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.     

Polymorphisms in genes involved in folate metabolism and colorectal neoplasia: a HuGE review

Epidemiologic and mechanistic evidence suggests that folate is involved in colorectal neoplasia. Some polymorphic genes involved in folate metabolism--methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), methionine synthase (MTR A2756G), methionine synthase reductase (MTRR A66G), cystathionine beta-synthase (CBS exon 8, 68-base-pair insertion), and thymidylate synthase (TS enhancer region and 3' untranslated region)--have been investigated in colorectal neoplasia. For MTHFR C677T and A1298C, the variant allele is associated with reduced enzyme activity in vitro. For the other polymorphisms, functional data are limited and/or inconsistent. Genotype frequencies for all of the polymorphisms show marked ethnic and geographic variation. In most studies, MTHFR 677TT (10 studies, >4,000 cases) and 1298CC (four studies, >1,500 cases) are associated with moderately reduced colorectal cancer risk. In four of five genotype-diet interaction studies, 677TT subjects who had higher folate levels (or a "high-methyl diet") had the lowest cancer risk. In two studies, 677TT homozygote subjects with the highest alcohol intake had the highest cancer risk. Findings from six studies of MTHFR C677T and adenomatous polyps are inconsistent. There have been only one or two studies of the other polymorphisms; replication is needed. Overall, the roles of folate-pathway genes, folate, and related dietary factors in colorectal neoplasia are complex. Research priorities are suggested.     

Homocysteine Metabolism Gene Polymorphisms (MTHFR C677T,MTHFR A1298C,MTR A2756G and MTRR A66G) Jointly Elevate the Risk of Folate Deficiency

Folate deficiency is strongly associated with cardiovascular disease. We aimed to explore the joint effect of the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, methionine synthase (MTR) A2756G, and methionine synthase reductase (MTRR) A66G polymorphisms on folate deficiency in a Chinese hypertensive population. A total of 480 subjects aged 28–75 were enrolled in this study from September 2005–December 2005 from six hospitals in different Chinese regions. Known genotypes were detected by PCR-RFLP methods and serum folate was measured by chemiluminescence immunoassay. Our results showed that MTHFR 677TT and MTR 2756AG + GG were independently associated with a higher risk of folate deficiency (TT vs. CC + CT, p < 0.001 and AG + GG vs. AA p = 0.030, respectively). However, the MTHFR A1298C mutation may confer protection by elevating the serum folate level (p = 0.025). Furthermore, patients carrying two or more risk genotypes showed higher odds of folate deficiency than null risk genotype carriers, especially those carrying four risk genotypes. These findings were verified by generalized multifactor dimensionality reduction (p = 0.0107) and a cumulative effects model (p = 0.001). The results of this study have shown that interactions among homocysteine metabolism gene polymorphisms lead to dramatic elevations in the folate deficiency risk.     

四川南充市健康体检者同型半胱氨酸代谢酶基因多态性分布及其水平关联

目的 研究南充市汉族人群同型半胱氨酸(Hcy)代谢关键酶基因多态性的分布及与Hcy水平的关联.方法以在南充市中心医院的汉族人群470人为研究对象,抽取受检者血样,收集研究对象一般临床资料,采用循环酶法测定血浆Hcy水平,提取基因组DNA后进行SNP基因多态性检测,分析Hcy代谢关键酶MTHFR C677T、MTHFR ...     

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.     

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.     

Homocysteine concentrations in adults with trisomy 21: effect of B vitamins and genetic polymorphisms

BACKGROUND: The effects of supplementation with B vitamins and of common polymorphisms in genes involved in homocysteine metabolism on plasma total homocysteine (tHcy) concentrations in trisomy 21 are unknown. OBJECTIVES: We aimed to determine the effects of orally administered folic acid and of folic acid combined with vitamin B-12, vitamin B-6, or both on tHcy in adults with trisomy 21. The study was also intended to analyze the possible influence of gene polymorphisms. DESIGN: One hundred sixty adults with trisomy 21 and 160 healthy, unrelated subjects aged 26 +/- 4 y were included. Plasma tHcy, red blood cell folate, serum folate, and vitamin B-12 were measured. Genotyping for the common methylenetetrahydrofolate reductase (MTHFR) 677C-->T, MTHFR 1298A-->C, cystathionine beta-synthase 844Ins68, methionine synthase 2756A-->C, methionine synthase reductase 66A-->G, and reduced folate carrier 80G-->A polymorphisms was carried out. RESULTS: The mean tHcy concentration (9.8 +/- 0.7 micromol/L) of cases who did not use vitamins was not significantly different from that of controls (9.4 +/- 0.3 micromol/L). Plasma tHcy concentrations (7.6 +/- 0.3 mmol/L) in cases who used folic acid were significantly lower than in cases who did not. Folic acid combined with vitamin B-12 did not significantly change tHcy concentrations compared with those in cases who used only folic acid. Folic acid combined with vitamins B-6 and B-12 significantly lowered tHcy (6.5 +/- 0.5 micromol/L). The difference in tHcy according to MTHFR genotype was not significant. However, tHcy concentrations were slightly higher in TT homozygotes among the controls but not among the cases. CONCLUSION: This study provides information on the relation between several polymorphisms in genes involved in homocysteine and folate metabolism in adults with trisomy 21.     

