MTHFR、MTRR和MTR基因多态性与唐氏综合征发生的相关性研究

应用PCR-RFLP方法分析31例唐氏综合征（Down＇s syndrome, DS）患儿母亲和68例正常生育女性叶酸代谢相关基因：MTHFR 677C〉T、MTRR 66A〉G和MTR 2756A〉G多态性,探讨其与唐氏综合征DS发生的关系。采用Pearson χ^2 检验基因和基因型频率分布,并分析各基因之间的相互作用,计算比值比评价相对危险度。MTHFR基因T等位基因频率在病例组和对照组中具有显著性差异（P〈0.05）,而MTRR和MTR基因G等位基因频率在病例组和对照组中的差异无显著性。MTHFR TT基因型母亲生育DS风险显著增加（OR=3.51,95 %CI=1.04-11.85,P〈0.05）。MTRR GG基因型生育DS的风险增加3.57倍（OR=3.57,95 %CI=1.19-10.73,P〈0.05）。MTR突变基因型AG和GG与生育DS的风险无显著关系。MTHFR （CT＋TT）/MTRR GG、MTHFR （CT＋TT）/MTR AA和MTRR GG/MTR AA联合基因型与DS发生风险显著相关。结果表明,MTHFR 677C〉T、MTRR 66A〉G位点变异是生育DS的独立风险因子,尚不能认为MTR 2756A〉G多态与DS发生相关。基因与基因多态位点之间存在交互和修饰效应。     

年轻母亲叶酸代谢基因多态性与唐氏综合征发生的关系

为探讨年轻母亲叶酸代谢相关基因MTHFR 677C>T、MTRR 66A>G、RFC-1 80G>A和MTR 2756A>G多态性与唐氏综合征(Down syndrome, DS)发生的关系, 采用随机病例-对照研究设计, 应用PCR-RFLP方法检测60例DS患儿的母亲与68例正常生育女性的基因型。经χ² 检验, MTHFR基因T等位基因频率在病例组和对照组中差异有统计学意义(P<0.05), 而MTRR、MTR和 RFC-1等位基因频率差异无统计学意义。Logistic回归分析显示: 携带MTHFR TT基因型的母亲孕育DS患儿的风险显著增加(OR=3.51, 95% CI=1.30~9.46, P<0.05), 而杂合子CT以及CT合并TT基因型与DS发生风险无显著关联; 携带MTRR GG基因型的母亲孕育DS患儿的风险增加3.16倍(OR=3.16, 95% CI=1.20~8.35, P<0.05), 而RFC-1和MTR突变基因型与DS发生风险无显著关联; MTHFR(CT+TT)/MTRR GG、MTHFR (CT+TT)/ RFC-1 AA、MTHFR CC / MTR (AG +GG)、 MTHFR (CT+TT)/MTR AA、MTRR GG/MTR AA和RFC-1 AA / MTR AA联合基因型与DS发生风险显著相关。结果表明, 年轻女性MTHFR 677C>T、MTRR 66A>G位点变异是孕育DS患儿的独立风险因子, 尚不能认为RFC-1 80G>A、MTR 2756A>G多态性与DS发生相关, 而基因与基因多态位点之间存在交互和修饰效应。     

MTHFR C677T and A1298C gene polymorphisms and their relation to homocysteine level in Egyptian children with congenital heart diseases

Objective

To investigate the association of combined MTHFR C677T and A1298C gene polymorphisms with congenital heart diseases (CHD) in Egyptian children and their mothers and to determine their effect on homocysteine level in these children.

Material and methods

MTHFR C677T and A1298C polymorphisms were genotyped in 160 Egyptian children (80 patients with CHD and 80 healthy controls) and their mothers using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP), while, homocysteine (Hcy) level was measured optically by enzymatic method.

Results

We found that MTHFR 677TT genotype, T allele, 1298CC genotype, and C allele were associated with 2.61, 2.0, 2.91 and 1.99 fold increased risk of CHD in Egyptian children respectively. Furthermore, the frequencies of MTHFR 1298AC and CC genotypes and C allele significantly increased in mothers with CHD affected children. The homocysteine levels were significantly increased in MTHFR 677TT and 1298CC genotypes in children with CHD.

