的关系。方法 对115个精神分裂症同胞及核心家系中，用XDT和MAPMAKER／SIBS软件系统进行MTHFRC677T与精神分裂症的连锁不平衡分析。按照不同的诊断范围将家系分类，分别在全体家系及发病年龄小于25岁的家系中进行连锁不平衡分析。结果 在4种不同的诊断分类下，对全体家系进行连锁不平衡分析未发现阳性结果。对发病年龄小于25岁的患者家系进行分析时发现，在4种不同的诊断灵感上均具有显著性意义，P值分别小于0．05及0．01。结论 MTHFR C677T错义突变可能为影响精神分裂症易感性的基因之一，尤其是在发病年龄较早的患病群体中。     

The C677T methylenetetrahydrofolate reductase mutation is not associated with Alzheimer's disease.

The methylenetetrahydrofolate reductase (MTHFR) gene has been recently considered as a candidate gene for Alzheimer's disease (AD). MTHFR is a key enzyme in the metabolism of homocysteine and elevated levels of that amino acid have been associated to Vascular Dementia and AD. A T-->C transition at codon 677 produces a thermolabile type of the enzyme. However, contrasting results on the distribution of the MTHFR C677T common polymorphism in AD have been published. We analyzed the distribution of the MTHFR and apolipoprotein E (APOE) polymorphisms in Italian patients with sporadic AD. The distribution of the C677T polymorphism did not differ in AD and controls. Our data suggest that the MTHFR polymorphism does not contribute to genetic susceptibility in Italian sporadic AD and does not mitigate the effect of ApoE epsilon4 allele on AD risk.     

Elevated plasma homocysteine is positively associated with age independent of C677T mutation of the methylenetetrahydrofolate reductase gene in selected Egyptian subjects

This study aimed to evaluate the plasma homocysteine (tHcy) and folate levels as well as the methylenetetrahydrofolate reductase (MTHFR) C677T mutation in Egyptian subjects. Fasting total homocysteine (tHcy) and the (MTHFR) C677T mutation were evaluated in 50 healthy young control males (age 35-50 years, Gp1), 50 elderly males age ranged between 50-75 years without any cardiovascular diseases (Gp2) and 50 age matched elderly male patients (Gp3) with myocardial infarction. There was a significant elevation of plasma tHcy in the patients group and Gp2 compared to the young control group (Gp1). The total plasma homocysteine (tHcy) in the control group, Gp2 and the patients group were 17.99 +/- 9.76, 39.9 +/- 20.06 and 43.8 +/- 13.13 mumol/L respectively. The frequency of the TT genotype was 12% in the patient group compared with 8 % in the young healthy controls and elderly subjects (Gp2). The CT genotype constituted 36%, 48% and 44% in the control group, Gp2 and the patients group respectively. There was no significant difference in the occurrence of the TT genotype between the studied groups. Plasma tHcy correlated positively with age, total cholesterol, urea, creatinine, glucose levels and carotid intimal thickness (CIT). Conclusion: The MTHFR mutation does not seem to be associated with either high tHcy or the occurrence of cardiovascular diseases in the studied patients. However, elevated plasma tHcy level positively correlates with age in the studied subjects.     

MTHFR基因C677T多态与神经管缺陷及先兆子痫关系的研究

目的 探讨亚甲基四氢叶酸还原酶（ｍｅｔｈｙｌｅｎｅｔｅｔｒａｈｙｄｒｏｆｏｌａｔｅ ｒｅｄｕｃｔａｓｅ,ＭＴＨＦＲ）基因Ｃ６７７Ｔ多态与神经管缺陷（ｎｅｕｒａｌ ｔｕｂｅ ｄｅｆｅｃｔｓ,ＮＴＤ）及先兆子痫发生的关系。方法 采用ＰＣＲ／ＲＦＬＰ技术对２７位生过ＮＴＤ患儿的母亲和２４位生过正常孩子的母亲,以及５７例患过先兆子痫的妇女和１２０名正常对照妇女进行了ＭＴＨＦＲ等位基因检测。结果 （１）下沉     

The C677T methylenetetrahydrofolate reductase polymorphism influences the homocysteine-lowering effect of hormone replacement therapy.

Elevated homocysteine is an independent risk factor for cardiovascular disease and has been associated with a common C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene. Estrogen use has been shown to reduce homocysteine concentrations, suggesting that this might contribute to the cardiovascular benefit of hormone replacement therapy. We examined 90 postmenopausal women to determine if MTHFR genotype affected the response of homocysteine to hormone replacement therapy. Women with the TT genotype did not show decreased homocysteine in response to hormone replacement therapy as demonstrated for women with the CC genotype and may receive decreased cardiovascular benefits from hormone replacement therapy.     

