MTHFR基因多态性对药物联合干预H型高血压血浆Hcy动态监测的影响

目的 研究H型高血压患者服用马来酸依那普利叶酸片对血浆同型半胱氨酸（Hcy）水平的影响及亚甲基四氢叶酸还原酶（MTHFR）基因多态性对该疗效监测的预警作用. 方法 依托深圳南山区脑卒中社区综合防治项目,选取150例H型高血压患者和80例对照者,采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）法检测MTHFR基因多态性,分析不同基因型Hcy的差异.同时循环酶法测定95例H型高血压患者服用马来酸依那普利叶酸片4周前后血浆Hcy水平变化. 结果 H型高血压组中CC、CT、TT不同基因型Hcy水平差异有统计学意义,尤以TT基因型Hcy水平最高（P＜0.01）.95例H型高血压组采用马来酸依那普利叶酸片进行4周干预后,TT基因型Hcy水平下降幅度最大,差异有统计学意义（P＜0.05）. 结论 H型高血压人群中MTHFR基因677C/T纯合突变TT基因型可能是Hcy升高的重要遗传因素.应用马来酸依那普利叶酸片可有效降低高血压患者发生高Hcy血症的风险,其中以MTHFR基因TT型者为最明显.     

西藏阿里地区西部四县藏族高血压人群同型半胱氨酸水平与基因多态性的相关性研究

目的 分析西藏阿里地区西部四县藏族高血压人群同型半胱氨酸（Hcy）水平与基因多态性的相关性。方法 对阿里地区西部四县居民进行随机调查,对本次调查的1514名居民进行血清生化指标以及MTHFR C677T、MTHFR A1298C、MTRR A66G基因型的检测,同时主要分析其中254名高血压患者同型半胱氨酸水平及其基因多态性。结果 西藏阿里地区西部四县高血压人群中HHcy检出率为82.68%,MTHFR C677T三组基因型（CC型、CT型、TT型）在收缩压(F=3.802)、舒张压(F=3.090)和Hcy(χ2=14.938)水平存在统计学意义（P<0.05）,其突变纯和型TT组Hcy水平较高;MTHFR A1298C三组基因型（AA型、AC型、CC型）在血糖(χ2=6.351)和Hcy(χ2=8.332)水平存在统计学意义（P<0.05）;MTRR A66G三组基因型（AA型、AG型、GG型）在Hcy以及其他指标水平上均没有统计学意义。三种基因型及等位基因均在高Hcy组分布较多。结论 西藏阿里西部地区高血压人群中伴有HHcy的人群居多,MTHFR C677T TT型可导致血浆Hcy水平增高。     

2型糖尿病合并冠心病患者的同型半胱氨酸水平及代谢关键酶基因多态性特点

目的探讨中国北方地区糖尿病合并冠心病者同型半胱氨酸(Hcy)及其代谢相关酶亚甲基四氢叶酸还原酶(MTHFR)C677T及胱硫醚β-合成酶(CBS)844 ins 68基因多态性的特点。方法研究对象均为北方汉族人群,包括无血缘关系的70名糖尿病合并冠心病患者、71名糖尿病患者和85名健康人群。应用荧光偏振免疫法(FPIA)测定Hcy水平,应用微粒子酶免分析免疫法(MEIA)测定血浆叶酸、维生素B12浓度,同时测定血脂。应用聚合酶链反应分析MTHFR C677T与CBS844 ins 68基因多态性。结果糖尿病合并冠心病组(DM+CHD组)Hcy中位数为14.8μmol/L,显著高于DM组(11.1μmol/L)和对照组(11.2μmol/L),(P<0.01),DM组与对照组之间差异无显著性(P>0.05)。DM+CHD组的T等位基因频率(45%)明显高于糖尿病组(26.8%)和对照组(31.2%),(P<0.01)。三组CBS844 ins 68的基因型及等位基因频率差异无显著性(P>0.05)。本研究定义Hcy>15μmol/L为高Hcy血症(HHcy)。Logistic回归分析显示HHcy的OR值为4.547(95%CI1.970～10.496),(P<0.01);MTHFR677携带T基因的OR值为2.369(95%CI1.160～4.841),(P=0.018);CBS844 ins 68基因的OR值为0.384(95%CI0.033～4.423),(P=0.443)。结论HHcy、MTHFR677携带T基因可能是中国北方地区汉族人2型糖尿病合并冠心病发生的危险因素。     

