MTHFR C677T基因多态性与高同型半胱氨酸型高血压关联性研究

目的 探索安徽农村地区影响高同型半胱氨酸型高血压(H型高血压)发生的基因和环境危险因素.方法 在安徽农村地区入选226名高血压患者,测定N5,10-亚甲基四氢叶酸还原酶(MTHFR)C677T基因型和血浆同型半胱氨酸(Hcy)水平.结果 (1)所调查的高血压人群男性Hcy水平显著高于女性(P<0.01);男性H型高血压患病率(71.3%)高于女性(48.0%).(2)TT基因型与CC+CT基因型相比,Hcy水平显著增加,H型高血压的比例显著增加.(3)其他相关变量与Hcy水平的多元线性回归模型及与H型高血压多因素Logistic回归模型分析,均未发现年龄、吸烟、饮酒和体质指数与Hcy水平有显著性的相关(均有P>0.05).结论 安徽农村地区高血压人群中MTHFR C677T基因突变可能是H型高血压发病的重要遗传因素且存在性别差异,建议该人群应该尽早做相关的检测以检查是否发生高同型半胱氨酸血症.     

MTHFR C677T genotype and cardiovascular risk in a general population without mandatory folic acid fortification

Purpose

Meta-analyses have suggested an effect of MTHFR C677T genotype (rs1801133), a proxy for blood total homocysteine, on cardiovascular disease (CVD) in populations with low population dietary folate. The aim was to examine the association and effect modification by serum folate and vitamin B12 levels between MTHFR and CVD-related outcomes in a general population with no mandatory folic acid fortification policy.

Methods

The study population included 13,748 adults retrieved from pooling of four population-based studies conducted in Denmark. MTHFR genotype, serum folate (measured in approximately 9,356 individuals), and serum vitamin B12 (9,215 individuals), hypertension, and dyslipidemia were measured at baseline, and participants were followed for a mean of 10.5–11.7 years in central registries for diagnoses of stroke (623 incidents), ischaemic heart disease (IHD) (835 incidents), and all-cause mortality (1,272 incidents).

Results

The MTHFR genotype (TT vs. CC/CT) was not associated with hypertension [OR (95 % CI) 1.09 (0.95–1.25)], dyslipidemia [OR (95 % CI) 0.97 (0.84–1.11)], stroke [HR (95 % CI) 0.92 (0.69–1.23)], and all-cause mortality [HR (95 % CI) 0.94 (0.77–1.14)], either overall, or in participants with low serum folate or B12 status (P values for interactions 0.15–0.94). Individuals with the MTHFR TT genotype had a higher risk of IHD (HR (95 % CI) 1.38 (1.11–1.71)), but this association was not modified by folate status (P value for interaction 0.45).

Conclusions

Our results do not support a causal relationship between homocysteine and CVD. However, we cannot exclude a direct causal effect of MTHFR C677T genotype on IHD.     

食管癌与MTHFR基因C677T表达变异关系

目的 探讨亚甲基四氢叶酸还原酶(MTHFR)基因C677T变异及其与环境危险因素交互作用对食管癌发病的影响。方法 采用病例-对照研究方法,以新诊断的食管癌患者为研究对象,用聚合酶链反应-限制性片段长度多态性分析法(PCR-RFLP)检测MTHFR基因C677T变异,运用多因素Logistic回归分析MTHFR基因C677T变异与环境危险因素交互作用对食管癌发病的影响。结果 MTHFR基因C677T变异与饮酒指数、热烫饮食、霉变食品、精神状态和年龄间存在相乘模型的协同作用,OR值依次为10.892(P=0.013 8),12.043(P=0.012 4),16.444(P=0.009 6),20.581(P≤0.000 1),5.201(P=0.014 5)。结论 MTHFR基因C677T变异可增加老年人、大量饮酒、热烫饮食、霉变食品和精神状态不良等危险因素者患食管癌的危险性。     