Dietary Intake of Folate,Vitamin B2, Vitamin B6, Vitamin B12, Genetic Polymorphism of Related Enzymes,and Risk of Breast Cancer: A Case-Control Study in Japan

We investigated associations among intake of folate, vitamin B2, vitamin B6, vitamin B12, and polymorphisms of 5,10-methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) genes and breast cancer risk in a Japanese population. A hospital based, case-control study was conducted in Nagano Prefecture, Japan, in 388 pairs of patients with histologically confirmed invasive breast cancer and age- and area-matched controls selected from medical checkup examinees. Energy-adjusted intakes of folate and other B vitamins were derived from a validated food frequency questionnaire. Genotyping was completed for MTHFR (C677T and A1298T) and MTR (A2756G). Odds ratios and 95% confidence intervals were calculated by the conditional logistical regression model. Median dietary folate intake (μg/day) in the control group was 438.2 (interquartile range: 354.9–542.9). Neither dietary intake of folate, vitamin B2, vitamin B6, or vitamin B12 nor polymorphisms of MTHFR or MTR genes were significantly associated with breast cancer risk. Further, no significant interaction was found among nutrients, polymorphisms, and breast cancer risk. Associations of nutrients with breast cancer risk did not differ by hormone receptors status. We conclude that dietary intake of folate and related B vitamins and genotypes of MTHFR or MTR have no overall association with breast cancer risk in Japanese women.     

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。     

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。     

海南省汉族和黎族妇女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分布研究

目的:比较海南省汉族和黎族妇女亚甲基四氢叶酸还原酶(MTHFR)C677T、A1298C及甲硫氨酸合成酶还原酶(MTRR)A66G多态性分布情况,获取其多态性位点的群体遗传学特征。方法:采用横断面调查研究方法,以海南省内11437例汉族与黎族孕妇为对象,采集口腔黏膜上皮细胞,提取DNA,采用Taqman-MGB技术,进行编码基因MTHFR和MTRR的相关多态性位点检测。结果:汉族妇女MTHFR C677T位点基因型纯合突变TT型高于黎族妇女,黎族妇女MTHFRA1298C基因型纯合突变CC型、MTRR A66G基因型纯合突变GG型的频率高于汉族妇女(P<0.01)。结论:海南省汉族与黎族妇女MTHFR和MTRR基因多态性分布存在差异。     

河北省9地区汉族育龄期女性MTHFR C677T、A1298C和MTRR A66G基因多态性分布研究

目的　分析河北省9个地区汉族育龄期女性亚甲基四氢还原酶（MTHFR）C677T、A1298C和甲硫氨酸合成酶还原酶（MTRR）A66G基因多态性的分布特征,以指导河北省地区汉族育龄女性叶酸的增补以及出生缺陷的预防。方法　共计1267位汉族育龄期女性位研究对象,采集静脉血,提取基因组DNA,采用KASP基因分型技术进行MTHFR和MTRR基因多态性检测,统计分析9个地区的基因多态性频率分布特征。结果　9地区MTHFR A1298C 位点基因型频率和等位基因频率比较差异有统计学意义（P＜0.05）,9地区MTHFR C677T 位点等位基因频率比较差异有统计学意义（P＜0.05）,9地区MTHFR C677T 位点基因型频率、MTRR A66G位点基因型频率和等位基因频率比较差异无统计学意义（P＞0.05）。结论　河北地区汉族女性MTHFR和MTRR基因多态性存在差异,具有一定的地域特异性。     