育龄妇女叶酸代谢通路关键酶基因多态性对血浆同型半胱氨酸水平的影响

目的 观察育龄妇女叶酸代谢通路关键酶基因多态性对血浆同型半胱氨酸水平的影响.方法 2012年通过整群抽样方法抽取535名江苏省绍兴市年龄为20～ 45岁之间的育龄妇女,平均年龄为28.2(95％ CI:27.8 ～28.6)岁.抽取静脉血5ml,加入抗凝剂EDTA或柠檬酸钠连续采集样本7d,共采集1 465名调查对象血样,分离血细胞后,采用离心柱法进行DNA提取.然后对采集到的样本进行叶酸代谢关键酶基因多态性检测及血浆同型半胱氨酸(homocysteine,Hcy)水平分析,分析不同位点基因型的Hcy差异.结果 共检测了调查对象MTHFR、MS、MSR和CBS基因上的8个单核苷酸多态性(SNP)位点.MTHFR基因上的rs1801131位点基因型AA的Hey平均浓度(8.99 μmol/L)高于CC(7.81μmol/L)及CA(8.38 μmol/L)型,P＜0.01.MTHFR基因上的rs1801133基因型为TT的调查对象Hcy平均浓度(11.10 μmol/L)高于CC(8.15 μmol/L)及CT(8.45 μmol/L)型,P＜0.01.该两个位点的基因型组合AA-TT会导致Hcy浓度的升高(11.02μmol/L),均高于其他基因型组合,特别是CC-CC基因型组合(7.83 μmol/L),风险系数是该基因型的1.41 (95％ CI:1.20～1.66)倍.结论 MTHFR基因上的rs1801131和rs1801133的基因突变可导致Hcy水平升高.     

兰州地区育龄妇女叶酸代谢与早产的相关性研究

目的探讨兰州地区育龄妇女血清同型半胱氨酸(Hcy)水平、5,10-亚甲基四氢叶酸还原酶(MTHFR)及甲硫氨酸合成酶还原酶(MTRR)基因多态性与早产的相关性。方法选取2015年2月-2016年7月在甘肃省妇幼保健院产检并分娩的孕妇1 298例为研究对象,按照新生儿是否早产,将新生儿及其母亲分为早产组和足月组,应用RT-PCR技术检测MTHFR基因C677T、A1298C和MTRR A66G位点的多态性,同时应用循环酶法检测血浆Hcy水平。比较早产组和足月组间各种基因型与血清Hcy水平的差异及相关性。结果早产组血浆Hcy水平明显高于足月组,差异均有统计学意义(P0. 05)。高Hcy为早产的危险因素(OR=2. 672,P=0. 032)。血浆Hcy水平在MTHFR C677T、A1298C和MTRR A66G突变纯合子患者中显著高于突变杂合子和野生型患者,且野生型患者血浆Hcy水平最低,差异均有统计学意义(均P0. 05)。结论早产孕妇血浆Hcy水平明显高于足月孕妇,孕妇血浆Hcy水平与早产相关,补充叶酸前需检测叶酸代谢关键基因的SNP类型,以便更有效的补充叶酸,从而降低早产的发生率。     

泸州汉族人群MTHFR基因多态性分布及育龄妇女该基因多态性与复发性流产相关性的研究

目的了解泸州市亚甲基四氢叶酸还原酶(MTHFR)基因多态性分布情况以及该单核苷酸多态性与复发性流产的相关性。方法选取2016-2018年在西南医科大学附属医院进行MTHFR基因检测的泸州汉族人群691例为研究对象,利用PCR-微阵列基因芯片法检测其C677T单核苷酸多态性,统计得出3种基因型的频率以及等位基因频率,并与全国其他地区已报道的多态性分布特征进行比较。结果泸州汉族人群CC、CT与TT基因型频率分别为39.2%、46.7%、14.0%,T等位基因频率为37.4%。其中女性T等位基因频率为38.1%,基因分布与纬度相近地区(N25°~31°)差异无统计学意义(P>0.05),与南方的海南、惠州及北方的西安、银川、赤峰、烟台人群差异有统计学意义(P<0.05)。在泸州育龄妇女中,复发性流产与MTHFR C677T基因多态性暂未发现存在直接关联。结论泸州地区汉族人群的MTHFR基因分布具有西南地区的分布特征,T等位基因频率整体呈现出随着纬度升高而升高的趋势。     