绝经妇女MTHFR基因多态性与骨密度关系的meta分析

目的:采用meta分析方法研究绝经后妇女亚甲基四氢叶酸还原酶(MTHFR)C677T基因多态性与骨密度的关系。方法:通过多种数据库检索国内外已发表绝经妇女MTHFR基因多态性和骨密度关系的相关文章进行资料分析。结果:5篇文献符合meta分析纳入标准,均报道了绝经妇女MTHFR基因多态性与股骨颈和椎骨骨密度的关系。分析结果表明,TT基因型与CC/CT基因型妇女相比,具有更低的股骨颈密度,合并效应尺度(WMD)为-0.01g/cm2(95%CI:-0.01～0.01,P<0.001);而TT基因型与CC/CT基因型妇女椎骨骨密度无差异,其WMD为-0.01mg/cm2(95%CI:-0.04～0.01,P=0.32)。结论:绝经妇女MTHFRC677T基因多态性与股骨颈骨密度相关,TT基因型女性具有较低的骨密度,TT基因型可作为预测绝经妇女骨质疏松症的风险因子。     

Changes in lifestyle and total homocysteine in relation to MTHFR(C677T) genotype: the Inter99 study

BACKGROUND: Reduction in total homocysteine (tHcy) may be clinically relevant in the prevention of cardiovascular disease (CVD) in the general population. OBJECTIVE: To examine the effects of changes in various lifestyle habits and lifestyle related biological CVD risk markers on changes in tHcy in relation to MTHFR(C677T) genotype. DESIGN: A 1 year follow-up study. SETTING: Copenhagen County, Denmark. SUBJECTS: Statistical analyses were based on a population-based sample of 915 men and women aged 30-60 years assessed to be at increased CVD risk at baseline and therefore offered lifestyle intervention and re-examination after one year. RESULTS: None of the studied lifestyle changes-- smoking, physical activity, dietary habits, and coffee, tea, and alcohol consumption-- was significantly associated with changes in tHcy, either overall, or in any of the MTHFR genotype subgroups. In addition, changes in tHcy did not differ between participants randomized to low- and high-intensity lifestyle intervention. However, the MTHFR TT genotype was associated with a significant decrease in tHcy compared with the CC/CT genotype in which an increase was observed. In addition, changes in tHcy were associated with changes in several of the biological CVD risk markers: weight, total cholesterol, HDL cholesterol, LDL cholesterol and systolic blood pressure. CONCLUSIONS: Our results indicate that tHcy may not be reduced by lifestyle changes; additionally, they suggest that tHcy may be related to biological CVD risk markers through a lifestyle independent pathway.     

遗忘性轻度认知功能障碍与MTHFR C677T基因多态性及血浆同型半胱氨酸水平研究

目的探讨MTHFR C677T基因多态性及血浆同型半胱氨酸(homocysteine,Hcy)水平与遗忘型MCI(amnestic MCI,a MCI)的关系。方法选入50例a MCI患者(a MCI组)和60例健康老年人(对照组)为研究对象,记录并比较2组年龄、性别、高血压、糖尿病、吸烟、嗜酒。测定并比较2组胆固醇(total cholesterol,TC)、甘油三酯(triglyceride,TG)、低密度脂蛋白胆固醇(low density lipoprotein cholesterol,LDL-C)、高密度脂蛋白胆固醇(high density lipoprotein cholesterol,HDL-C)、尿酸(uric acid,UA)、血浆Hcy浓度及MTHFR C677T基因多态性分布。采用蒙特利尔认知评估量表(montreal cognitive assessment,MoCA)评价aMCI患者认知功能与MTHFR C677T基因多态性和血浆Hcy水平的关系。采用Logistic回归分析a MCI发生的独立危险因素。结果 2组研究对象在年龄、性别构成、受教育年限、高血压、糖尿病、高血脂、吸烟和饮酒等一般资料方面比较差异无统计学意义(P>0.05)。2组研究对象的TG、HDL-C水平比较,差异无统计学意义(P>0.05);2组在TC、LDL-C、UA、Hcy水平及MTHFR C677T基因型分布和等位基因频率比较,差异具有统计学意义(P<0.05)。a MCI组TC、Hcy水平显著高于对照组(P<0.05)。与对照组比较,a MCI组TT基因型增高,CC基因型降低,T等位基因频率增高,C等位基因降低,差异有统计学意义(P<0.05)。不同MTHFR C677T基因型a MCI组Hcy水平显著高于对照组,差异均具有统计学意义(P<0.05)。2组TT基因型血浆Hcy水平均显著高于CC基因型(P<0.05)。CC、CT和TT基因型aMCI患者对应的平均MoCA评分分别为(24.37±1.21)分、(23.26±1.02)分和(22.14±0.96)分,差异具有统计学意义(P<0.05),两两比较差异也具有统计学意义(P<0.05)。多元Logistic回归分析显示,UA与a MCI存在负相关关系,TC、Hcy和MTHFR C677T基因型与aMCI存在正相关关系。结论 MTHFR C677T基因突变致血浆Hcy浓度升高可能是aMCI发病及不断进展的重要危险因素。     