叶酸代谢相关基因MTHFR、MS基因多态与胰腺癌风险关联

目的 探讨亚甲基四氢叶酸还原酶（MTHFR）及甲硫氨酸合成酶（MS）基因多态与胰腺癌风险的关系.方法 采用以医院为基础的病例对照研究（胰腺癌新发病例101例,对照337人）方法,进行MTHFR C677T、A1298C及MS A2756G基因多态与胰腺癌风险关联分析,采用PCR-RFLP方法进行两候选基因分型.结果 携带MTHFR-677 CT及TT基因型者发生胰腺癌风险是CC基因型个体的2.17（95%CI：1.26～3.85）及3.53（95%CI：1.85～6.84）倍,呈明显的等位基因-效应关系;未观察到MTHFR 1298多态单独对胰腺癌发生的影响,但发现它与C677T有联合作用.MTHFR677CT与TT基因型与吸烟、饮酒有明显的正向交互,产生交互作用的ORint值分别为1.78（P=0.0010）和2.10（P=0.0051）.未发现MS A2756G多态与胰腺癌的发生之间存在统计学的显著关联.结论 MTHFR C677T多态与胰腺癌发生风险显著关联,且与吸烟、饮酒存在正向交互作用.     

甲硫氨酸合成酶及其还原酶A2756G、G66A基因多态性与冠心病易感性的Meta分析

目的 探讨甲硫氨酸合成酶(methionine synthase,MTR)基因A2756G和甲硫氨酸合成酶还原酶(methionine synthase reductase,MTRR)基因G66A多态性与冠心病易感性的相关性.方法 系统检索Medline数据库中自1990年1月到2010年5月的英文相关文献及其引文,共获得14篇相关文献,纳入13篇.利用STATA软件及Meta程序对各研究结果 进行异质性检验和效应值合并分析.结果 纳入的13篇有效文献包括MTR A2756G基因多态性相关文献8篇,MTRR G66A基因多态性相关文献5篇.MTR A2756G基因多态性与冠心病易感性相关研究中,共有冠心病患者2143例,对照2270名(例);MTRR G66A基因多态性与冠心病易感性相关研究中,共有冠心病患者811例,对照387名(例).MTRR G66A基因多态性与冠心病易感性相关研究中,合并统计冠心病组总的GG基因型频数为246,AG基因型频数为397,AA基因型频数为168;对照组总的GG基因型频数为102,AG基因型频数为203,AA基因型频数为82;AG基因型与GG基因型相比,冠心病易感性降低27%,差异有统计学意义(OR=0.73,95%CI:0.54～0.99);AA基因型与GG基因型相比,冠心病易感性降低,但差异无统计学意义(OR=0.84,95%CI:0.42～1.68);将AG基因型和AA基因型合并后与GG基因型比较,冠心病易感性降低25%,差异有统计学意义(OR=0.75,95%CI:0.56～1.00),且Egger检验未见明显发表偏倚(t=-0.19,P=0.862).而各遗传模型下,MTR A2756G多态性与冠心病易感性均未见相关.结论 MTRR G66A位点基因多态性与冠心病易感性相关联,A等位基因携带者冠心病遗传易感性下降.     

Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome.

BACKGROUND: Down syndrome, or trisomy 21, is a complex genetic disease resulting from the presence of 3 copies of chromosome 21. The origin of the extra chromosome is maternal in 95% of cases and is due to the failure of normal chromosomal segregation during meiosis. Although advanced maternal age is a major risk factor for trisomy 21, most children with Down syndrome are born to mothers <30 y of age. OBJECTIVE: On the basis of evidence that abnormal folate and methyl metabolism can lead to DNA hypomethylation and abnormal chromosomal segregation, we hypothesized that the C-to-T substitution at nucleotide 677 (677C-->T) mutation of the methylenetetrahydrofolate reductase (MTHFR) gene may be a risk factor for maternal meiotic nondisjunction and Down syndrome in young mothers. DESIGN: The frequency of the MTHFR 677C-->T mutation was evaluated in 57 mothers of children with Down syndrome and in 50 age-matched control mothers. Ratios of plasma homocysteine to methionine and lymphocyte methotrexate cytotoxicity were measured as indicators of functional folate status. RESULTS: A significant increase in plasma homocysteine concentrations and lymphocyte methotrexate cytotoxicity was observed in the mothers of children with Down syndrome, consistent with abnormal folate and methyl metabolism. Mothers with the 677C-->T mutation had a 2.6-fold higher risk of having a child with Down syndrome than did mothers without the T substitution (odds ratio: 2.6; 95% CI: 1.2, 5.8; P < 0.03). CONCLUSION: The results of this initial study indicate that folate metabolism is abnormal in mothers of children with Down syndrome and that this may be explained, in part, by a mutation in the MTHFR gene.     

