叶酸代谢酶基因多态性与反复自然性流产易感性的研究

目的探讨叶酸代谢相关酶基因多态性在不明原因反复自然流产遗传易感性中的作用地位。方法运用聚合酶链反应-限制性片段长度多态性技术（PCR—RFLP）检测蛋氨酸合成酶还原酶（MTRR）A66G,蛋氨酸合成酶（MS）A2756G,N5,10-亚甲基四氢叶酸还原酶（MTHFR）C677T,胱硫醚β-合成酶（CBβS）844ins68基因多态性。结果不明原因反复自然流产患者MTHFR的T等位基因突变频率较正常对照组明显升高。而MS、MTRR和CBβS突变频率在病例组与对照组之间无显著差异。结论MTHFR C677T基因突变多态性可作为不明原因反复自然流产预后的检测指标。     

叶酸代谢酶基因多态性与妊娠期贫血孕妇妊娠结局的相关性

目的 探究叶酸代谢酶基因多态性与妊娠期贫血孕妇妊娠结局的相关性.方法 选取2018年6月至2020年6月期间在本院住院分娩的妊娠期贫血孕妇192例作为研究对象,根据是否存在不良妊娠分为妊娠良好组(102例)和妊娠不良组(90例),不良妊娠结局包括早产儿、低出生体重儿和贫血.另选取同期在本院做产前检查的并无贫血病症的健康孕妇100例作为对照组.通过Taqman MGB技术检测受试者MTHFR基因C677T位点、MTRR基因A66G位点多态性分布频率;分析MTHFR基因C677T位点、MTRR基因A66G位点多态性与不良妊娠结局的关系.Logistic回归分析妊娠期贫血孕妇发生不良妊娠的影响因素.结果 受试者MTHFR基因C677T位点、MTRR基因A66G位点各基因型符合Hardy-Weinberg平衡定律.妊娠良好组与对照组间MTHFR基因C677T位点、MTRR基因A66G位点基因多态性差异无统计学意义(P>0.05);与妊娠良好组相比,妊娠不良组MTHFR基因C677T位点CT、TT基因型及T等位基因频率及MTRR基因A66G位点AG、GG及G等位基因频率均显著升高(P<0.05);妊娠不良组患者MTHFR基因C677T位点中与野生CC型比较,纯合子TT型孕妇早产儿、低出生体重儿、贫血发生率均升高(P<0.05).MTRR基因A66G位点中与野生AA型比较,纯合子GG型孕妇早产儿、低出生体重儿、贫血发生率均升高(P<0.05).MTHFR基因C677T位点纯合子突变TT型及MTRR基因A66G位点纯合子GG型是不良妊娠结局发生的危险因素(P<0.05).结论 叶酸代谢酶基因多态性与妊娠期贫血孕妇不良妊娠结局的发生有关,可能作为预测妊娠期贫血孕妇不良妊娠结局的指标.     

唐氏综合征患儿母亲MTHFR C677T基因多态性及血浆叶酸、同型半胱氨酸水平的研究

目的研究浙南地区汉族妇女叶酸及代谢产物同型半胱氨酸水平、亚甲基四氢叶酸还原酶(MTHFR)基因C677T位点多态性与唐氏综合征(Down’s Syndrome,DS)发生的关系。方法对84例已生育DS患儿的母亲(观察组)和120例生育过正常儿童的母亲(对照组)采用PCR扩增及DNA测序法检测亚甲基四氢叶酸还原酶基因MTHFR C677T单核苷酸多态性;免疫发光法检测叶酸(Folate)及循环酶法检测血浆同型半胱氨酸(Hcy)水平。结果 MTHFR 677 T基因及CT、TT基因型的频率两组无统计学意义(P>0.05)。对观察组与对照组的部分标本行血浆Folate与Hcy水平测定,观察组Folate水平显著高于对照组(t=-5.572,P<0.05);Hcy水平两组平均水平无统计学意义(t=0.152,P>0.05);Fo-late与Hcy水平呈负相关关系(r=-0.217,P<0.05)。观察组与对照组MTHFR 677CT、TT基因型与CC基因型Hcy水平比较均无统计学意义(P>0.05),观察组TT基因型Hcy水平比对照组有显著性升高(t=2.546,P<0.05)。结论本研究MTHFR C677T位点不是浙南地区汉族妇女DS的风险因素;DS母亲Folate水平高于对照组及MTHFR 677 TT基因型Hcy水平高于对照组,可能存在影响叶酸代谢的其他相关基因的多态性或营养的缺乏,有待进一步深入研究。     