Conclusions

Our study demonstrated an association of MTHFR A1298C polymorphisms with CHD in Egyptian children and their mothers, while, MTHFR C677T polymorphisms were significantly associated with the risk of CHD in the children only. An association between combined MTHFR A1298C and C677T polymorphisms and CHD was recorded in the children and their mothers. Also, homocysteine levels were significantly increased with both MTHFR 677TT and 1298CC genotypes in Egyptian children with CHD.     

The polymorphisms in methylenetetrahydrofolate reductase, methionine synthase, methionine synthase reductase, and the risk of colorectal cancer

Polymorphisms in genes involved in folate metabolism may modulate the risk of colorectal cancer (CRC), but data from published studies are conflicting. The current meta-analysis was performed to address a more accurate estimation. A total of 41 (17,552 cases and 26,238 controls), 24(8,263 cases and 12,033 controls), 12(3,758 cases and 5,646 controls), and 13 (5,511 cases and 7,265 controls) studies were finally included for the association between methylenetetrahydrofolate reductase (MTHFR) C677T and A1289C, methione synthase reductase (MTRR) A66G, methionine synthase (MTR) A2756G polymorphisms and the risk of CRC, respectively. The data showed that the MTHFR 677T allele was significantly associated with reduced risk of CRC (OR = 0.93, 95%CI 0.90-0.96), while the MTRR 66G allele was significantly associated with increased risk of CRC (OR = 1.11, 95%CI 1.01-1.18). Sub-group analysis by ethnicity revealed that MTHFR C677T polymorphism was significantly associated with reduced risk of CRC in Asians (OR = 0.80, 95%CI 0.72-0.89) and Caucasians (OR = 0.84, 95%CI 0.76-0.93) in recessive genetic model, while the MTRR 66GG genotype was found to significantly increase the risk of CRC in Caucasians (GG vs. AA: OR = 1.18, 95%CI 1.03-1.36). No significant association was found between MTHFR A1298C and MTR A2756G polymorphisms and the risk of CRC. Cumulative meta-analysis showed no particular time trend existed in the summary estimate. Probability of publication bias was low across all comparisons illustrated by the funnel plots and Egger's test. Collectively, this meta-analysis suggested that MTHFR 677T allele might provide protection against CRC in worldwide populations, while MTRR 66G allele might increase the risk of CRC in Caucasians. Since potential confounders could not be ruled out completely, further studies were needed to confirm these results.     

MTHFR C677T、A1298C基因多态性与老年单纯收缩期高血压患者Hcy、血脂水平的关系研究

摘要 目的：研究5,10-亚甲基四氢叶酸还原酶（MTHFR）C677T、A1298C基因多态性与老年单纯收缩期高血压（ISH）患者同型半胱氨酸（Hcy）、血脂水平的关系。方法：选取2019年3月至2021年3月期间中南大学湘雅医学院附属海口医院全科医学科收治的212例老年ISH患者作为ISH组,以同期体检无高血压老年人120例为对照组。检测两组MTHFR C677T、A1298C基因多态性。收集两组一般资料及血浆Hcy及血脂检查结果。观察MTHFR C677T、A1298C不同基因型的血浆Hcy、血脂水平差异。采用多因素Logistic回归分析老年ISH发生的影响因素。结果：相比于对照组,ISH组MTHFR C677T位点T等位基因频率较高,C等位基因频率较低;ISH组CC基因型频率较低,CT、TT基因型频率较高（P<0.05）。相比于对照组,ISH组A1298C位点C等位基因频率较高,A等位基因频率较低;ISH组A1298C位点AA基因型频率较低,CC、AC基因型频率较高（P<0.05）。MTHFR基因C677T位点不同基因型血浆Hcy、总胆固醇（TC）水平差异具有显著性（P<0.05）。MTHFR基因A1298C位点不同基因型血浆Hcy、TC水平明显差异具有显著性（P<0.05）。血浆Hcy、MTHFR C677T及A1298C基因多态性是老年ISH发生的影响因素（均P<0.05）。结论：MTHFR C677T、A1298C基因多态性与老年ISH患者血浆TC、Hcy水平有关,血浆Hcy、MTHFR C677T及A1298C基因多态性是老年ISH发生的影响因素。     

Gene–environment and gene–gene interactions of specific MTHFR,MTR and CBS gene variants in relation to homocysteine in black South Africans

