Are common mutations of cystathionine β-synthase involved in the aetiology of neural tube defects?

Mildly elevated maternal plasma homocysteine (Hcy) levels (hyperhomocysteinemia) have recently been observed in some neural tube defect (NTD) pregnancies. Plasma levels of Hcy are governed by both genetic and nutritional factors and the aetiology of NTDs is also known to have both genetic and nutritional components. We therefore examined the frequency of relatively common mutations in the enzyme cystathionine β-synthase (CBS), which is one of the main enzymes that controls Hcy levels, in the NTD population. Neither the severely dysfunctional G307S CBS allele nor the recently reported 68 bp insertion/I278T CBS allele was observed at increased frequency in the cases relative to controls. We therefore conclude that loss of function CBS alleles do not account for a significant proportion of NTDs in Ireland.     

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。     

亚甲基四氢叶酸还原酶基因多态性与脑血管疾病的研究

目的　探讨N 亚甲基四氢叶酸还原酶 (MTHFR)基因多态性与脑血管疾病的关系。方法　利用聚合酶链反应和限制性片段长度多态性 (PCR RFLP)方法 ,检测了 72名健康人和 71名脑血管疾病患者MTHFR基因的6 77碱基多态性突变C→T情况 ,并加以对照分析。结果　脑血管疾病患者MTHFR基因突变型V6 77基因的频率 ,与正常健康人对比差异无显著意义 (P >0 .0 5 )。结论　MTHFR基因突变型V6 77基因可能是脑血管疾病的又一个遗传风险因子 ,但本研究结果显示与脑血管疾病的发病无关 ,是否为脑血管病的遗传风险因素有待进一步研究。     

Methylenetetrahydrofolate Reductase Genotypes, Dietary Habits and Susceptibility to Stomach Cancer

OBJECTIVE To study the relation among methylenetetrahydrofolate reductase (MTHFR) C677T genotypes, dietary habits and the risk of stomach cancer (SC).METHODS A case-control study was conducted with 107 cases of SC and 200 population-based controls in Chuzhou district, Huaian, Jiangsu province, China. The epidemiological data were collected, and DNA of peripheral blood leukocytes was obtained from all of the subjects..MTHFR genotypes were detected by PCR-RFLP. RESULTS (1) The prevalence of the MTHFR C/T or T/T genotypes was found to be significantly different between controls (68.5%) and SC cases (79.4%,P=0.0416), the increased risk had an adjusted OR of 1.79 (95?:1.01-3.19). (2) Among subjects who had a low intake of garlic or Chinese onion, MTHFR C/T or T/T genotypes significantly increased the risk of developing SC. Among non-tea drinkers or among subjects who had a frequent intakeof meat, the carriers of the MTHFR C/T or T/T genotypes had a higher risk of SC than individuals with the C/C type MTHFR. CONCLUSION The polymorphism of MTHFR C677T was associated with increased risk of developing SC, and that individuals with differing genotypes may have different susceptibilities to SC, based on their exposure level to environmental factors.     

原发性高血压肾损害及肾实质性高血压患者MTHFR基因多态性分析

目的探讨亚甲基四氢叶酸还原酶(MTHFR)基因C677T多态性与原发性高血压(EH)肾脏损害及肾实质性高血压(RH)的关系。方法用聚合酶链式反应限制性片段长度多态性(PCR-RFLP)分析法检测MTHFR基因多态性在正常人群(CN)、EH肾功能正常(EH-RN)患者、EH肾衰竭(EH-RF)患者及RH患者中的频率分布情况。结果EH-RF组和RH组的收缩压和舒张压水平均显著高于EH-RN组(P<0.05),各组间年龄、性别、血脂水平比较差异均无统计学意义(P>0.05)。EH-RF组MTHFR T等位基因频率为42.1%,明显高于正常对照(NC)组的18.3%和EH-RN组的19.2%(均P<0.05),其余各组间比较差异均无统计学意义(P>0.05)。各组之间MTHFR C/C、C/T和T/T基因型频率比较差异均无统计学意义(P>0.05)。结论MTHFR T等位基因可能是中国北方汉族EH患者发生肾衰竭的一个易感基因。     

No evidence of association of methylenetetrahydrofolate reductase polymorphism with occurrence of second neoplasms after treatment of childhood leukemia

Methylenetetrahydrofolate reductase (MTHFR) polymorphisms have been associated not only with the risk for acute lymphoblastic leukemia (ALL) in adults and children, but also with increased methotrexate toxicity. The present study aimed to investigate whether MTHFR polymorphisms modify the risk for development of secondary malignancies in children treated for ALL with protocols that included high-dose methotrexate. MTHFR genotypes were determined in DNA samples isolated from archived bone marrow smears of 15 patients with a second malignancy and a matched control group of 30 patients who did not developed a second malignancy after the treatment for ALL. The frequencies of MTHFR C677T and A1298C genotypes in all patients were: C677T: CC 40%, CT 46.7% and TT 13.3% and A1298C: AA 46.7%, AC 44.4% and CC 8.9%. The relative risk for second malignancy was not significantly increased in ALL patients having at least one polymorphic C667T [odds ratio (OR) 1.51; 95% confidence interval (CI) 0.43 - 5.31] or one polymorphic A1298C allele (OR 1; 95% CI 0.29 - 3.46). Our study suggests that MTHFR polymorphisms are not associated with increased risk of second cancer in children treated with high-dose methotrexate.     