亚甲基四氢叶酸还原酶基因C677T多态性与习惯性流产相关的Meta分析

目的探讨5,10-亚甲基四氢叶酸还原酶（MTHFR）基因C677T位点多态性与习惯性流产易感性关系。方法检索习惯性流产组和对照组MTHFR基因C677T位点多态性的OR值或RR值为效应指标的相关文献,符合入选标准的文献,应用RevMan 5.0软件对各研究结果进行异质性检验和效应值合并,并进行敏感性分析和偏倚评估。结果纳入MTHFR基因C677T位点多态性文献12篇,共计病例1127例,对照1119例,根据异质性检验结果,采用相应的效应模型进行合并分析。结果 MTHFR基因677位点CT、TT、CT＋TT基因型的OR值为1.24（1.02～1.52）、2.20（1.31～3.68）、1.39（1.15～1.67）。各研究的敏感性分析比较稳定,漏斗图形基本对称。亚组分析结果提示亚洲地区CT、TT、TT＋CT基因型的OR值分别为1.41、2.41、1.65,P=0.17、0.02、0.03。而非亚洲地区3种基因型的OR值分别为1.13、1.78、1.24,P=0.40、0.02、0.11。结论 MTHFR基因C677T位点多态性与习惯性流产的发生密切相关。尤其是MTHFR677位点TT、CT＋TT基因型是亚洲人群习惯性流产的危险因素。     

血浆Hcy水平及MTHFR和MTRR基因多态性与复发性流产的相关性研究

目的探讨血清同型半胱氨酸(Hcy)水平及亚甲基四氢叶酸还原酶(MTHFR)、甲硫氨酸合成酶还原酶(MTRR)基因多态性与不明原因复发性流产的相关性。方法以84例复发性自然流产的患者作为病例组,60例已有1次正常生育史,且既往无不良孕产史的妇女作为对照组,应用荧光定量PCR技术检测MTHFR基因C677T、A1298C和MTRR A66G位点的多态性,同时应用比色法检测血清Hcy水平。比较病例组和对照组间各种基因型和血清Hcy水平的差异。结果病例组血清Hcy水平明显高于对照组;高Hcy是先兆流产的危险因素(OR=2.132,P=0.021);MTHFR C677位点TT基因型携带者血清Hcy水平明显高于其他基因型;A1298位点CC基因型携带者血清Hcy水平明显高于AA野生型;MTRR A66位点GG基因型携带者血清Hcy水平明显高于其他基因型,差异均有统计学意义(P0.05)。结论 Hcy升高是导致复发性流产的重要危险因素;MTHFR基因C677T、A1298C和MTRR A66G位点的多态性改变均可致血清Hcy水平升高,与复发性流产的发生有一定的相关性。     

叶酸代谢酶MTHFR基因多态性与不明原因复发性流产的相关性研究

目的初步探讨亚甲基四氢叶酸还原酶(MTHFR)C677T、A1298C位点单核苷酸多态性与苏南地区不明原因的复发性流产(URSA)发生的相关性。方法采用病例对照研究的方法,对170例苏南地区不明原因复发性流产者(病例组)和170例正常妇女(对照组),利用PCR荧光探针技术检测MTHFR基因C677T、A1298C位点的单核苷酸多态性。结果病例组MTHFRC677T位点的TT基因型的发生频率显著高于对照组,T等位基因频率同样高于对照组,差异均有统计学意义(P0.05),而病例组MTHFR基因A1298C位点的CC基因型频率和C等位基因频率与对照组的相比,差异均无统计学意义(P0.05)。结论苏南地区MTHFR基因C677T位点多态性与育龄妇女发生不明原因复发性流产有一定的相关性。     

青岛地区汉族育龄妇女亚甲基四氢叶酸还原酶基因667位点多态性分布研究

目的探讨亚甲基四氢叶酸还原酶（MTHFR）基因667位点多态性在青岛市汉族育龄妇女中的分布状况。方法用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）技术检测98份育龄妇女外周血MTHFR C667T基因型分布。结果本研究人群MTHFR 677位点基因的CC、CT、TT基因型频率分别为24.5%、53.1%、22.4%,T等位基因频率为0.49。结论青岛市汉族育龄妇女MTHFR基因667位点多态性与其他地区有较大不同,调查可以为相关研究提供相应的分子生物学依据。     