The methylenetetrahydrofolate reductase (MTHFR), cystathione-β-synthase (CBS) and methionine synthase (MTR) genes interact with each other and the environment. These interactions could influence homocysteine (Hcy) and diseases contingent thereon. We determined single nucleotide polymorphisms (SNPs) within these genes, their relationships and interactions with total Hcy concentrations within black South Africans to address the increased prevalence of diseases associated with Hcy. The MTHFR 677 TT and MTR 2756 AA genotypes were associated with higher Hcy concentrations (16.6 and 10.1 μmol/L; p < 0.05) compared to subjects harboring the MTHFR 677 CT/CC and the MTR 2756 AG genotypes (10.5, 9.7 and 9.5 μmol/L, respectively). The investigated CBS genotypes did not influence Hcy. We demonstrated interactions between the area of residence and the CBS T833C/844ins68 genotypes (p = 0.005) so that when harboring the wildtype allele, rural subjects had significantly higher Hcy than their urban counterparts, but when hosting the variant allele the environment made no difference to Hcy. Between the CBS T833C/844ins68 or G9276A and MTHFR C677T genotypes, there were two-way interactions (p = 0.003 and = 0.004, respectively), with regard to Hcy. Subjects harboring the MTHFR 677 TT genotype in combination with the CBS 833 TT/homozygous 844 non-insert or the MTHFR 677 TT genotype in combination with the CBS 9276 GA/GG displayed higher Hcy concentrations.     

Gene-nutrient and gene-gene interactions of controlled folate intake by Japanese women

Elevated serum total homocysteine (tHcy) levels are associated with increased risk for cardiovascular disease and dementia. The prevalence rates of homozygous mutants among Japanese women (n = 300) were 17.3%, 1.3%, 18.6%, and 5.3% for methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, reduced folate carrier (RFC-1) A80G, and methionine synthase (MS) A2756G, respectively. The tHcy value was significantly lower (p < 0.001) in young women with CC or CT of MTHFR than with TT (10.9+/-4.7 micromol/L) (n =250). Diversities of serum folate and tHcy in women with 23 combinations of different alleles at low folate intake converged to the highest (34.0+/-8.6 nmol/L) and lowest (7.6+/-1.5 micromol/L) levels, respectively, after folic acid (400 microg/day) supplementation. In the regression equation ( y= ax + b) of serum folate ( y nmol/L) plotted against mean folate intake ( x microg/day), the values of "a" were 0.032, 0.037, and 0.045 for individuals with CC, CT, and TT alleles, respectively, of MTHFR.     

Homocysteine Level and Mechanisms of Injury in Parkinson's Disease as Related to MTHFR,MTR, and MTHFD1 Genes Polymorphisms and L-Dopa Treatment

An elevated concentration of total homocysteine (tHcy) in plasma and cerebrospinal fluid is considered to be a risk factor for Alzheimer''s disease (AD) and Parkinson''s disease (PD). Homocysteine (Hcy) levels are influenced by folate concentrations and numerous genetic factors through the folate cycle, however, their role in the pathogenesis of PD remains controversial. Hcy exerts a neurotoxic action and may participate in the mechanisms of neurodegeneration, such as excitotoxicity, oxidative stress, calcium accumulation, and apoptosis. Elevated Hcy levels can lead to prooxidative activity, most probably through direct interaction with N-methyl-D-aspartate (NMDA) receptors and sensitization of dopaminergic neurons to age-related dysfunction and death. Several studies have shown that higher concentration of Hcy in PD is related to long-term administration of levodopa (L-dopa). An elevation of plasma tHcy levels can also reflect deficiencies of cofactors in remethylation of Hcy to methionine (Met) (folates and vitamin B12) and in its transsulfuration to cysteine (Cys) (vitamin B6). It is believed that the increase in the concentration of Hcy in PD can affect genetic polymorphisms of the folate metabolic pathway genes, such as MTHFR (C677T, A1298C and G1793A), MTR (A2756G), and MTHFD1 (G1958A), whose frequencies tend to increase in PD patients, as well as the reduced concentration of B vitamins. In PD, increased levels of Hcy may lead to dementia, depression and progression of the disease.     

