DNMT3B C46359T and SHMT1 C1420T polymorphisms in the folate pathway in carcinogenesis of head and neck

Folate is an essential nutrient with important roles in the synthesis, repair, and DNA methylation. Polymorphisms in genes encoding enzymes involved in folate metabolism can change these processes and modulate cancer development. We investigated DNMT3B C46359T (rs2424913) and SHMT1 C1420T (rs1979277) polymorphisms related to folate pathway in head and neck cancer (HNC) risk and the association of the disease with gender, risk factors and clinical histopathological parameters. A case–control study was conducted in 725 individuals (237 patients with HNC and 488 control individuals). Real-time PCR technique was performed for genotyping. Chi square and multiple logistic regression tests were used for statistical analysis. Male gender (OR 1.80; 95 % CI 1.11–2.94; P < 0.02) and tobacco consumption (OR 6.14; 95 % CI 4.13–9.13; P < 0.001) were associated with increased risk for this neoplasia. There were no significant associations between the polymorphisms and risk of disease, however, the tobacco and alcohol habits together showed association with SHMT1 C1420T polymorphism (OR 1.48; 95 % CI 1.08–2.03; P = 0.014). SHMT1 C1420T polymorphism was associated with larynx tumor (OR 0.48; 95 % CI 0.27–0.86; P < 0.05). In conclusion, tobacco habit and male gender can be predictors for HNC risk. SHMT1 C1420T and DNMT3B C46359T polymorphisms are not associated with HNC development in Brazilian population, however, SHMT1 C1420T polymorphism is less frequent in patients with primary site of tumor in larynx and more frequent in individuals who consume tobacco and alcohol together. Further studies involving gene–gene interactions in folate pathway in different populations can contribute to the understanding of the polymorphisms effect on HNC risk.     

Prevalence of methylenetetrahydrofolate reductase 677 C-T polymorphism among mothers of Down syndrome children

INTRODUCTION:

The relationship between chromosomal non-disjunction leading to aneuploidy and folate metabolism has drawn attention in the recent years. In this study, we examined the polymorphism in the gene encoding the folate metabolizing enzyme methylenetetrahydrofolate reductase (MTHFR), namely, 677 C-T in women having Down syndrome (DS) children.

MATERIALS AND METHODS:

The prevalence of these variant genotypes (MTHFR 677 C-T polymorphism) in women having DS children (case mothers) (n = 110) was compared with controls (n = 111) from Punjab. Genotyping was done using the polymerase chain reaction method followed by restriction fragment length polymorphism.

RESULTS:

In the present study, 1.8% of case mothers had TT genotype while none of the control mothers showed this genotype. T allele frequency among cases was 0.13 and 0.11 in controls. The Chi-square value showed a non-significant difference between cases and controls.

CONCLUSION:

No association has been observed between 677 C-T polymorphism and risk of non-disjunction in case mothers. Detection of polymorphisms in more genes of folate pathway is required to find out the exact cause of non-disjunction.     

Methylenetetrahydrofolate reductase polymorphism is not risk factor for Down syndrome in North India

BACKGROUND:

Down syndrome (DS) is the most common cause of mental retardation of genetic etiology with the prevalence rate of 1/700 to 1/1000 live births worldwide. Several polymorphisms in folate/homocysteine metabolism pathways genes have been reported as a risk factor in women for bearing DS child, but very few studies investigated these polymorphisms in DS cases whether there are a risk factor for being DS or not.

OBJECTIVE:

We have investigated the association of methylenetetrahydrofolate reductase (MTHFR) with the occurrence of DS in Indian population. MTHFR is one of the key regulatory enzymes involved in the metabolic pathway of homocysteine responsible for the reduction of methyltetrahydrofolate. A total of 32 DS cases and 64 age, sex matched controls were genotyped for MTHFR C677T polymorphism by polymerase chain reaction-restriction fragment length polymorphism.