郑州市中原区汉族育龄女性MTHFR和MTRR基因多态性

目的利用基因检测技术筛查出育龄女性叶酸利用能力差的高风险人群,指导育龄女性合理补充叶酸。方法通过荧光定量PCR,对2017年12月至2018年10月采集的2652例郑州市中原区育龄女性进行5,10-亚甲基四氢叶酸还原酶(MTHFR)C667T、A1298C位点和甲硫氨酸合酶还原酶(MTRR)A66G位点的基因型测定,并与其他地区人群基因型和等位基因频率分布进行比较,然后根据基因型综合判断育龄女性叶酸代谢能力强弱,由此得出育龄女性是否有叶酸补充风险及风险级别。结果检测的MTHFR C667T位点中,野生型(CC)、杂合突变型(CT)及纯合突变型(TT)分别占15.05%、46.60%和38.35%,突变基因T的基因频率为61.65%;不同年龄组(≤30和>30岁)均以杂合突变型为主。MTHFR A1298C位点中分别为74.55%、23.49%和1.96%,突变基因C的基因频率为13.71%;不同年龄组(≤30和>30岁)均以野生型为主。MTRR A66G位点中分别为57.43%、36.73%和5.84%,突变基因G的基因频率为24.21%;不同年龄组(≤30和>30岁)均以野生型为主。结论郑州地区育龄女性MTHFR C677T基因多态性分布与地域有相关性,超过50%以上的育龄女性携带高风险基因。因此,对叶酸代谢基因多态性检测高风险孕妇合理增补叶酸剂量,可进一步降低新生儿出生缺陷。     

孕期妇女MTHFR、MTRR基因多态性与同型半胱氨酸水平的关系

目的分析甘肃省孕期妇女N5,10-亚甲基四氢叶酸还原酶(N5,10-methylenetetrahydrofolate reductase,MTHFR)C677T、A1298C及甲硫氨酸合成酶还原酶(5-methyltetrahydrofolate-homocysteine methyltransferasereductase,MTRR)A66G位点基因多态性的分布特点,并研究其多态性与血浆同型半胱氨酸(Homocysteine,Hcy)浓度的相关性,为孕期妇女补服叶酸提供理论依据。方法以2016年在甘肃省妇幼保健院做孕期检查的522例孕妇为研究对象,检测MTHFR基因C677T、A1298C和MTRR基因A66G位点的基因型,并测定血浆Hcy浓度,应用t检验与Spearman秩检验比较不同基因型间Hcy浓度的差异。结果 MTHFR基因C677T位点CC型、CT型与TT型分别占26.83%、45.12%、28.05%,A1298C位点AA型、AC型、CC型分别占68.29%、26.83%、4.88%。MTRR基因A66G位点AA型、AG型与GG型分别占53.66%、39.02%、7.32%。MTHFR基因C677T位点等位基因C占49.39%,等位基因T占50.61%,A1298C位点等位基因A占81.71%,C占18.29%。MTRR基因A66G位点等位基因A占73.17%,等位基因G占26.83%。MTHFR基因C677T位点CC型、CT型与TT型Hcy含量分布经两两t检验,P0.05,说明各基因型间Hcy分布差异均有统计学意义。MTHFR基因A1298C位点AA型、AC型、CC型,MTRR基因A66G位点AA型、AG型与GG型Hcy含量分布经两两t检验,P0.05,说明各基因型间Hcy分布差异无统计学意义。MTHFR基因C677T、A1298C和MTRR基因A66G位点多态性各风险组经两两t检验,与未发现风险组比较,低度风险组、中度风险组、高度风险组P均小于0.05,差异具有统计学意义;与低度风险组比较,中度风险组、高度风险组P均大于0.05,差异没有统计学意义;与中度风险组比较,高度风险组P小于0.05,差异有统计学意义。根据Spearman秩相关检验,P0.05,Hcy含量与风险等级具有显著相关性。结论 MTHFR基因C677T、A1298C和MTRR基因A66G位点存在基因多态性,MTHFR基因C677T、A1298C和MTRR基因A66G位点基因多态性与血浆Hcy具有显著相关性,随着基因型风险等级的增加,血浆Hcy浓度增高。     