The relationship between C677T methylenetetrahydrofolate reductase gene polymorphism and retinopathy in type 2 diabetes: a meta-analysis

The association between retinopathy in type 2 diabetes [diabetic retinopathy (DR)] and the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene has been investigated in several case-control studies. These studies rendered contradictory results, some indicating that the polymorphism is associated with the risk of developing DR whereas others concluded there is no association. To shed light on these inconclusive findings, a meta-analysis of all available studies relating the C677T polymorphism to the risk of developing DR was conducted. Four out of five identified studies included populations of East Asian descent, and only one involved samples from European descent (Caucasians). Overall, the meta-analysis suggested large heterogeneity between studies (p = 0.08, I² = 52%) and marginal association between C677T transition and the risk of developing DR: random effects odds ratio (OR) = 1.39 [95% CI (1.05, 1.83)]. The sensitivity analysis [exclusion of one East Asian study with the controls not in Hardy–Weinberg equilibrium (HWE)] showed no heterogeneity (p = 0.25, I² = 27%) and no significant association: fixed effects OR = 1.22 [95% CI (0.99, 1.51)] and random effects OR = 1.24 [95% CI (0.96, 1.60)]. The sub-group analysis for the East Asian population produced a significant association: fixed effects OR = 1.48 [95% CI (1.20, 1.83)] and random effects OR = 1.52 [95% CI (1.14, 2.03)]. However, sensitivity analysis in East Asians revealed that the association is marginal: fixed effects OR = 1.33 [95% CI (1.04, 1.70)] and random effects OR = 1.36 [95% CI (1.01, 1.83)]. There is a source of bias in the selected studies: the largest studies failed to show association while the smallest study claimed an association. The above findings reinforce the need for larger and more rigourous studies in this area.     

生育过神经管缺陷儿的妇女MTHFR基因C677T多态性与血浆Hcy水平测定

目的探讨MTHFR基因C677T多态性及血浆Hcy水平与神经管缺陷的关系。方法采用PCR-RFLP方法对30例生育过NTD患儿的母亲（NTD组）和34例生育过正常儿的母亲（对照组）进行MTHFR基因C677T等位基因检测,同时用高效液相色谱结合荧光检测法对两组母亲血浆中Hcy水平进行测定。结果NTD母亲组中VV基因型的频率为（36.7%）,V等位基因频率为（65.0%）,正常对照母亲组中VV基因型的频率为（17.6%）,V等位基因频率为（44.1%）,两组比较有显著性差异（P〈0.05）。NTD母亲组Hcy水平为（11.24±3.2）μmol/L,正常对照母亲组Hcy水平为（8.96±3.3）μmol/L,两组比较也有显著性差异（P〈0.01）。结论MTHFR基因C677T多态是神经管缺陷发病的遗传危险因素,它通过血浆中同型半胱氨酸水平升高而引起神经管缺陷。     

A meta-analysis of association between C677T polymorphism in the methylenetetrahydrofolate reductase gene and hypertension

The C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene was implicated to be associated with hypertension due to its role in catalyzing the formation of 5-methylenetetrahydrofolate, a co-substrate for the conversion of homocysteine to methionine. Association studies were reported in different populations; however, a great number of subsequent studies have produced contrary results, possibly reflecting inadequate statistical power. With the cumulative data in recent years in both Caucasian and Asian populations, it was necessary to carry out a comprehensive analysis of previous findings. In this meta-analysis, we combined 26 English and Chinese studies in Caucasian and Asian populations published up to November 2006 to give a new picture of the role of the C677T polymorphism in the MTHFR gene. Evidence of significant association was detected between C677T polymorphism and hypertension in both populations. Additionally, the significant association between C677T polymorphism and hypertension/hypertension-in-pregnancy suggested that this polymorphism was one independent risk factor of hypertension.     

MTHFR基因C677T多态性与冠心病患者血浆同型半胱氨酸和叶酸水平相关

目的研究宁夏地区汉族人群5,10-亚甲基四氢叶酸还原酶基因(MTHFR)C677T多态性、同型半胱氨酸水平(Hcy)及叶酸水平与冠心病(CHD)的相关性。方法用病例-对照研究方法、应用限制性片段长度多态性扩增技术(PCR-RFLP)分析宁夏地区汉族202例冠心病患者及199例正常人群MTHFRC677T基因型频率及基因频率的分布特点。荧光偏振免疫分析法测定血浆Hcy水平,化学发光免疫分析法测定血清叶酸、VitB12浓度。结果 (1)病例组与对照组MTHFRC677T基因型频率分别为CC型23.3%vs20.7%、CT型52.3%vs54.5%和TT型24.4%vs24.8%,两组间基因型及等位基因频率分布无差异。(2)冠心病患者组中MTHFR基因C677TCC基因型患者血浆Hcy浓度(10.84μmol/L)较T基因携带者(12.24μmol/L)低(P<0.01)。CC基因型患者血浆叶酸浓度(5.38μg/L)较T基因携带者(3.72μg/L)高(P<0.05)。结论 MTHFRC677T的3种基因型频率在宁夏汉族冠心病患者和正常人群中的分布无统计学意义。MTHFR基因C677T多态性与冠心病的危险因素Hc...     