RESULTS:

The observed genotype frequencies were CC = 0.81; CT = 0.17 and TT = 0.02 in controls and CC = 0.81 and CT = 0.19 in DS cases. Frequency of T allele in DS and controls were 0.09 and 0.1, respectively. Significant difference in the distribution of mutant 677T allele was not observed between DS cases and controls (odds ratio = 0.915; 95% confidence intervals: 0.331-2.53; P = 0.864).

CONCLUSION:

Results of this study indicate that MTHFR C677T polymorphism is not risk factor for DS.     

Betaine–homocysteine methyltransferase 742G>A polymorphism and risk of down syndrome offspring in a Brazilian population

Down syndrome (DS) is the most common form of mental retardation of genetic etiology. Several polymorphisms in genes involved with the folic acid cycle have been associated to the risk of bearing a DS child; however, the results are controversial. Betaine-homocysteine methyltransferase (BHMT) is a key enzyme of folate pathway, and catalyzes the remethylation of homocysteine into methionine. Recent studies suggest that the polymorphism BHMT 742G>A may be associated with a decreased risk of having a DS child. We herein investigate the association of this polymorphism with the occurrence of DS in a Brazilian population. We have genotyped 94 mothers of DS infants (DSM) and 134 control mothers (CM) for this polymorphism through PCR–RFLP, and found significant differences for both BHMT 742G>A genotype (P = 0.04) and allele (P = 0.03) frequencies between DSM and CM. The observed genotypic frequencies were GG = 0.45; GA = 0.45 and AA = 0.10 in CM, and GG = 0.54; GA = 0.38 and AA = 0.02 in DSM. Allelic frequencies were G = 0.68 and A = 0.32 in CM and G = 0.78 and A = 0.22 in DSM. The presence of the mutant BHMT 742 A allele decreases 40 % the risk of bearing a DS child (OR = 0.61; 95 % CI: 0.40–0.93; P = 0.03), and the risk is diminished up to >80 % in association with the homozygous genotype (OR = 0.17; 95 % CI: 0.04–0.80; P = 0.01). Our results indicate that women harboring the single nucleotide polymorphism BHMT 742G>A have a decreased risk of a DS pregnancy, and further studies are necessary to confirm this protective effect.     

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。     

Oxidative Stress is Associated with Genetic Polymorphisms in One-Carbon Metabolism in Coronary Artery Disease

In view of growing body of evidence favouring the association of aberrations in one-carbon metabolism and oxidative stress in the aetiology of coronary artery disease (CAD), we investigated the risk associated with polymorphisms regulating the folate uptake and transport such as the glutamate carboxypeptidase II (GCPII) C1561T, reduced folate carrier 1 (RFC1) G80A and cytosolic serine hydroxymethyltransferase (cSHMT) C1420T. We further evaluated the impact of seven putatively functional polymorphisms of this pathway on oxidative stress markers. Genotyping was performed on 288 CAD cases and 266 healthy controls along with the dietary folate assessment. GCPII C1561T polymorphism was found to be an independent risk factor (OR 2.71, 95% CI 1.47–4.98) for CAD, whereas cSHMT C1420T conferred protection (OR 0.51, 95% CI 0.37–0.70). Oxidative stress markers like the plasma levels of malondialdehyde, protein carbonyls and 8-oxo-deoxyguanosine were significantly increased and total glutathione was significantly decreased in CAD cases. Elevated oxidative stress was observed in subjects carrying GCPII 1561T and MTRR 66A-variant alleles and low oxidative stress was observed in the subjects carrying cSHMT 1420T and TYMS 5′-UTR 2R allele. GCPII C1561T, MTHFR C677T and MTRR A66G polymorphisms were observed to influence the homocysteine levels (P < 0.05). SHMT and TYMS variants were found to decrease oxidative stress by increasing the folate pool (r = 0.38, P = 0.003) and also by increasing the antioxidant status (r = 0.28, P = 0.03). Influence of dietary folate status was not observed. Overall, this study revealed elevated oxidative stress that was associated with the aberrations in one-carbon metabolism which could possibly influence the CAD risk.     