贵州省荔波县汉族和布依族女性MTHFR与MTRR多态性的分布

目的针对贵州省荔波县汉族和布依族女性开展分子流行病学调查,研究叶酸代谢关键酶亚甲基四氢叶酸还原酶(MTHFR)和甲硫氨酸合成酶还原酶(MTRR)的基因多态性分布。方法以在荔波县人民医院进行围孕期保健的1 342名健康女性为研究对象,其中汉族236人、布依族1 106人。采集口腔黏膜上皮脱落细胞,抽提基因组DNA,使用荧光定量PCR检测MTHFR C677T、A1298C和MTRR A66G基因多态性,进行统计分析。结果 1)入组对象的基因多态性分布符合遗传平衡。2)汉族女性MTHFR 677CC、CT和TT的基因型频率分别为49.6%、39.8%和10.6%,布依族女性为61.8%、33.7%和4.4%;汉族女性MTHFR 1298AA、AC和CC的基因型频率分别为62.3%、33.1%和4.7%,布依族女性为47.4%、42.9%和9.7%,两位点均有差异(P0.05)。汉族女性MTRR 66AA、AG和GG的基因型频率分别为56.4%、37.4%和5.9%,布依族女性为57.0%、36.0%和7.1%,差异无统计学意义。3)汉族和布依族女性MTHFR C677T与A1298C两位点连锁均有6种组合,没有CT/CC、TT/AC和TT/CC。汉族女性频率最高的是CT/AA,布依族女性频率最高的是CC/AC。两个位点构建的单倍型存在CA、TA和CC 3种组合,两位点间存在完全连锁不平衡。结论获取荔波县汉族和布依族女性MTHFR与MTRR多态性的群体遗传学特征,为指导科学增补叶酸营养、实施个性化孕期保健提供依据。     

Increased frequency of combined methylenetetrahydrofolate reductase C677T and A1298C mutated alleles in spontaneously aborted embryos

The pathogenesis of spontaneous abortion is complex, presumably involving the interaction of several genetic and environmental factors. The methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphisms are commonly associated with defects in folate dependent homocysteine metabolism and have been implicated as risk factors for recurrent embryo loss in early pregnancy. In the present study we have determined the prevalence of combined MTHFR C677T and A1298C polymorphisms in DNA samples from spontaneously aborted embryos (foetal death between sixth and twentieth week after conception) and adult controls using solid-phase minisequencing technique. There was a significant odds ratio of 14.2 (95% CI 1.78-113) in spontaneously aborted embryos comparing the prevalence of one or more 677T and 1298C alleles vs the wild type combined genotype (677CC/1298AA), indicating that the MTHFR polymorphisms may have a major impact on foetal survival. Combined 677CT/1298CC, 677TT/1298AC or 677TT/1298CC genotypes, which contain three or four mutant alleles, were not detected in any of the groups, suggesting complete linkage disequilibrium between the two polymorphisms. The present finding of high prevalence of mutated MTHFR genotypes in spontaneously aborted embryos emphasises the potential protective role of periconceptional folic acid supplementation.     

MTHFR基因C677T位点多态性与不明原因重复性自然流产的相关性

目的　检测不明原因重复性流产 (unexplained recurrent spontaneous abortion,URSA)患者亚甲基四氢叶酸还原酶 (methylenetetrahydrofolate reductase,MTH FR)基因 C6 77T位点多态性 ,探讨其与血清同型半胱氨酸、叶酸、维生素 B1 2 及与不同临床特征的关系。　方法　 U RSA非孕期患者 5 7例 ,对照组 5 0名 ,空腹血清总高半胱氨酸 (homocysteine,Hcy)的检测采用高压液相色谱法 ,血清叶酸、维生素 B1 2 的检测采用放射免疫法。MTH FR基因 C6 77T多态性采用聚合酶链反应 -限制性片段长度多态性技术检测。结果　 URSA患者组 C/ C基因型频率显著低于正常对照组者 ,总的突变 T等位基因频率显著高于对照组。MTHFR T/ T基因型患者血清 Hcy水平显著增高 ,血清叶酸水平显著降低 ,MTHFR C6 77T基因型在不同年龄、地区、流产时间、流产性质患者的分布差异无显著性。流产 3次以上 (包括 3次 )的患者 6 77T/ T基因型、携带 T等位基因的 C/ T T/ T基因型频率均大于流产次数少于 3次的患者。　结论　 MTH FRC6 77T基因多态性是 URSA发病的遗传风险因素。     