A Common Haplotype on Methylenetetrahydrofolate Reductase Gene Modifies the Effect of Angiotensin-Converting Enzyme Inhibitor on Blood Pressure in Essential Hypertension Patients—A Family-Based Association Study

Our recent study indicated that MTHFR C677T polymorphism may involve in genetic control of blood pressure response to treatment by benazepril, an ACE inhibitor. Currently, we proposed to further investigate whether short-term blood pressure response to benazepril, was modulated by haplotypes re-constructed from both C677T and A1298C polymorphisms in MTHFR gene. A total of 410 hypertensive patients recruited from 344 nuclear families were treated orally with benazepril at a daily dosage of 10 mg for 15 consecutive days. Blood pressures were measured at baseline and on the 16th day of treatment. In addition, 689 family members of these patients were also genotyped. Among these patients, the frequency of MTHFR A1298C AA, AC and CC genotypes was 74.4%, 23.9%, and 1.7%, respectively. The frequency of MTHFR C677T CC, CT and TT genotypes was 23.7%, 51.2%, and 25.1%, respectively. Only three haplotypes, 677T-1298A (50.8%), 677C-1298A (35.7%), and 677C-1298C (13.5%) were re-constructed. Multivariate regression models with generalized estimating equation (GEE) correction detected that the individuals carrying one copy of haplotype 677C-1298C had significantly lower diastolic and systolic blood pressure response (ΔDBP and ΔSBP) to benazepril treatment (p= 0.003 and p =0.043, respectively), in comparison to those without haplotype 677C-1298C. The results of family-based association test further confirmed that haplotype 677C-1298C was more frequently transmitted in subjects with either lower residual of ΔDBP or ΔSBP. For residual of ΔDBP, the p-values are 0.007 in an additive model and 0.005 in a dominant model. For residual of ΔSBP, the p-values are 0.009 in an additive model and 0.006 in a dominant model. Our findings suggest that MTHFR 677C-1298C haplotype modulate blood pressure responsiveness to shortterm treatment of ACE inhibitor in Chinese essential hypertensive patients.     

Frequency of the 677 C-->T mutation of the methylenetetrahydrofolate reductase gene among Kuwaiti sickle cell disease patients

Sickle cell disease (SCD) is relatively mild among Kuwaiti Arabs. However, an atypical subset of patients exists with frequent, severe vaso-occlusive crisis and osteonecrosis. The thermolabile variant of MTHFR, resulting from a C-->T mutation at nucleotide 677, has been shown to be associated with hyperhomocysteinemia, which is an important risk factor for premature vascular disease. We have screened an unselected group of 41 Kuwaiti SCD patients (33 SS and 8 Sbeta(0)-thal) attending the Hematology Clinic of Kuwait University Teaching Hospital for the MTHFR mutation, using a PCR-RFLP method. The patients were aged 2-41 years (mean of 12.8 +/- 8.6). One (2.4%) individual was homozygous for the mutation while 15 (36.6%) were heterozygous, giving an allele frequency of 20.7%. Twenty-one patients (14 SS and 7 Sbeta(0)-thal) were screened for osteonecrosis using MRI of the hip (spin-echo T1- and T2-weighted images). Seven (33.3%) had varying degrees of osteonecrosis, among whom the frequency of the 677 C-->T allele was 21.4%. The frequency was identical among those without osteonecrosis. Although the allele frequency is higher among our patients compared to American SS patients, our results do not suggest an association with osteonecrosis.     

Evaluation of association between methylenetetrahydrofolate reductase and azoospermia: A meta-analysis

Background:Infertility affects childbearing age couples all over the world. One of the important reasons for infertility is genetic factors. Our study evaluated the association between methylenetetrahydrofolate reductase (MTHFR) and azoospermia.Methods:Multiple databases like MEDLINE, EMBASE, Cochrane library, and China journal full-text database were used to search for relevant studies, and full-text articles involved in the evaluation of MTHFR and azoospermia. The results were evaluated using STATA 12.0. Heterogeneity analysis, sensitivity analysis, and bias analysis were also performed on the data.Results:Thirteen related studies eventually met the inclusion criteria. Significant association between C677T polymorphism and azoospermia (relative risk [RR] = 0.94 [0.90, 0.99], I² = 60.9%, P = .002), and between A1298C polymorphism and azoospermia (RR = 0.98 [0.94, 1.02], I² = 56.3%, P = .011) was observed. Meanwhile, in subgroup analysis, Caucasians had higher risk than Mongolians in association between MTHFR and azoospermia.Conclusion:There was association between MTHFR polymorphism and azoospermia. Caucasian populations had higher risk than Mongolian populations in association between MTHFR and azoospermia.