血浆同型半胱氨酸水平及MTHFR基因多态性与阿尔茨海默病的关系

目的 探讨血浆同型半胱氨酸(Hcy)水平及MTHFR基因多态性与阿尔茨海默病(AD)的关系. 方法 选取43例AD患者(AD组),应用高效液相色谱-电化学检测(HPLC-ED)法测定血浆Hcy水平,应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)检测MTHFR基因多态性,同时测定血浆叶酸、维生素B12水平,并与40例健康老年人(对照组)比较. 结果 AD组血浆Hcy水平为(25.43±5.60)μmol/L,显著高于对照组的(9.81±2.86)μmol/L(P＜0.01),血浆叶酸、维生素B12水平明显低于对照组(P＜0.05);MTHFR基因型有3种,即纯合子(T/T)型、杂合子(T/C)型和纯合子(C/C)型,两组MTHFR基因型和等位基因频率比较差异均无统计学意义(P＞0.05). 结论 高Hcy血症是AD发生和发展的一个重要危险因素.     

血浆同型半胱氨酸水平及亚甲基四氢叶酸还原酶基因突变与脑卒中关系的病例对照研究

目的 探讨中国人脑卒中与血浆同型半胱氨酸(Hcy)水平及N~5N~(10)亚甲基四氢叶酸还原酶(MTHFR)基因突变的关系。方法 收集脑卒中患者300例为病例组,选择300名性别、年龄和种族等与病例组相匹配的无脑卒中者作为对照组,采用高效液相色谱的方法检测两组的血浆Hcy水平,并通过聚合酶链反应和限制性酶切的方法对其MTHFR C677T基因型进行鉴定,统计分析血浆Hcy水平与脑卒中的关系,以及MTHFR C677T基因突变与脑卒中发生的关系及其对血浆Hcy水平的影响。结果 脑卒中组血浆Hcy水平显著高于对照组[(16`92±3.43)μmol/L vs.(14.57±2.59)μmol/L,P<0.05];MTHFR C677T基因突变率在脑卒中组与对照组之间差异无统计学意义(P>0.05),在脑溢血和脑梗死组之间差异也无统计学意义(P>0.05);MTHFR C677T基因变异对血浆Hcy水平无明显影响[(15.28±2.17)μmol/L vs.(15.11±3.81)μmol/L,P>0.05]。结论 血浆Hcy水平升高在中国人脑卒中的发生中起着重要的作用,而Hcy代谢过程中的关键酶MTHFR基因的C677T突变与血浆Hcy水平无明显关系,而且与脑卒中的发生无相关性,因此控制血浆Hcy水平在预防心脑血管疾病的发生中有重要意义。     

体检人群血清同型半胱氨酸水平与MTHFRC677T基因型频率的调查

目的调查北京地区体检人群血清同型半胱氨酸(Hcy)水平及其代谢酶亚甲基四氢叶酸还原酶(MTHFR)基因的C677T基因型分布情况。方法利用全自动生化分析仪循环酶法检测892例体检者血清同型半胱氨酸水平,采用微测序法检测MTHFR C677T基因多态性,并进行基因分型。结果 TT基因型受检者血清Hcy水平高于CT基因型和CC基因型受检者水平,所调查的体检人群中男性血清Hcy水平显著高于女性,差异有统计学意义(P0.01)。结论MTHFR基因的C677T纯合突变型与血浆Hcy水平升高相关,此外健康人群血清Hcy水平存在年龄及性别差异。基因分型检测对于降低血清Hcy水平,预测脑卒中等心脑血管疾病具有重要意义。     

MTHFR基因C677T位点多态性与胎儿生长受限的相关性

目的:探讨亚甲基四氢叶酸还原酶(MTHFR)基因C677T位点多态性与胎儿生长受限(FGR)的关系。方法:FGR患者62例,正常妊娠妇女65例。聚合酶链反应—限制性内切酶片段长度多肽性(PCR-RFLP)法检测MTHFR C677T基因多态性;荧光偏振免疫法测定血浆总同型半胱氨酸水平;微粒子酶免分析法测定血浆叶酸、VitB12浓度。结果:①FGR组MTHFR C677TC/T基因型频率显著高于正常对照组,C/C基因型频率显著低于对照组,总的突变T等位基因频率显著高于对照组(P<0.05)。②FGR组MTHFRT/T基因型Hcy水平较C/C、C/T基因型患者显著增高,而血清叶酸水平则明显降低(P<0.05)。血清VitB12水平在FGR3种基因型之间差异无显著性(P>0.05)。对照组MTHFR C677T3种基因型之间血清Hcy、叶酸、VitB12,水平差异无显著性(P>0.05)。结论:MTHFR基因C677T位点多态性与FGR有关,高同型半胱氨酸血症是FGR发病的危险因素。     