Gene-gene interaction between fetal MTHFR 677C>T and transcobalamin 776C>G polymorphisms in human spontaneous abortion

BACKGROUND: Genetic polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) and transcobalamin (TC) genes influence homocysteine metabolism which in turn may influence the risk of spontaneous abortion. It was hypothesized that there may be a significant interaction between MTHFR and TC genotypes which affects the pathogenesis of spontaneous abortion. METHODS AND RESULTS: A total of 76 fetal tissue samples from spontaneous abortions between weeks 6 and 20 of pregnancy, and 114 control samples from healthy blood donors were genotyped for the MTHFR 677C>T and 776C>G polymorphisms. Subjects with combined MTHFR 677TT/TC 776GG and combined MTHFR 677TT/TC 776CG genotypes gave an odds ratio for spontaneous abortion of 3.8 (95% confidence interval 1.4-9.9, P = 0.005). CONCLUSIONS: Embryos that have combined MTHFR 677TT and TC 776CG or 776GG genotypes; genotypes that individually are associated with impaired homocysteine metabolism in adults, are at increased risk for spontaneous abortion compared with embryos that have only one of these genotypes.     

Methylenetetrahydrofolate reductase C677T and A1298C variants do not affect ongoing pregnancy rates following IVF

BACKGROUND: There is concern that IVF could compromise normal imprinting and methylation of DNA. Methylenetetrahydrofolate reductase (MTHFR) regulates the flow of folic acid-derived, one-carbon moieties for methylation and is critical to early embryonic development. Therefore, we hypothesized that common polymorphisms in MTHFR could associate with IVF outcome. METHODS: MTHFR C677T and A1298C polymorphism genotyping was performed on 374 subjects for this study, representing 197 couples undergoing IVF in a university setting from July 2005 to January 2006. Analysis of variance (ANOVA), chi-square and/or multivariate analyses were used to assess whether these polymorphisms are associated with embryo quality or with ongoing pregnancy or spontaneous abortion rates. RESULTS: Allele frequencies for C677T ( p=0.67, q=0.33) and A1298C ( p=0.71, q=0.29) were in Hardy-Weinberg equilibrium. The C677T and A1298C variants, either alone or in combination, did not associate with embryo quality or short-term pregnancy outcome. CONCLUSIONS: The common polymorphisms in MTHFR are not associated with embryo quality, as defined by cell number or fragmentation score, or with short-term pregnancy outcomes. Therefore, in our population in which women receive adequate folic acid, MTHFR genotypes are not informative in explaining IVF failure. Further studies, however, examining birth outcomes and the other enzymes in the folic acid pathway are warranted.     

5,10-亚甲基四氢叶酸还原酶基因多态性及补充叶酸与非综合征性唇腭裂的相关性

背景：对于5, 10-亚甲基四氢叶酸还原酶(5, 10-methylene tetrahydrofolate reductase, MTHFR)基因C677T位点多态性与唇腭裂相关性的研究国内外结果不一,未见结合干预因素叶酸影响的相关报道。 目的：探讨河南地区汉族人群MTHFR基因C677T位点多态性及补充叶酸与非综合征性唇腭裂的发病关系。 方法：选取2008-09/2010-03在郑州大学第一附属医院及郑州市第一人民医院整形外科就诊的非综合征性唇腭裂患者110例,采用PCR-RFLP法检测外周血中MTHFR基因C677T位点基因型并与40例健康对照比较频数差异。同时结合母孕期是否补充叶酸进行统计学分析。 结果与结论：病例组和对照组C677T基因型及等位基因频率比较差异均具有显著性意义(P < 0.01),且有家族史的患者TT基因型及T等位基因频率高于无家族史患者(P < 0.05)。对母孕期是否补充叶酸进行比较,发现非综合征性唇腭裂与叶酸摄入呈负相关(χ²=4.304,r=-0.169,P  < 0.05)。结果提示MTHFR基因C677T位点突变与河南汉族人群非综合征性唇腭裂的发生相关,母孕期补充叶酸能降低非综合征性唇腭裂的发病风险。     