The effect of MTHFR(C677T) genotype on plasma homocysteine concentrations in healthy children is influenced by gender

OBJECTIVE: To explore the influence of gender, together with folate status, on the relation between the common methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and plasma total homocysteine (tHcy) concentrations in healthy children. DESIGN: Cross-sectional study by face-to-face interview.Setting and subjects:A total of 186 sixth-grade students participated from twelve randomly selected primary schools in Volos, Greece. METHODS: Fasting tHcy, folate, and vitamin B(12) were measured in plasma. The MTHFR genotypes were determined. Anthropometric and dietary intake data by 24-h recall were collected. RESULTS: Geometric means for plasma tHcy, plasma folate and energy-adjusted dietary folate did not differ between females and males. The homozygous mutant TT genotype was associated with higher tHcy only in children with lower plasma folate concentrations (<19.9 nmol/l, P = 0.012). As a significant gender interaction was observed (P = 0.050), we stratified the lower plasma folate group by gender and found that the association between the genotype and tHcy was restricted to males (P = 0.026). Similar results were obtained when folate status was based on estimated dietary folate. Specifically, only TT males that reported lower dietary folate consumption (<37 microg/MJ/day) had tHcy that was significantly higher than tHcy levels of C-allele carriers (P = 0.001). CONCLUSIONS: Under conditions of lower folate status (as estimated by either plasma concentration or reported dietary consumption), gender modifies the association of the MTHFR(C677T) polymorphism with tHcy concentrations in healthy children. SPONSORSHIP: Kellog Europe.     

轻中度高血压患者中MTHFR C677T与血清叶酸水平变化的相关性研究

目的探讨轻中度高血压患者亚甲基四氢叶酸还原酶（MTHFR）C677T多态性位点与血清叶酸水平变化间的关系。方法从哈尔滨、沈阳、北京、西安、上海、南京6城市收集的480位28～75岁轻中度原发性高血压患者,按1：1：1的原则随机分为3组;对照组、0．4mg叶酸组、0．8mg叶酸组每日分别服用10mg马来酸依那普利、10mg马来酸依那普利＋0．4mg叶酸、10mg马来酸依那普利＋0．8mg叶酸,连续服用8周。收集治疗前后的血清叶酸水平、MTHFR C677T位点的基因型及其他相关指标。本研究对主要资料完整者371人（男156人,女215人）的MTHFR C677T位点与血清叶酸水平变化间的关系进行统计分析。结果①对照组中C677T基因型对叶酸变化水平无明显作用,各基因型间的差异均无统计学意义。②试验组中血清叶酸变化水平在C677T CC、CT和TT基因型间的变化趋势基本一致,TT型增加水平最少,CC型增加最多。以677CC基因型人群的叶酸变化水平为参照,合并叶酸组中TT基因型在调整前（β=3．99,P=0．034）后（β=5．68,P〈0．001）差异均有统计学意义;0．4mg叶酸组和0．8mg叶酸组TT基因型在调整前（β分别为5．33和2．64,P分别为0．061和0．280）差异无统计学意义,调整后（β分别为5．60和4．68,P分别为0．031和0．050）差异有统计学意义。各组中CT基因型调整前后的差异均无统计学意义（P〉0．05）。结论轻中度高血压患者中MTHFR C677T的基因型对叶酸的疗效具有一定的作用。     

Lack of association between MTHFR C677T and MTHFR A1298C genetic polymorphisms and mental retardation

Findings suggest that there is no association between MTHFR C677T and MTHFR A1298C and mental retardation in the studied Italian population and that these polymorphisms are not contributing to the aetiology of mental retardation.     