Polymorphisms and haplotypes in methylenetetrahydrofolate reductase gene and head and neck squamous cell carcinoma risk

Functional polymorphisms in genes encoding enzymes involved in folate metabolism might modulate head and neck carcinoma risk because folate participates in DNA methylation and synthesis. We therefore conducted a case–control study of 853 individuals (322 head and neck cancer cases and 531 non-cancer controls) to investigate associations among MTHFR C677T and MTHFR A1298C polymorphisms and head and neck squamous cell carcinoma risk. Interactions between these two polymorphisms and risk factors and clinical histopathological parameters were also evaluated. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was used to genotype the polymorphisms and Chi-square test and multiple logistic regression were used for statistical analyses. The variables age ≥49 years, male gender, tobacco habits and alcohol consumption, MTHFR 1298 AC or CC genotypes, combined genotypes with two or more polymorphic alleles and 677T and 1298C polymorphic alleles were associated with increased risk for this disease (P < 0.05). Furthermore, we found that 1298 AC or CC genotypes were associated with age ≥49 years, tobacco and alcohol habits (P < 0.05). Regarding clinical histopathological parameters, the A1298C polymorphism was more frequent in patients with oral cavity as primary site (P < 0.05). MTHFR polymorphisms may contribute for increase risk for head and neck carcinoma and the variables age ≥49 years, male gender, tobacco and alcohol habits were associated with MTHFR 1298AC or CC genotypes, confirming that individuals with these variables and MTHFR A1298C polymorphism has higher risk for this disease.     

MTHFR Gene variants C677T, A1298C and association with Down syndrome: A Case-control study from South India

BACKGROUND:

The 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms and low folate levels are associated with inhibition of DNA methyltransferase and consequently DNA hypomethylation. The expanding spectrum of common conditions linked with MTHFR polymorphisms includes certain adverse birth outcome, pregnancy complications, cancers, adult cardiovascular diseases and psychiatric disorders, with several of these associations remaining still controversial. Trisomy 21 or Down syndrome (DS) is the most common genetic cause of mental retardation. It stems predominantly from the failure of chromosome 21 to segregate normally during meiosis. Despite substantial research, the molecular mechanisms underlying non-disjunction leading to trisomy 21 are poorly understood.

MATERIALS AND METHODS:

Two common variants C677T and A1298C of the MTHFR gene were screened in 36 parents with DS children and 60 healthy couples from Tamil Nadu and Karnataka. The MTHFR genotypes were studied by RFLP analysis of PCR-amplified products and confirmed by sequencing.

RESULTS:

The CT genotype was seen in three each (8.3%) of case mothers and fathers. One case father showed TT genotype. All the control individuals exhibited the wild type CC genotype. A similar frequency for the uncommon allele C of the second polymorphism was recorded in case mothers (0.35) and fathers (0.37) in comparison with the control mothers (0.39) and fathers (0.37).

CONCLUSION:

This first report on MTHFR C677T and A1298C polymorphisms in trisomy 21 parents from south Indian population revealed that MTHFR 677CT polymorphism was associated with a risk for Down syndrome.     

Association of methylenetetrahydrofolate reductase gene 677C > T polymorphism and Down syndrome

The association between Down syndrome (DS) and maternal polymorphisms in genes encoding folic acid metabolizing enzymes remains a controversial issue. A meta-analysis was performed to evaluate the association of maternal MTHFR 677C > T polymorphism and the risk of having a child with DS. Case–control studies were screened from major literature databases. Twenty articles from 13 countries worldwide, with a total of 2,101 DS and 2,702 control mothers, attended the inclusion criteria. We found a 50 % increase for the association of maternal homozygous TT genotype and DS in both fixed (OR = 1.51; 95 % CI 1.22–1.87) and random effects models (OR 1.54; 95 % 1.15–2.05). Similarly, a significant pooled OR was found for the heterozygote CT, with an OR 1.26; 95 % CI 1.10–1.43 (fixed effects model) and OR 1.28; 95 % 1.08–1.51 (random effects model). As ultra-violet B solar radiation highly depends on latitude, and can promote, in less pigmented skin, intravascular folate photolysis, we stratified the analysis by latitude region, defining as Tropical (between 23.5^° S and 23.5^° N), Sub-Tropical (between 23.5^° and 40^° N and S), and Northern (≥40^o N). Significant association was only found for Sub-Tropical area, both using fixed and random effect models. In conclusion, MTHFR 677C > T polymorphism is a moderate risk factor for DS for some populations, and populations located in Sub-Tropical region seem to be at greater risk. Latitude, ethnicity, skin pigmentation, and red blood cell folate are important variables to be considered in future studies.     