Oxidative stress mediates cardiac fibrosis by enhancing transforming growth factor-beta1 in hypertensive rats

The methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism has been shown to be associated with cardiovascular disease and in patients with end-stage renal disease (ESRD). However, the relationship between MTHFR polymorphisms and cardiovascular disease (CVD) in patients on hemodialysis has not been examined. The aim of this study was to assess the association of polymorphisms of MTHFR gene with homocysteine (Hcy) and intimal medial thickness (IMT) in patients on hemodialysis. We performed case-control study involving107 patients with ESRD and 103 healthy controls. Plasma Hcy was measured in all the subjects and these subjects were genotyped for three MTHFR polymorphisms (C677T, A1298C, and G1793A). We observed significantly higher Hcy levels in patients as compared to controls. The frequency of MTHFR 1298CC genotype was significantly higher in ESRD patients than in controls (21.4% vs. 2.9%); the frequency of the MTHFR C677T genotypes did not differ between groups (26.1% vs. 17.4%). Compound heterozygous MTHFR 677CT/1298AC genotypes showed maximum association with the risk of ESRD (OR: 12.8; 5%CI: 1.64–10.01, P < 0.05). Concurrent occurrence of MTHFR 677CC wild genotype with either 1298CC or 1793GA significantly increased the risk of disease (OR: 7.20; 95%CI: 2.06–2.51, P < 0.001 and OR: 7.60; 95%CI: 1.68–34.35; P < 0.05, respectively). MTHFR 1298CC genotype was associated with higher Hcy levels. IMT was also significantly higher in patients with the 1298CC genotype (P < 0.05). Thus, A1298C polymorphism of MTHFR gene appears to be associated with the severity of carotid atherosclerosis and co-occurrence of MTHFR polymorphisms may be a risk factor for CVD in patients on hemodialysis.     

5,10‐Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms: genotype frequency and association with homocysteine and folate levels in middle‐southern Italian adults.

Two genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene (C677T and A1298C) can influence the plasma homocysteine (Hcy) levels, especially in the presence of an inadequate folate status. The aim of this study was to evaluate the frequencies of C677T and of A1298C MTHFR polymorphisms and their correlation with Hcy and serum folate concentrations in a population of blood donors living in a region of middle‐southern Italy (the Molise Region). One hundred ninety seven blood donors were studied for total plasma Hcy, serum folate and C677T and A1298C MTHFR genotypes. The frequency of C677T genotypes was 20.8% (CC), 49.8% (CT) and 29.4% (TT); for the A1298C genotypes: 48.7% (AA), 43.7% (AC) and 7.6% (CC). Hcy and serum folate concentrations were significantly different among genotypes of the C677T polymorphism (CC versus CT versus TT: <0.0001 both for Hcy and folate), with Hcy values increasing, and serum folate decreasing, from CC to TT subjects. Regarding to A1298C polymorphism, the difference among genotypes (AA versus AC versus CC; p: 0.026 for Hcy and 0.014 for serum folate), showed an opposite trend for both parameters, with Hcy higher in the wild‐type and lower in the homozygotes and serum folate higher in CC than in AA subjects. In conclusion, we found a high frequency of MTHFR allele associated with high level of Hcy and low levels of folate in an Italian southern population. Copyright © 2013 John Wiley & Sons, Ltd.     

Association of MTHFR, MTR, MTRR, RFC1, and DHFR gene polymorphisms with susceptibility to sporadic colon cancer

Altered folate levels may play an important role in colon carcinogenesis. The aim of this study was to investigate the association of polymorphisms in key folate-metabolizing genes with susceptibility to sporadic colon cancer. Six common polymorphisms (two in MTHFR and one each in MTR, MTRR, RFC1, and DHFR genes) were genotyped in 300 healthy subjects and 300 colon cancer patients from Croatia. Obtained results indicate possible protective role of MTRR 66 AA in sporadic colon cancer (OR=0.655; 95% CI=0.441-0.973; p=0.04). Maximum-likelihood analysis of haplotypes revealed a linkage disequilibrium (LD) between the two investigated polymorphisms of the MTHFR gene (C677T and A1298C), both in the control and patient groups (p<0.01 for both). LD was also detected between MTRR A66G and MTHFR A1298C polymorphisms but only in a group of patients (p<0.01). A haplotype of A66G and A1298C polymorphisms, A/A, proved to be protective (OR=0.775; 95% CI=0.603-0.996; p=0.04), whereas haplotype A/G was a risk factor for colon cancer (OR=1.270; 95% CI=1.007-1.602; p=0.04). Contrary to some previous studies, single-locus analyses identified no polymorphisms associated with risk for colon cancer, but demonstrated a possible protective effect of MTRR 66 AA genotype. The detected significant LD between two loci (MTHFR A1298C and MTRR A66G) located on different chromosomes indicates a strong selective force as a mechanism for the maintenance of their linkage. Specific combinations of alleles of these two polymorphisms showed a protective but also a risk effect on colon cancer susceptibility.     