The homozygous C677T mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for migraine

Increased homocysteine levels are associated with various pathological conditions in humans, including stroke and cardiovascular disorders. Homocysteine acts as an excitatory amino acid in vivo and may influence the threshold of migraine headache. Frosst et al. [1995] reported an association between the homozygous C677T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene and serum homocysteine levels. This study was designed to determine the prevalence of the MTHFR mutation in Japanese patients with migraine and tension-type headache (TH). Seventy-four patients with migraine headaches (22 with aura and 52 without aura), 47 with THs, and 261 normal controls were recruited. Genotyping of MTHFR C677T polymorphism was performed by polymerase chain reaction-restriction fragment length polymorphism. We detected that the incidence of the homozygous transition (T/T) in migraine sufferers (20.3%) was significantly higher than that in controls (9.6%). Moreover, the frequency of the T/T genotype in individuals with migraine headaches with aura was remarkably high (40.9%). The MTHFR T allele was more frequent in the migraine group than in the control group. Our results support the conclusion that the MTHFR gene, causing mild hyperhomocysteinemia may be a genetic risk factor for migraine. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:762-764, 2000.     

C677T polymorphism of methylenetetrahydrofolate reductase may contribute to cervical cancer risk in complete over-dominant model

Purpose Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the metabolism of folate. The single nucleotide polymorphism (SNP), C677T (Ala > Val, rs1801133), has been confirmed to decrease the enzyme activity. The association between C677T and cervical cancer susceptibility has been widely studied. However, the results were inconsistent. In order to elucidate the role of this SNP in cervical cancer, a meta-analysis was conducted. Methods The literature search was performed using the following databases: PubMed, Embase and ISI Web of Science up to December 2012. The effect of association was indicated as crude odds ratio (OR) with the corresponding 95% confidence interval (CI). Results Six studies including 1431 cases and 1915 controls explored C677T genotypes were involved in this meta-analysis. Overall meta-analysis showed that C677T polymorphism increased cervical cancer risk in the complete over-dominant model (random-effect OR = 1.33, 95% CI: 1.00–1.77, I² = 69%). After excluding one study which showed apparent heterogeneity, the heterogeneity disappeared. The meta-analysis of five studies including 1231 cases and 1715 controls showed the fixed-effect OR reached 1.20 (95% CI: 1.03–1.40, I² = 0) as (TT + CC) in the complete over-dominant model. Conclusions C677T polymorphism of MTHFR gene may increase the risk of cervical cancer in the complete over-dominant model. The association merits replicating and validating in further studies.     

The methylenetetrahydrofolate reductase gene variant C677T influences susceptibility to migraine with aura

Background  

The C677T variant in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with increased levels of circulating homocysteine and is a mild risk factor for vascular disease. Migraine, with and without aura (MA and MO), is a prevalent and complex neurovascular disorder that may also be affected by genetically influenced hyperhomocysteinaemia. To determine whether the C677T variant in the MTHFR gene is associated with migraine susceptibility we utilised unrelated and family-based case-control study designs.     

Distribution of alleles of the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism in familial spina bifida

Spina bifida cystica (SB) is one of the most common and disabling of birth defects. Folic acid supplementation in mothers during the periconceptional period has been shown to prevent more than 70% of neural tube defects (NTD) including SB. However, the mechanism is unknown. We tested a series of multicase SB families in which 224 individuals were genotyped and a group of 215 unrelated unaffected (external) control individuals for association of SB with the T allele of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism that produces a heat-labile enzyme protein. The data were analyzed using first the transmission/disequilibrium test (TDT) and second a modified case-control study design with Monte Carlo sampling methods. No association of SB with the MTHFR T allele was found by either method. Presently, association between SB and the T allele has been found in four studies, a Dutch study, an Irish study, a North American study, and an Italian study. But no association was found in four other studies, a British study, a French study, a Turkish study, and a German study. A California population-based study found only modestly increased risk of SB with this allele that was not significant at the P < 0.05 level. The present study finds no evidence of the association. Only one other study, the German study, has used TDT analysis. The present study is the first to use a modified case-control study design with Monte Carlo sampling methods to test this association. Thus, it appears that the MTHFR T allele is a risk factor for SB in some populations but not others. Major genetic risk factors for folate-related SB remain to be found.     

No association of C677T methylenetetrahydrofolate reductase and an endothelial nitric oxide synthase polymorphism with recurrent pregnancy loss

PROBLEM: It is controversial whether polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and the endothelial nitric oxide synthase (eNOS) are associated with recurrent pregnancy loss. METHOD OF STUDY: We studied the frequency of the C677T polymorphism of MTHFR and a eNOS gene polymorphism, as well as the plasma levels of homocysteine and NO, in 85 cases with a history of two or more unexplained embryonal losses, 40 patients suffering fetal loss and 76 controls. RESULTS: The frequency of the MTHFR gene T allele, which has been reported to be associated with miscarriages, in patients suffering fetal loss was rather significantly lower than in controls whereas there was no difference in the frequency of the eNOS gene A allele. There were no differences in the plasma homocysteine levels among the three groups. However, the NO concentrations in the embryonal loss and fetal loss groups were significantly higher than that in controls. CONCLUSION: We conclude that the NO concentration but not the polymorphism of MTHFR and eNOS gene and hyperhomocysteinemia are associated with recurrent pregnancy loss in Japanese.