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.     

湖北松滋市汉族女性 MTHFR 和 MTRR 基因多态性分布

目的分析湖北省松滋地区女性亚甲基四氢叶酸还原酶（methylenetetrahydrofolatereductase,MTHFR）C677T、A1298C及甲硫氨酸合成酶还原酶（methioninesynthasereductase,MTRR）A66G基因多态性的分布特征。方法采用现况研究方法,以松滋市1077例女性为研究对象,提取其口腔黏膜上皮细胞的基因组DNA,通过荧光定量PCR方法检测MTHFR和MTRR基因多态性。统计分析本地区基因多态性的分布特征,并与已报道其他地区进行比较。结果松滋市女性的MTHFR677TT纯合突变基因型频率为15．41％,与四川省德阳市（13．80％）基本一致,差异无统计学意义（P〉0．05）;高于广东省惠州市（10．86％）、海南省琼海市（6．14％）,低于江苏省镇江市（21．84％）、河南省郑州市（34．5％）、山东省临沂市（35．03％）,均有极显著性差异（P〈0．01）。MTHFR1298CC纯合突变基因型的分布百分数为2．60％,与四川省德阳市（6．26％）基本一致,差异均无统计学意义（P〉0．05）;低于海南省琼海市（7．13％）、广东省惠州市（7．24％）,高于山东省临沂市（2．42％）,差异均有统计学意义（P〈0．01）。MTRR66GG纯合突变基因型频率为6．41％,与琼海市比较,差异有统计学意义（P〈0．01）。结论松滋市女性MTHFR和MTRR基因多态性分布具有地域特异性。     

叶酸、蛋氨酸摄入量,MTR、TS基因多态与结直肠癌关系的巢式病例对照研究

目的:研究蛋氨酸合酶(methioninesynthase,MTR)、胸苷酸合酶(thymidylatesynthase,TS)基因多态性,叶酸、蛋氨酸摄入量与结直肠癌易感性的关系。方法:采用巢式病例对照研究设计(病例140例和对照343例),通过非条件Logistic回归模型分析各多态与结直肠癌易感性的关系,及其与叶酸、蛋氨酸摄入量之间的联合作用。结果:MTR2756G等位基因携带者患结直肠癌的风险显著增高(OR=2.04,95%CI,1.22～3.39)。TS5’-UTR多态与叶酸摄入量之间的联合作用与结直肠易感性的关系有统计学意义(P=0.01)。结论:MTR2756G等位基因是结直肠癌的危险因素,TS5’-UTR多态与叶酸摄入量之间可能存在交互作用。     

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.     

Prevalence of methylenetetrahydrofolate reductase 677T and 1298C alleles and folate status: a comparative study in Mexican, West African, and European populations

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphism is heterogeneously distributed worldwide, with the highest and lowest frequencies of the T allele in Mexico and Africa, respectively, and a south-to-north gradient in Europe. Distribution of MTHFR 1298A-->C is less well known. It has been hypothesized that 677T frequency could result in part from gene-nutrient interactions. OBJECTIVE: The objective was to compare the association of 677T and 1298C alleles with plasma concentrations of homocysteine, folate, and vitamin B-12 in geographical areas with contrasting 677T allele frequencies. DESIGN: Healthy young adults (n = 1277) were recruited in Mexico City, the West African countries of Bénin and Togo, France, and Sicily (Italy). Homocysteine, folate, and vitamin B-12 were measured in plasma, and MTHFR polymorphisms were measured in genomic DNA. RESULTS: Mexico City and Sicily reported the highest and Bénin and Togo reported the lowest plasma concentrations of folate. Mexico City had the highest 677T allele prevalence and the lowest influence of 677TT genotype on homocysteine, whereas the opposite was observed in Africa. The prevalence of the 1298C allele was lowest in the Mexicans and Africans and highest in the French. The percentage of the 677T genotype was significantly associated with the folate concentrations in 677CC carriers in a univariate analysis (R = 0.976; 95% CI: 0.797, 0.996; P < 0.0002) and in a multiple regression model that included homocysteine, vitamin B-12, and age (P = 0.0002). CONCLUSION: Our data agree with the hypothesis of a gene-nutrient interaction between MTHFR 677C-->T polymorphism and folate status that may confer a selective advantage of TT-homozygous genotype when dietary intake of folate is adequate, at least in the areas studied.