Association between decreased vitamin levels and MTHFR, MTR and MTRR gene polymorphisms as determinants for elevated total homocysteine concentrations in pregnant women

OBJECTIVES: To examine the association between methylenetetrahydrofolate reductase (MTHFR) (C677T and A1298C), methionine synthase (MTR) A2756G and methionine synthase reductase (MTRR) A66G gene polymorphisms and total homocysteine (tHcy), methylmalonic acid (MMA) and S-adenosylmethionine/S-adenosylhomocysteine (SAM/SAH) levels; and to evaluate the potential interactions with folate or cobalamin (Cbl) status. SUBJECTS/METHODS: Two hundred seventy-five healthy women at labor who delivered full-term normal babies. Cbl, folate, tHcy, MMA, SAM and SAH were measured in serum specimens. The genotypes for polymorphisms were determined by PCR-restriction fragment length polymorphism (RFLP). RESULTS: Serum folate, MTHFR 677T allele and MTR 2756AA genotypes were the predictors of tHcy levels in pregnant women. Serum Cbl and creatinine were the predictors of SAM/SAH ratio and MMA levels, respectively. The gene polymorphisms were not determinants for MMA levels and SAM/SAH ratios. Low levels of serum folate were associated with elevated tHcy in pregnant women, independently of the gene polymorphisms. In pregnant women carrying MTHFR 677T allele, or MTHFR 1298AA or MTRR 66AA genotypes, lower Cbl levels were associated with higher levels of tHcy. Lower SAM/SAH ratio was found in MTHFR 677CC or MTRR A2756AA genotypes carriers when Cbl levels were lower than 142 pmol/l. CONCLUSIONS: Serum folate and MTHFR C677T and MTR A2576G gene polymorphisms were the determinants for tHcy levels. The interaction between low levels of serum Cbl and MTHFR (C677T or A1298C) or MTRR A66G gene polymorphisms was associated with increased tHcy.     

No association between common polymorphisms in genes of folate and homocysteine metabolism and the risk of Down's syndrome among French mothers

The cause of the non-disjunction leading to trisomy 21 remains unclear. Recent evidence has suggested that 5,10-methylenetetrahydrofolate reductase (MTHFR) and/or methionine synthase reductase (MTRR) might contribute to the maternal risk of trisomy 21. The purpose of the present study was to analyse these findings among the French population and to investigate whether common polymorphisms in genes of the folate and homocysteine pathway, including the MTHFR 677C > T, MTHFR 1298A > C, the methionine synthase (MTR) 2756A > G, the cystathionine beta-synthase (CBS) 844Ins68 and the reduced folate carrier (RFC-1) 80G > A polymorphisms, contribute to the risk of trisomy 21. The risk was studied by analysing independent and combined genotypes in 119 case mothers and 119 control mothers. The MTHFR 677T, MTHFR 1298C, MTR2756G, MTRR66G, CBSIns68+ and the RFC-1 80G allele frequencies were not significantly different among French case mothers, compared with control mothers. The risk of having a child with trisomy 21 did not appear to be linked to polymorphisms in genes associated with folate and homocysteine metabolism.     

Methionine synthase reductase 66A->G polymorphism is associated with increased plasma homocysteine concentration when combined with the homozygous methylenetetrahydrofolate reductase 677C->T variant

Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) are important for homocysteine remethylation. This study was designed to determine the influence of genetic variants (MTHFR 677C-->T, MTHFR 1298A-->C, and MTRR 66A-->G), folate, and vitamin B-12 status on plasma homocysteine in women (20-30 y; n = 362). Plasma homocysteine was inversely (P < 0.0001) associated with serum folate and plasma vitamin B-12 regardless of genotype. Plasma homocysteine was higher (P < 0.05) for women with the MTHFR 677 TT/1298 AA genotype combination compared with the CC/AA, CC/AC, and CT/AA genotypes. Women with the MTHFR 677 TT/MTRR 66 AG genotype had higher (P < 0.05) plasma homocysteine than all other genotype combinations except the TT/AA and TT/GG genotypes. There were 5.4-, 4.3-, and 3.8-fold increases (P < 0.001) in risk for plasma homocysteine in the top 5, 10, and 20%, respectively, of the homocysteine distribution for subjects with the MTHFR 677 TT compared with the CC and CT genotypes. Predicted plasma homocysteine was inversely associated with serum folate (P = 0.003) and plasma vitamin B-12 (P = 0.002), with the degree of correlation dependent on MTHFR 677C-->T genotype. These data suggest that coexistence of the MTHFR 677 TT genotype with the MTRR 66A-->G polymorphism may exacerbate the effect of the MTHFR variant alone. The potential negative effect of combined polymorphisms of the MTHFR and MTRR genes on plasma homocysteine in at-risk population groups with low folate and/or vitamin B-12 status, such as women of reproductive potential, deserves further investigation.     

贵阳市育龄女性MTHFR和MTRR基因多态性与自然流产的相关性分析

目的分析贵阳市育龄女性亚甲基四氢叶酸还原酶(MTHFR)、甲硫氨酸合成酶还原酶(MTRR)基因多态性与自然流产的相关性,降低贵阳市育龄女性自然流产发生率。方法选取2016—2019年在贵阳市妇幼保健院进行孕前优生咨询的525例育龄女性为研究对象,按照有无自然流产史分为两组,病例组175例女性,对照组350例女性。比较两组育龄女性MTHFR C677T、A1298C及MTRR A66G基因型和等位基因分布。结果病例组MTHFR C677T野生基因型CC型69例(39.4%),杂合突变CT型76例(43.4%),纯合突变TT型30例(17.1%),对照组MTHFR C677T野生基因型CC型154例(44.0%),杂合突变CT型164例(46.9%),纯合突变TT型32例(9.1%),两组比较差异具有统计学意义(χ²=7.20,P<0.05);病例组的T等位基因频率为38.9%,较对照组T等位基因频率(32.6%)明显升高,差异有统计学意义(χ²=4.07,P<0.05)。两组MTHFR A1298C基因型分布比较差异无统计学意义(P...     

MTHFR、MTRR基因多态性与多囊卵巢综合征的相关性研究

目的探讨亚甲四氢叶酸还原酶(MTHFR)、甲硫氨酸合成酶还原酶(MTRR)基因多态性与多囊卵巢综合征(PCOS)的相关性。方法应用病例对照研究,收集2018年4月-2018年8月在广东省妇幼保健院就诊的育龄期PCOS患者55例为PCOS组,选取46例月经规则、有排卵,并完成一次生育的非PCOS患者作为对照组。在PCOS组中,按HOMA稳态模型(HOMA-IR)分为两组,PCOS胰岛素抵抗(PCOS-IR)组和PCOS非胰岛素抵抗(PCOS-NIR)组,按多毛评分标准(m FG score)和血清游离雄激素指数(FAI)分为两组,高雄激素症组和非高雄激素症组,分别提取血浆,利用荧光定量PCR方法检测MTHFR基因C677T、A1298C及MTRR基因A66G的单核苷酸多态性(SNPs),同时采用化学发光法检测两组血浆维生素B12、叶酸及同型半胱氨酸(HCY)的含量。结果MTHFR基因C677T等位基因C在PCOS组分布频率高于对照组,差异有统计学意义(P<0.05),等位基因C使PCOS的风险增加2.077倍(95%CI:1.132~3.812)。677CC基因型在PCOS组的分布频率明显高于对照组,差异有统计学意义(P<0.05),野生基因型(CC)与纯合突变基因型(TT)相比,患PCOS的风险提高了4.392倍(95%CI:1.005~19.196)。两组MTHFR基因A1298C、MTRR基因A66G各基因型和等位基因频率的分布差异无统计学意义(P>0.05)。在PCOS组中,PCOS-IR组和PCOS-NIR组以及高雄激素症组和非高雄激素症组在MTHFR基因C677T、A1298C及MTRR基因A66G各基因型分布差异无统计学意义(P>0.05),MTHFR C677T、A1298C及MTRR A66G位点分布之间不存在交互作用(P>0.05)。PCOS组中HCY水平较对照组明显升高,差异有统计学意义(P<0.05),两组血清维生素B12、叶酸水平差异均无统计学意义(均P>0.05)。结论MTHFR基因C677T多态性与PCOS的发病有一定的相关性,CC基因型可增加PCOS的发生风险,但与胰岛素抵抗(IR)和高雄激素症的发生风险无关。MTHFR基因A1298C、MTRRA66G各基因型与PCOS的发生、IR及高雄激素症的发生无关,PCOS组HCY偏高。     

