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.     

The expectations and realities of nutrigenomic testing in australia: A qualitative study

BackgroundConsumer genomic testing for nutrition and wellness, (nutritional genomics), is becoming increasingly popular. Concurrently, health‐care practitioners (HPs) working in private practice (including doctors interested in integrative medicine, private genetic counsellors, pharmacists, dieticians, naturopaths and nutritionists) are involved as test facilitators or interpreters.ObjectiveTo explore Australian consumers’ and HPs’ experiences with nutrigenomic testing.MethodSemi‐structured in‐depth interviews were conducted using predominantly purposive sampling. The two data sets were analysed individually, then combined, using a constant comparative, thematic approach.ResultsOverall, 45 interviews were conducted with consumers (n = 18) and HPs (n = 27). Many of the consumer interviewees experienced chronic ill‐health. Nutrigenomic testing was perceived as empowering and a source of hope for answers. While most made changes to their diet/supplements post‐test, self‐reported health improvements were small. A positive relationship with their HP appeared to minimize disappointment. HPs’ adoption and views of nutrigenomic testing varied. Those enthusiastic about testing saw the possibilities it could offer. However, many felt nutrigenomic testing was not the only ‘tool’ to utilize when offering health care.DiscussionThis research highlights the important role HPs play in consumers’ experiences of nutrigenomics. The varied practice suggests relevant HPs require upskilling in this area to at least support their patients/clients, even if nutrigenomic testing is not part of their practice.Patient or public contributionAdvisory group included patient/public group representatives who informed study design; focus group participants gave feedback on the survey from which consumer interviewees were sourced. This informed the HP data set design. Interviewees from HP data set assisted with snowball sampling.     

DPD、MTHFR和TS表达水平与氟尿嘧啶类药物治疗消化道肿瘤疗效及预后关系的研究进展

消化道恶性肿瘤包括结直肠癌、胃癌和食管癌等。尽管使用了各种治疗方式，癌症患者仍然有复发和转移。绝大多数患者确诊时即为中晚期，因而化疗在癌症患者中发挥重要作用。作为5-FU抗癌活性中的三个关键酶，二氢嘧啶脱氢酶（DPD）、5,10-亚甲基四氢叶酸还原酶（MTHFR）、胸苷酸合成酶（TS）与消化道肿瘤的疗效、对化疗药物的敏感性及患者的预后有密切关系。     

Methylenetetrahydrofolate reductase C677T and methionine synthase A2756G gene polymorphisms and associated risk of cardiovascular diseases: A study from Jammu region

AimPotent risk factors at both genetic and non-genetic levels are accountable for susceptibility and instigation of different cardiovascular phenotypes. Recently, homocysteine is being identified as an important predictor for cardiovascular diseases. Homocysteine remethylation plays a key role in the synthesis of methionine and S-adenosine methionine. Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) genes are known to regulate the homocysteine remethylation reaction and higher homocysteine level is significantly associated with diverse cardiovascular phenotypes. In this context, we aimed to carry out a study on the association of MTHFR (C677T) and MTR (A2756G) gene polymorphism with CVD in population of Jammu region of J&K state.Materials and methodsA total of 435 individuals were enrolled (195 CVD patients and 240 controls) for the case–control study. Genotyping of MTHFR C677T and MTR A2756G gene polymorphism was done by PCR-RFLP technique. Biochemical parameters were estimated by biochemical analyser.ResultsMetabolic variables such as serum LDL-C, TC and TG were significantly higher in patients (p < 0.0001), whereas serum HDL-C was higher in controls. Majority of the patients were having history of hypertension (57.44%; p < 0.0001) as a concomitant condition. The evaluation of genetic association showed that, MTHFR C6877T (OR: 8.89, 95% CI: 2.01–39.40) and MTR A2756G (OR: 1.48, 95% CI: 1.09–2.00) polymorphisms associated with higher risk of CVD.ConclusionThe present study reveals significant differences in nongenetic variables among patients and control as well as association of gene polymorphisms with CVD risk.     

同型半胱氨酸代谢关键酶基因多态性与2型糖尿病合并冠心病的关系

目的探讨我国北方地区汉族人同型半胱氨酸(Hcy)代谢相关酶(MTHFR C677T、CBS844ins68)基因多态性的特点及基因多态性与2型糖尿病(T2DM)合并冠心病(CHD)的关系。方法研究对象均为北方汉族人群,包括无血缘关系的105例T2DM合并CHD患者、125例单纯T2DM患者和91例健康对照组。应用分子生物学方法分析MTHFR C677T、CBS844ins68基因多态性。结果T2DM合并CHD组的T等位基因频率明显高于与对照组(45.3%vs34.6%,P<0.05),其中CT基因型频率高于对照组(58.1%vs38.5%,P<0.05),CC型频率明显低于对照组(25.7%vs46.2%,P<0.05)。CBS844ins68多态性三组CBS844ins68的基因型及等位基因频率差别均无统计学意义(均P>0.05)。Logistic回归分析显示MTHFR基因型的OR值为1.394,95%CI0.989-1.965(P=0.058);MTHFR677携带T基因(MTHFR CT基因型和TT基因型)的OR值为1.939,95%CI1.159-3.243(P=0.012);CBS的OR值为0.52,95%CI0.108-2.495(P=0.414)。结论MTHFR677携带T基因是我国北方地区汉族人T2DM合并CHD发生的独立危险因素,筛查MTHFR677T基因型可能在预防糖尿病合并冠心病的发生、发展过程中起到一定作用。     