Genetic determinants of folate status in Central Bohemia

Although several genetic factors have been implicated as determinants of blood folate concentration in various populations, their effect on folate status in the Czech population has not yet been examined. We explored whether blood folate concentrations in healthy Czech population are associated with polymorphisms in 5,10-methylenetetrahydrofolate reductase (MTHFR), folate hydrolase 1 (FOLH1), reduced folate carrier (RFC), and folate receptor (FOLR1) genes. In a cross-sectional study of 591 control subjects we determined genotypes by PCR-RFLP or ARMS-PCR methods, and plasma and erythrocyte folates by MEIA. The effect of different genotypes on folate status was examined by non-parametric tests and by regression analysis. The prevalence of the MTHFR 677C>T, MTHFR 1298A>C, FOLH1 1561C>T, RFC 80G>A and FOLR1 480G>C variant alleles was 0.34, 0.33, 0.05, 0.44 and 0.00, respectively. Only the MTHFR 677C>T variant was significantly associated with plasma folate concentrations (median 14.7, 14.0 and 12.2 nmol/l for the CC, CT and TT genotypes, respectively). Our study showed that among the five studied allelic variants, only the 677C>T polymorphism in the MTHFR gene is a significant genetic determinant of plasma folate concentrations in Czech population.     

Genetic polymorphisms modulate the folate metabolism of Brazilian individuals with Down syndrome

Individuals with Down syndrome (DS) carry three copies of the Cystathionine β-synthase (CβS) gene. The increase in the dosage of this gene results in an altered profile of metabolites involved in the folate pathway, including reduced homocysteine (Hcy), methionine, S-adenosylhomocysteine (SAH) and S-adenosylmethionine (SAM). Furthermore, previous studies in individuals with DS have shown that genetic variants in genes involved in the folate pathway influence the concentrations of this metabolism's products. The purpose of this study is to investigate whether polymorphisms in genes involved in folate metabolism affect the plasma concentrations of Hcy and methylmalonic acid (MMA) along with the concentration of serum folate in individuals with DS. Twelve genetic polymorphisms were investigated in 90 individuals with DS (median age 1.29?years, range 0.07-30.35?years; 49 male and 41 female). Genotyping for the polymorphisms was performed either by polymerase chain reaction (PCR) based techniques or by direct sequencing. Plasma concentrations of Hcy and MMA were measured by liquid chromatography-tandem mass spectrometry as previously described, and serum folate was quantified using a competitive immunoassay. Our results indicate that the MTHFR C677T, MTR A2756G, TC2 C776G and BHMT G742A polymorphisms along with MMA concentration are predictors of Hcy concentration. They also show that age and Hcy concentration are predictors of MMA concentration. These findings could help to understand how genetic variation impacts folate metabolism and what metabolic consequences these variants have in individuals with trisomy 21.     

Epistatic interactions between loci of one-carbon metabolism modulate susceptibility to breast cancer

In view of growing body of evidence substantiating the role of aberrations in one-carbon metabolism in the pathophysiology of breast cancer and lack of studies on gene–gene interactions, we investigated the role of dietary micronutrients and eight functional polymorphisms of one-carbon metabolism in modulating the breast cancer risk in 244 case–control pairs of Indian women and explored possible gene–gene interactions using Multifactor dimensionality reduction analysis (MDR). Dietary micronutrient status was assessed using the validated Food Frequency Questionnaire. Genotyping was done for glutamate carboxypeptidase II (GCPII) C1561T, reduced folate carrier (RFC)1 G80A, cytosolic serine hydroxymethyltransferase (cSHMT) C1420T, thymidylate synthase (TYMS) 5′-UTR tandem repeat, TYMS 3′-UTR ins6/del6, methylenetetrahydrofolate reductase (MTHFR) C677T, methyltetrahydrofolate-homocysteine methyltransferase (MTR) A2756G, methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) A66G polymorphisms by using the PCR-RFLP/AFLP methods. Low dietary folate intake (P < 0.001), RFC1 G80A (OR: 1.38, 95% CI 1.06–1.81) and MTHFR C677T (OR: 1.74 (1.11–2.73) were independently associated with the breast cancer risk whereas cSHMT C1420T conferred protection (OR: 0.72, 95% CI 0.55–0.94). MDR analysis demonstrated a significant tri-variate interaction among RFC1 80, MTHFR 677 and TYMS 5′-UTR loci (P _trend < 0.02) with high-risk genotype combination showing inflated risk for breast cancer (OR 4.65, 95% CI 1.77–12.24). To conclude, dietary as well as genetic factors were found to influence susceptibility to breast cancer. Further, the current study highlighted the importance of multi-loci analyses over the single-locus analysis towards establishing the epistatic interactions between loci of one-carbon metabolism modulate susceptibility to the breast cancer.     