The effect of 677C-->T and 1298A-->C mutations on plasma homocysteine and 5,10-methylenetetrahydrofolate reductase activity in healthy subjects

We have studied the effect of common mutations (677C-->T and 1298A-->C) of the methylenetetrahydrofolate reductase (MTHFR) gene in sixty-six healthy French subjects, aged 27-47 years. Serum folate, vitamin B12, and plasma total homocysteine were measured as well as the specific activity of MTHFR in lymphocytes. The frequency of subjects homozygous for the 677TT genotype was 18%, and that of those homozygous for the 1298CC genotype was 12.5%. The frequency of individuals heterozygous for both mutations was 23.5%. The 1298A-->C mutation was associated with decreased MTHFR specific activity in subjects with both 677CC and 677CT genotypes. This activity was 60% for the 677CC/1298AC genotype and 52% for the 677CC/1298CC genotype when compared with the MTHFR specific activity of the 677CC/1298AA genotype. Heterozygotes for both mutations (677CT/1298AC genotype) had 36% of the reference specific activity. Although homocysteine levels in 677TT and 1298CC genotype subjects were higher than for other genotypes, no significant differences were observed among different genotypes. This may be due to high serum folate level in our samples, and suggests that folate therapy may be useful to prevent hyperhomocysteinaemia in homozygous mutant subjects.     

Vitamin B-12 status is inversely associated with plasma homocysteine in young women with C677T and/or A1298C methylenetetrahydrofolate reductase polymorphisms

Methylenetetrahydrofolate reductase (MTHFR) polymorphisms may negatively influence one-carbon metabolism and increase health risks in women of reproductive age. The effect of MTHFR single nucleotide polymorphisms at bp 677 and/or 1298 and differences in folate and vitamin B-12 status on plasma homocysteine concentration in women of reproductive age (20-30 y; n = 186) were investigated. From the multivariate regression model, homozygotes (n = 23) for the C677T MTHFR variant had plasma homocysteine concentrations that were higher (P < 0.05) than those observed in the other 5 genotype groups, including those who were heterozygous for both variants (677CT/1298AC; n = 32). Plasma homocysteine was negatively associated with plasma vitamin B-12 concentration (P = 0.015) and serum folate (P = 0.049), with the degree of correlation between plasma vitamin B-12 and homocysteine concentrations dependent on MTHFR genotype. The C677T and A1298C MTHFR polymorphisms were significant predictors (P < 0.05) of plasma homocysteine when regression analysis was used to model plasma homocysteine concentration as a function of genotype, supplement use, serum folate and plasma vitamin B-12 concentration. Plasma homocysteine decreased as vitamin B-12 concentration increased (P = 0.0005) in individuals who were heterozygous for both the C677T and A1298C variants with nonsignificant trends (P = 0.114-0.128) in individuals homozygous for either the C677T or A1298C variants. In contrast, within the group of individuals with the wild-type genotype for both the C677T and A1298C MTHFR variants, homocysteine was not associated with changes in plasma vitamin B-12 concentrations. These data suggest that enhancing vitamin B-12 status may significantly decrease homocysteine in young women with C677T and/or A1298C MTHFR polymorphisms, even when vitamin B-12 concentrations are within the normal range.     