Polygenic association with total homocysteine in the post-folic acid fortification era: The CARDIA study

Elevated plasma concentration of total homocysteine (tHcy) has been linked with many diseases. tHcy is associated with a variety of factors, including polymorphisms in genes involved in homocysteine metabolism. It is not clear whether US-mandated fortification of grain products with folic acid has affected the association of genetic variants with tHcy levels. We determined tHcy concentrations in sera from 997 Caucasians and 692 African Americans participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study before and after folic acid fortification. DNA was genotyped for variants present in four genes involved in homocysteine metabolism: cystathionine β-synthase (CBS) 844ins68, methionine synthase (MS) 2756A>G; methionine synthase reductase (MTRR) 66A>G and methylenetetrahydrofolate reductase (MTHFR) 677C>T and 1298A>C. A greater number of African Americans were homozygous for the MS 2756GG, MTRR 66GG and CBS 844ins68 genotypes compared to Caucasians, while prevalence of MTHFR 677TT and 1298CC genotypes was substantially lower in African Americans compared to Caucasians. The overall variance in tHcy levels at y 0, 7 and 15 that can be explained by the combined presence of all five variants increased slightly over time in Caucasians (17%, y 0; 21%, y 7; and 26%, y 15) and in African Americans (13%, y 0; 17% y 7; and 18% y 15) largely due to decrease in tHcy variance.     

Nutritional and genetic determinants of vitamin B and homocysteine metabolisms in neural tube defects: a multicenter case-control study

Neural tube defects (NTDs) are severe congenital malformations due to failure of neural tube formation in early pregnancy. The proof that folic acid prevents NTDs raises the question of whether other parts of homocysteine (Hcy) metabolism may affect rates of NTDs. This French case-control study covered: 77 women aged 17-42 years sampled prior to elective abortion for a severe NTDs (cases) and 61 women aged 20-43 years with a normal pregnancy. Plasma and erythrocyte folate, plasma B6, B12 and Hcy were tested as five polymorphisms MTHFR 677 C --> T, MTHFR 1298 A --> C, MTR 2756 A --> G, MTTR 66 A --> G and TCN2 776 C --> G. Cases had significantly lower erythrocyte folate, plasma folate, B12 and B6 concentrations than the controls, and higher Hcy concentration. The odds ratio was 2.15 (95% CI: 1.00-4.59) for women with the MTRR 66 A --> G allele and it was decreased for mothers carrying the MTHFR 1298 A --> C allele. In multivariate analysis, only the erythrocyte folate concentration (P = 0.005) and plasma B6 concentration (P = 0.020) were predictors. Red cell folate is the main determinant of NTDs in France. Folic acid supplement or flour fortification would prevent most cases. Increased consumption of vitamins B12 and B6 could contribute to the prevention of NTDs. Genetic polymorphisms played only a small role. Until folic acid fortification becomes mandatory, all women of reproductive age should consume folic acid in a multivitamin that also contains B12 and B6.     

Polymorphisms in the CBS gene and homocysteine, folate and vitamin B12 levels: association with polymorphisms in the MTHFR and MTRR genes in Brazilian children

Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR) and cystathionine beta-synthase (CBS) genes, involved in the intracellular metabolism of homocysteine (Hcy), can result in hyperhomocysteinemia. The objective of this study was to evaluate prevalence estimates of CBS T833C, G919A and the insertion of 68-bp (844ins68) polymorphisms and their correlation with Hcy, folate and B(12) in 220 children previously genotyped for MTHFR C677T, A1298C, and MTRR A66G. The prevalence of heterozygote children for 844ins68 was 19.5%. The T833C CBS mutation was identified in association with 844ins68 in all the carriers of the insertion. Genotyping for CBS G919A mutation showed that all the children presented the GG genotype. Analysis of Hcy, B(12) and folate, according to the combination of the different genotypes of the C677T and A1298C MTHFR, A66G MTRR, and 844ins68 CBS showed that the 677TT/1298AA/68WW genotype is associated with an increase in Hcy, when compared to the 677CC/1298AC/68WW (P = 0.033) and the 677CT/1298AA/68WW genotypes (P = 0.034). Since B(12) and folate were not different between these groups, a genetic interaction between diverse polymorphisms probably influences Hcy. Our results emphasize the role of genetic interactions in Hcy levels.