MTHFR 677 CT/MTHFR 1298 CC genotypes are associated with increased risk of hypertension in Indians

The goals of our present study were to measure plasma homocysteine levels and determine their association with methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms (C677T and A1298C) in essential hypertensive subjects. Plasma total homocysteine and folic acid levels were measured in essential hypertensive patients (n = 153) before and after oral supplementation with either 5 mg folic acid tablet/day or 5 mg placebo/day for 4 weeks and compared with age and sex matched normotensive controls (n = 133). MTHFR gene polymorphisms (C677T and A1298C) were studied by restriction fragment length polymorphism and correlated with plasma homocysteine levels. Homocysteine levels were significantly higher in hypertensive patients as compared to controls and showed a negative correlation with plasma folate levels. Folic acid supplementation (5 mg/day) for 4 weeks resulted in a significant decrease in plasma homocysteine concentrations in these patients. Patients carrying MTHFR 677T allele (OR = 1.90; 95%CI: 1.14–3.19) or MTHFR 1298C (OR = 2.6, 95%CI: 1.55–4.40) allele were at increased risk of hypertension. The frequency of co-occurrence of MTHFR 677 CT/1298 CC genotypes was significantly higher in the patients compared to controls (P < 0.05) and was associated with increased risk of hypertension (OR = 3.54, 95%CI: 0.37–4.30). Subjects with MTHFR 1298 CC genotype had significantly higher homocysteine levels compared to those with MTHFR 1298 AA genotype (P < 0.05). Our results indicate that MTHFR 677T and 1298C alleles and co-occurrence of MTHFR 677 CT/MTHFR 1298 CC genotypes are associated with increased risk of hypertension and MTHFR 1298 CC genotype is associated with higher homocysteine levels in our subjects.     

Two MTHFR polymorphisms, maternal B-vitamin intake, and CHDs

BACKGROUND: The methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms are associated with complex congenital malformations. Whether these polymorphisms are associated with CHDs is not clear. We studied both MTHFR polymorphisms, folate and vitamin B2 by maternal food intake and supplements, and CHD risk. METHODS: A case‐control family study was conducted in a European population in the Netherlands including 230 case and 251 control children with both parents. Approximately 17 months after the index pregnancy, mothers filled out standardized questionnaires on periconception use of folic acid supplements and a validated food frequency questionnaire on current dietary folate and vitamin B2 intake. All subjects were genotyped for the MTHFR C677T and A1298C polymorphisms. Data were analyzed by logistic regression analysis and ORs and 95% CIs were calculated. For the interaction analysis the dominant model was used. RESULTS: The risk estimates for the MTHFR 677 CT genotypes were 1.4 (0.9–2.0) in mothers, 1.1 (0.8–1.6) in fathers, and 1.2 (0.8–1.7) in children, and for the MTHFR 677 TT genotypes 0.9 (0.6–1.2), 1.4 (1.0–1.9), and 1.0 (0.7–1.3), respectively. The MTHFR 1298 CC genotype in fathers and the MTHFR 1298 AC genotype in children significantly reduced CHD risk, 0.6 (0.5–0.9) and 0.6 (0.4–0.9), respectively. Of interest is the significant interaction (p = .008) towards a nearly twofold increased risk in mothers carrying the MTHFR 1298C allele and using a periconception folic acid supplement. CONCLUSIONS: The MTHFR C677T and A1298C polymorphisms are not strong risk factors for CHDs. Birth Defects Research (Part A), 2008. © 2008 Wiley‐Liss, Inc.     