Lack of association between MTHFR C677T and MTHFR A1298C genetic polymorphisms and mental retardation

Abstract

Findings suggest that there is no association between MTHFR C677T and MTHFR A1298C and mental retardation in the studied Italian population and that these polymorphisms are not contributing to the aetiology of mental retardation.     

晋东南地区人群亚甲基四氢叶酸还原酶C677T基因多态性分析

目的了解晋东南地区人群亚甲基四氢叶酸还原酶(MTHFR)C677T基因多态性的分布情况,为流行病学分析提供科学依据。方法采用实时荧光定量PCR方法,检测1200人MTHFR的C677T基因多态性应用χ~2进行统计分析。结果该地区人群MTHFR的677CC、677CT、677TT基因型频率分别为17.67%,47.00%和35.33%。其中男性人群分别为17.79%,51.21%和31.00%;女性人群分别为17.61%,45.11%和37.27%。男女人群间MTHFR的C677T基因型频率相比差异无统计学意义(χ~2=4.89,P>0.05)。本地区人群C和T等位基因的频率分别为41.17%,58.83%,其中男性分别为43.40%和56.60%,女性分别为40.17%和59.83%。男女人群间C和T位基因的频率相比差异无统计学意义(χ~2=2.42,P>0.05)。结论晋东南人群中MTHFR的C677T基因多态性的分布符合Hardy-Weinberg平衡,为该地区叶酸代谢相关疾病提供流行病学资料。     

新疆哈萨克族食管癌与叶酸摄入水平、亚甲基四氢叶酸还原酶基因多态关系的研究

目的探讨新疆哈萨克族人群食管癌与叶酸摄人水平及与叶酸代谢相关基因亚甲基四氢叶酸还原酶（MTHER）基因多态的关系。方法采用1：2配比的病例对照研究方法，收集120例哈萨克族食管癌患者，按同性别、同民族、年龄相差≤5岁、同一个居住地区等选取对照240例；选用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法检测MTHFR C677T基因型，采用条件logistic回归进行统计分析。结果叶酸摄入量与哈萨克族食管癌有关（X^2=7．868，υ=1，P〈0．01），其OR值为0．519（95％CI：0．329-0．821），叶酸摄入水平高是保护因素；病例组和对照组MTHFR C677T基因型分布，经统计学检验，差异有统计学意义（X^2=15．823，υ=1，P〈0．01）；MTHFR 677CT、TT基因型个体发生食管癌的危险性是CC基因型个体的2．613倍（95％CI：1．628-4．194）；交互作用提示：叶酸摄入充足，可降低携带MTHFR 677CT、TT基因型个体发生食管癌的危险性。多因素条件logistic回归分析显示：饮用河水或渠水、饮食不规律、辛辣饮食、暴饮暴食、粮食存放超过1年、有食管或胃病变史√MTHFR677位点发生C→T改变等是哈萨克族食管癌的危险因素，叶酸摄入水平高是保护因素。结论叶酸摄入缺乏是新疆哈萨克族食管癌的主要危险因素；MTHFR C677T多态是哈萨克族食管癌的易感因素。     

MTHFR基因C677T多态性与原因不明复发性自然流产的相关性

目的:检测MTHFR基因C677T多态性及其与原因不明复发性自然流产(Unexplained recurrent spontaneous abortion,URSA)的关系。方法:应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术对非孕期URSA妇女159例及127例正常对照妇女进行MTHFR基因C677T等位基因检测,并对部分标本进行测序验证,计算患者组与对照组的基因型频率以及该多态性与URSA的相关性。结果:患者组与对照组T/T纯合子频率分别为37.1%(59/159)和16.5%(21/127),患者组与对照组T等位基因频率分别为62.9%(200/318)和47.2%(120/254),两组分别比较,差异均有统计学意义(P<0.01),对TT基因型与URSA的相关性分析表明,TT基因型妇女发生URSA的相对风险增加(OR=2.978,95%CI 1.678～5.256)。结论:MTHFR基因C677T多态性可能是山东地区URSA发病的遗传风险因素。     