Insights into Severe 5,10‐Methylenetetrahydrofolate Reductase Deficiency: Molecular Genetic and Enzymatic Characterization of 76 Patients

5,10‐Methylenetetrahydrofolate reductase (MTHFR) deficiency is the most common inherited disorder of folate metabolism and causes severe hyperhomocysteinaemia. To better understand the relationship between mutation and function, we performed molecular genetic analysis of 76 MTHFR deficient patients, followed by extensive enzymatic characterization of fibroblasts from 72 of these. A deleterious mutation was detected on each of the 152 patient alleles, with one allele harboring two mutations. Sixty five different mutations (42 novel) were detected, including a common splicing mutation (c.1542G>A) found in 21 alleles. Using an enzyme assay in the physiological direction, we found residual activity (1.7%–42% of control) in 42 cell lines, of which 28 showed reduced affinity for nicotinamide adenine dinucleotide phosphate (NADPH), one reduced affinity for methylenetetrahydrofolate, five flavin adenine dinucleotide‐responsiveness, and 24 abnormal kinetics of S‐adenosylmethionine inhibition. Missense mutations causing virtually absent activity were found exclusively in the N‐terminal catalytic domain, whereas missense mutations in the C‐terminal regulatory domain caused decreased NADPH binding and disturbed inhibition by S‐adenosylmethionine. Characterization of patients in this way provides a basis for improved diagnosis using expanded enzymatic criteria, increases understanding of the molecular basis of MTHFR dysfunction, and points to the possible role of cofactor or substrate in the treatment of patients with specific mutations.     

N5,10-亚甲基四氢叶酸还原酶基因多态性与原发性高血压病的关系研究

目的 探讨N^5,10-亚甲基四氢叶酸还原酶基因（MTHFR）C677T多态性与原发性高血压病（EH）的关系.方法 收集两家省级住院的原发性高血压病患者（EH）252例,健康体检正常血压者（NT）195例,抽外周静脉血提取DNA,采用聚合酶链反应-限制性片段长度（PCR-RFLP）多态性分析,检测MTHFR基因型.结果 两组CC、CT和TT三种基因型构成比总的卡方检验示分布差异显著（χ^2=12.731,P＜0.005）,EH组T等位基因高于NT组,差异有统计学意义（χ^2=13.456,P＜0.005）;经进一步卡方分割检验显示CT/TT基因型在EH组构成比高于NT组,差异显著（χ^2=11.367,P＜0.005）,调整年龄、性别、血糖、肌酐、尿素氮、体重指数和血清尿酸水平后CT/TT基因型人群患EH危险性是CC基因型的1.964倍（OR=1.964,95%CI：1.302～2.961,P=0.001）.结论 MTHFR基因CT/TT基因型可能是南方高血压病住院人群的发病危险因素之一.     

Methylenetetrahydrofolate reductase C677T polymorphism and liver fibrosis progression in patients with recurrent hepatitis C

Background/Aims: Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, being a putative steatogenic factor, may promote liver fibrosis progression in patients with chronic hepatitis C. This study aimed to verify the role of recipient MTHFR polymorphism in favouring graft fibrosis progression in patients with recurrent HCV after orthotopic liver transplantation (OLT). Methods: We studied 63 such patients, followed for >1 year. MTHFR allelic variants were determined by a polymerase chain reaction/restriction fragment length polymorphism method. Results: Recipients carrying the TT genotype had more frequently, 1‐year post‐OLT, homocysteine serum levels >23 μmol/L (P<0.05), serum triglycerides >180 mg/dL (P<0.02) and de novo diabetes mellitus (P<0.05) but not a higher frequency of graft steatosis. Time‐to‐event analysis in reaching an Ishak staging score >2 was performed by stratifying the recipients as follows: (a) patients with donor age ≤45 years, (b) patients with donor age >45 and C/^* genotype, and (c) patients with donor age >45 years and TT genotype. A significant linear trend was observed, with increasing frequencies as follows: (a) 8/37, (b) 10/19 and (c) 6/7 (P=0.0005). Conclusion: The MTHFR C677T polymorphism may play a role in influencing liver fibrosis progression in patients with recurrent hepatitis C, in conjunction with donor age, but not via steatosis promotion.     

山西人群MTHFR基因rs1801133位点多态性与非综合征性唇腭裂的关联性研究

目的:研究亚甲基四氢叶酸还原酶(methylenetetrahydrofolate reductase,MTHFR)基因rs1801133位点多态性与非综合征性唇腭裂(NSCL/P)的关系。方法:采用聚合酶链反应-限制性片段长度多态性方法,检测334例非综合征性唇腭裂患者和314例正常对照组的MTHFR基因rs1801133位点的多态性。结果:MTHFR基因rs1801133位点基因型频率分布符合Hardy-Weinberg平衡;MTHFR基因rs1801133位点基因型及等位基因的分布在NSCL/P组与对照组之间均无统计学意义(P>0.05)。结论:MTHFR基因rs1801133位点多态性与山西人群非综合征性唇腭裂的发生无关。