Interaction of eNOS polymorphism with MTHFR variants increase the risk of diabetic nephropathy and its progression in type 2 diabetes mellitus patients

The present study has investigated the role of endothelial nitric oxide (eNOS) G894T polymorphism and its interaction with methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C variants on the predisposition to diabetic nephropathy and its progression. Using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method the eNOS G894T and MTHFR polymorphisms were detected in 72 microalbuminuric, 68 macroalbuminuric, and 72 normoalbuinuric type 2 diabetes mellitus (T2DM) patients from Western Iran. The presence of GT and GT + TT genotypes of eNOS were associated with insignificantly 1.86- and 1.68-fold increased risk of macroalbuminuria, respectively and 1.21- and 1.13-fold increased risk of microalbuminuria, respectively. However, the concomitant presence of eNOST and MTHFR 1298C alleles were significantly increased the risk of macroalbuminuria (6.6-fold, P < 0.001) and progression from micro- to macro-albuminuria (3.85 times, P = 0.011). Also, the presence of both alleles of eNOST and MTHFR 677T were significantly associated with increased risk of macroalbuminuria (4.8-fold, P = 0.005). The presence of GT + TT genotypes of eNOS was significantly associated with increased risk of coronary artery disease in micro- and macro-albuminuric patients compared to normoalbuminuric patients. The concomitant presence of three mutant alleles significantly increased the risk of macroalbuminuria and progression from micro- to macro-albuminuria 38.5- and 10.5-fold, respectively. Our study indicated that eNOS T allele interacts with MTHFR variants, especially MTHFR A1298C to increase the risk of macroalbuminuria and progression from micro-to macro-albuminuria. Also, Interaction between three alleles of eNOST, MTHFR 677T, and 1298C highly increased the risk of macroalbuminuria and progression of diabetic nephropathy in T2DM patients.     

Genotype and allele frequencies of the polymorphic methylenetetrahydrofolate reductase gene in Turkey

The polymorphic methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms C677T and A1298C cause mild hyperhomocysteinemia, not only in homozygotes for C677T, but also in compound heterozygotes for C677T/A1298C. The aim of this study was to determine allelic frequencies of the polymorphic MTHFR gene C677T, A1298C. In this regard, we have investigated the allelic frequencies of C677T and A1298C polymorphisms of the MTHFR gene in 1684 randomized individuals around Turkey. DNA samples isolated from peripheral blood samples of randomized individuals were analysed. The study population consisted of 1004 females and 680 males. The frequency in Turkey of the C677T was 42.9 %; of C677C, 47.4 %; and of T677T, 9.6 %. The frequency in Turkey of A1298C was 43.7 %; of A1298A, 46.3 %; and of C1298C, 10.0 %. The allelic frequencies of the T allele of MTHFR 677 and the C allele of MTHFR 1298 were 33.34 and 33.16 %, respectively. The frequency of C677T/A1298C compound heterozygosity is highest in Turkey (21.6 %), as compared to Canada (15 %), the United States (17 %) and The Netherlands (20 %).     

Lower incidence of nonsyndromic cleft lip with or without cleft palate in females: Is homocysteine a factor?

In India, as in other parts of the world, nonsyndromic cleft lip with or without cleft palate (NSCL±P) is a highly prevalent birth defect, its incidence in males being twice that in females. A case–control association study has been carried out with respect to homocysteine level and MTHFR C677T, A1298C and SLC19A1 (RFC1) G80A genotypes from an eastern Indian cohort to investigate whether Hcy and other Hcy-pathway genes also contribute to the risk level. While MTHFR 677T and SLC19A1 80G are individually and cumulatively risk factors, SLC19A1 80A appears to be protective against MTHFR 677T risk allele. Elevated Hcy associates with NSCL±P both in case mothers and cases. Significantly, this difference shows a gender bias: the level of elevation of Hcy in female cases is distinctly higher than in males, and more case females are hyperhomocyteinemic than the case males. It implies that compared with the males, higher level of Hcy is needed for NSCL±P to manifest in the females. We consider this as one of the possible factors why the incidence of this disorder in females is much lower than in males.     

Frequencies of C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase gene at the early stage of human individual development

In most cases, the cause of embryo and fetus death remains unclear although the multifactorial causes are suspected. The polymorphic C677T and A1298C variants of the MTHFR gene are associated with an increase in the level of homocysteine, which is risk factor of pregnancy loss. The subject of this study is analysis of genotypes and haplotypes of C677T and A1298C polymorphic variants of MTHFR genes in the groups of spontaneous abortions with the normal karyotype and newborns in the Tomsk population. Between these groups, no statistically significant differences were determined in the allele, genotype, and haplotype distributions of C677T and A1298C polymorphisms of the MTHFR gene. The haplotype frequencies of C677T and A1298C polymorphic variants of MTHFR gene in the Russian populations, which proved to be similar to those in most European populations, are presented.