Prevalence and effects of gene-gene and gene-nutrient interactions on serum folate and serum total homocysteine concentrations in the United States: findings from the third National Health and Nutrition Examination Survey DNA Bank

BACKGROUND: Abnormalities of folate and homocysteine metabolism are associated with a number of pediatric and adult disorders. Folate intake and genetic polymorphisms encoding folate-metabolizing enzymes influence blood folate and homocysteine concentrations, but the effects and interactions of these factors have not been studied on a population-wide basis. OBJECTIVE: The objective was to assess the prevalence of these genetic polymorphisms and their relation to serum folate and homocysteine concentrations. DESIGN: DNA samples from 6793 participants in the third National Health and Nutrition Examination Survey (NHANES III) during 1991-1994 were genotyped for polymorphisms of genes coding for folate pathway enzymes 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C-->T and 1298A-->C, methionine synthase reductase (MTRR) 66A-->G, and cystathionine-beta-synthase 844ins68. The influence of these genetic variants on serum folate and homocysteine concentrations was analyzed by age, sex, and folate intake in 3 race-ethnicity groups. RESULTS: For all race-ethnicity groups, serum folate and homocysteine concentrations were significantly related to the MTHFR 677C-->T genotype but not to the other polymorphisms. Persons with the MTHFR 677 TT genotype had a 22.1% (95% CI: 14.6%, 28.9%) lower serum folate and a 25.7% (95% CI: 18.6%, 33.2%) higher homocysteine concentration than did persons with the CC genotype. Moderate daily folic acid intake (mean: 150 microg/d; 95% CI: 138, 162) significantly reduced the difference in mean homocysteine concentrations between those with the MTHFR 677 CC and TT genotypes. We found a significant interaction between MTHFR 677C-->T and MTRR 66A-->G on serum homocysteine concentrations among non-Hispanic whites. CONCLUSIONS: The MTHFR 677C-->T polymorphism was associated with significant differences in serum folate and homocysteine concentrations in the US population before folic acid fortification. The effect of MTHFR 677C-->T on homocysteine concentrations was reduced by moderate daily folic acid intake.     

Dietary and genetic determinants of homocysteine levels among Mexican women of reproductive age

OBJECTIVE: To evaluate the independent and joint effects of dietary folate, vitamin B(12) consumption and methylenetetrahydrofolate reductase (MTHFR) polymorphisms (677C>T and 1298A>C) on the circulating folate and homocysteine (Hcy) levels among Mexican women of reproductive age. DESIGN: A cross-sectional, population-based study. SUBJECTS: The first 130 healthy non-pregnant women (aged 16-34 years) who agreed to participate in a reproductive cohort in Morelos, Mexico. MAIN OUTCOME MEASUREMENTS: Dietary intakes of vitamin B(12) and folate were estimated using a semiquantitative food frequency questionnaire. MTHFR 677C>T and 1298A>C polymorphisms were ascertained using the PCR-based method. Serum levels of Hcy and folate were determined using high-performance liquid chromatography and radioimmunoassay, respectively. RESULTS: Genotype frequencies for the MTHFR 677C>T polymorphism were 21.5% (CC), 52.3% (CT) and 26.2% (TT) among Mexican women. Of the population, 22% had the MTHFR 1298AC genotype, while no individual carried the 1298CC genotype. We observed an increased level of Hcy among carriers of the 677TT genotype, compared to carriers of the 677CC genotype. The highest level of Hcy was observed among MTHFR 677TT carriers with low B(12) intake (<2.0 microg/day), which resulted with a significant interaction (P=0.01). CONCLUSION: Vitamin B(12) is an important determinant of Hcy levels in Mexico. Supplementation of folic acid with vitamin B(12) may be preferable when the MTHFR 677T variant allele is prevalent.     

亚甲基四氢叶酸还原酶和甲硫氨酸合成酶还原酶基因多态性研究

目的:探讨编码叶酸代谢通路中关键酶的基因多态性与新生儿神经管缺陷(NTDs)间的关联性,及在部分中国女性人群中的分布特征,从而指导孕期叶酸补充和风险监测。方法:采用循证医学方法对5,10-亚甲基四氢叶酸还原酶(MTHFR)C677T、A1298C和甲硫氨酸合成酶还原酶(MTRR)A66G与NTDs的关联性进行Meta分析,并在中国的北方(山东、河南)和南方(四川、海南)地区进行了1 017例样本的分子流行病学研究。结果:MTHFR C677T位点TT基因型相对于CC型的比值比为3.35(95%CI:1.39～8.13),TT型在北方和南方女性人群中的频率分别为37.35%和10.44%,差异有统计学意义;MTHFR A1298C和MTRR A66G虽然从生物学机制上与NTDs的发生密切相关,但尚需进行大规模的人群研究。结论:基于MTHFR和MTRR多态性检测的孕期叶酸补充指导和监测将是进一步降低新生儿出生缺陷的重要方法。