Folate intake, serum homocysteine and methylenetetrahydrofolate reductase (MTHFR) C677T genotype are not associated with oral cancer risk in Puerto Rico

We examined the relationships between folate and methionine intake, serum homocysteine levels (as a biomarker for folate metabolism), and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism genotype and risk of oral cancer in a population-based, case-control study in Puerto Rico. Structured questionnaires were used to collect information on demographic factors, usual adult diet, and tobacco and alcohol use. Oral epithelial cells and blood samples were collected from a subset of subjects. Analyses were conducted by logistic regression, adjusting for age, sex, lifetime smoking and lifetime alcohol intake, with the following numbers of cases/controls, respectively: dietary data (341/521); MTHFR genotype (148/149); and homocysteine (60/90). Although increased folate intake was associated with decreased oral cancer risk [adjusted odds ratio (OR) in highest vs. lowest quartile = 0.6, 95% confidence interval (CI): 0.4, 1.0, P(trend) = 0.05)], this finding was due almost entirely to folate intake from fruit (adjusted OR = 0.4, 95% CI: 0.2, 0.6; P(trend) = 0.0001), whereas other dietary folate sources showed no clear association. Methionine intake and serum homocysteine levels were not associated with oral cancer risk. Subjects with the MTHFR C677T homozygous variant (TT) genotype had a nonsignificantly lower risk, and risk patterns tended to differ by level of folate, methionine, alcohol intake and smoking, although the power to detect significant associations in subgroups of these variables was low. Risks for oral cancer are not folate specific; preventive recommendations for this disease should emphasize the importance of a healthy diet, including substantial intake of fruits.     

单纯性低位脊柱裂与MTHFR基因C677T多态位点的相关性研究

目的:研究N5'N10-亚甲基四氢叶酸还原酶(MTHFR)基因第4外显子C677T突变在汉族先天性单纯性低位脊柱裂(SB)患者及其家庭中的多态性分布和致病相关性。方法:应用限制性片段长度多态聚合酶链反应(PCR-RFLP)技术对69名低位脊柱裂患者、93名患者双亲及129名健康人的C677T多态性进行分析及部分测序鉴定。结果:脊柱裂患者、双亲、对照组两两之间的TT基因型频率差异无统计学意义(P>0.05),T等位基因频率的差异也没有统计学意义(P>0.05)。结论:MTHFR基因第4外显子的C677T突变可能不是单纯性低位脊柱裂的独立遗传致病因素,单纯性低位脊柱裂作为表型轻微的神经管畸形(neural tube defects,NTDs),遗传病因可能与其他NTDs不同。     

Effect of lifestyle factors on plasma total homocysteine concentrations in relation to MTHFR(C677T) genotype. Inter99 (7)

OBJECTIVE: To examine the associations between various lifestyle factors--smoking habits, physical activity, dietary habits, coffee, tea, and alcohol consumption--and homocysteine (tHcy) in relation to MTHFR(C677T) genotype. DESIGN: Cross-sectional population-based study. SETTING: Residents of Copenhagen County, Denmark. SUBJECTS: A random sample of 6457 men and women aged 30-60 years drawn from the Civil Registration System and invited to a health examination in 1999-2001. A total of 2788 participants were included in the statistical analysis. MAIN OUTCOME MEASURES: tHcy was measured using a Fluorescent Polarization Immuno Assay. MTHFR-genotype was determined by PCR and RFLP analysis. Information about lifestyle factors was obtained from a self-administered questionnaire. RESULTS: Daily smoking, less healthy dietary habits, and coffee drinking were associated with elevated tHcy concentrations independent of other determinants. Wine consumption was related to tHcy in a J-shaped manner, whereas beer consumption was negatively associated with tHcy after multiple adjustments. Interaction was observed between smoking status and MTHFR-genotype, smoking status and sex, and beer consumption and age. The effect of smoking was more pronounced in persons with the TT genotype and in women. The effect of beer consumption was more pronounced at younger than at older ages. CONCLUSIONS: Smoking status, dietary habits, coffee intake, wine, and beer consumption were major lifestyle determinants of tHcy. Changes in these lifestyle factors may reduce tHcy concentrations, thereby lowering cardiovascular risk in the general population. SPONSORSHIP: Danish Medical Research Council, Danish Centre for Evaluation and Health Technology Assessment, and Danish Heart Foundation.     

MTHFR基因C677T多态性与心血管疾病相关性的Meta分析

目的系统评价N5,N10-亚甲四氢叶酸还原酶(methylenetetrahydrofolate reductase,MTHFR)基因677位点单核苷酸多态性(C677T)与心血管疾病易感性的相关性。方法计算机检索Pub Med、EMbase、Medline、The Cochrane Library、CNKI、VIP及Wan Fang Data,收集相关人群MTHFR基因C677T多态性与心血管疾病风险的病例-对照研究,检索时限从各数据库建库至2015年7月。按照纳入与排除标准筛选文献、提取资料并评价纳入研究的质量后,用Rev Man 5.2软件采用随机效应模型进行Meta分析;Stata 12.0进行敏感性分析和发表偏倚评估。结果纳入23个病例-对照研究,合计病例5 835例,对照4 251例。Meta分析结果显示在以下5个遗传模型中合并分析时,均提示MTHFR基因C677T多态性与心血管疾病发病风险的相关性具有统计学意义。等位基因模型(T vs C)[OR=1.39,95%CI(1.17,1.65),P=0.000 2];纯合子模型(TT vs CC)[OR=1.57,95%CI(1.16,2.12),P=0.003];杂合子模型(TC vs CC)[OR=1.69,95%CI(1.26,2.27),P=0.000 4];显性遗传模型(TT+TC vs CC)[OR=1.53,95%CI(1.21,1.94),P=0.000 5];隐性遗传模型(TT vs TC+CC)[OR=1.37,95%CI(1.08,1.73),P=0.01]。进行亚组分析时,在以下亚组中显示出更高的发病风险。冠心病组,隐性遗传模型(TT vs TC+CC)[OR=1.38,95%CI(1.17,1.62),P=0.000 1];心肌梗死组,等位基因模型(T vs C)[OR=1.71,95%CI(1.37,2.13),P<0.000 01];年龄<50岁组,纯合子模型(TT vs CC)[OR=2.23,95%CI(1.58,3.17),P<0.000 01]。结论MTHFR基因C677T多态性与心血管疾病的发病具有显著相关性;与等位基因C相比,等位基因T可增加心血管疾病风险。     

The interaction between MTHFR 677 C-->T genotype and folate status is a determinant of coronary atherosclerosis risk

The 677 C-->T polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene interacts with folate status in determining elevated total plasma levels of homocysteine, a risk factor for coronary atherosclerotic disease (CAD). The present study had the following goals: 1) to define the 677 C-->T genotype-specific threshold values of both plasma and RBC folate, associated with hyperhomocysteinemia (>15 micro mol/L); and 2) to determine the risk of CAD among subjects with levels of folate below the genotype-specific threshold considered at risk for hyperhomocysteinemia. We examined 655 subjects, with (433) or without (222) angiographically documented CAD. The MTHFR 677 C-->T genotype-specific threshold values of plasma folate corresponded to the 40th, 30th and 10th percentile in the TT, CT and CC genotype, respectively. A multivariate logistic regression analysis showed that the risk of CAD among subjects with plasma folate levels below the genotype-specific thresholds was 1.6 (95% CI, 1.04-2.46). Similar results were obtained when RBC folate was considered as a measure of folate status (odds ratio = 1.8, 95% CI, 1.03-3.15). A gene-nutrient interaction that defines a higher risk for CAD is determined by folate levels below specific thresholds, which differ depending on the MTHFR 677 C-->T genotype.