The MTRR 66A>G polymorphism and maternal risk of birth of a child with Down syndrome in Caucasian women: a case–control study and a meta-analysis

We performed a large case–control study and a meta-analysis of the literature to address the role of the methionine synthase reductase (MTRR) c.66A>G polymorphism as a maternal risk factor for the birth of a child with Down Syndrome (DS) among Caucasian women. A total of 253 mothers of a DS child (MDS) and 298 control mothers of Italian origin were included in the case–control study. The meta-analysis of previous and present data involved a total of seven studies performed in Caucasian populations (971 MDS and 1,387 control mothers). Results from the meta-analysis indicated overall a positive significant association between MTRR c.66A>G genotype [OR 1.36 (95 % CI 1.10–1.68), dominant model] and allele frequencies [OR 1.26 (95 % CI 1.04–1.51), allele contrast model] and maternal risk of birth of a child with DS. A sensitivity analysis revealed some interesting differences between Europeans, Caucasians of European descent, and inhabitants of Mediterranean regions, suggesting the possibility of population-specific modifying factors. The case–control study revealed association of the polymorphism with increased folate levels, and a possible interaction with the methionine synthase (MTR) c.2756A>G one, that resulted in a borderline significant maternal risk of birth of a child with DS for the double heterozygous MTR 2756AG/MTRR 66AG genotype [OR 1.79 (95 % CI 1.00–3.18)]. Overall, present data suggest that the MTRR c.66A>G polymorphism represents a risk factor for the birth of a child with DS among white Caucasian women. However, the combined presence of other genetic factors and interactions with geographic and environmental ones, can modify the effect of the single polymorphism alone, leading to population specific effect sizes.     

PCMT1 gene polymorphisms, maternal folate metabolism, and neural tube defects: a case–control study in a population with relatively low folate intake

The PCMT1 gene encodes the protein repair enzyme protein-l-isoaspartate (d-aspartate) O-methyltransferase, which is known to protect certain neural cells against Bax-induced apoptosis. Previous studies have produced inconsistent results regarding the effects of PCMT1 (rs4816 and rs4552) polymorphisms on neural tube defects (NTDs). Reduced maternal plasma folate levels and/or elevated homocysteine (Hcy) levels are considered to be risk factors for NTDs. In order to clarify the key factors contributing to the apparent discrepancy and investigate gene–environment interaction, we conducted a case–control study including 121 cases and 146 matched controls to investigate the association between the two PCMT1 polymorphisms in fetuses and the risk of NTDs in the Chinese population of Lvliang, which has low folate intake. Maternal plasma folate and Hcy levels were also measured, and the interaction between fetal PCMT1 gene status and maternal folate metabolites was assessed. Maternal plasma folate concentrations in the NTD group were lower than in controls (10.23 vs. 13.08 nmol/L, adjusted P = 0.059), and Hcy concentrations were significantly higher (14.46 vs. 11.65 μmol/L, adjusted P = 0.026). Fetuses carrying the rs4816 AG + GG genotype, combined with higher maternal plasma Hcy, had a 6.46-fold (95 % CI 1.15–36.46) increased risk of anencephaly. The results of this study imply that the fetal PCMT1 rs4816 polymorphism may play only a weak role in NTD formation and that gene–environment interactions might be more significant.     

Maternal <Emphasis Type="Italic">MTHFR</Emphasis> polymorphism (677 C–T) and risk of Down’s syndrome child: meta-analysis

Methylenetetrahydrofolate reductase (MTHFR) is the most important gene that participates in folate metabolism. Presence of valine instead of alanine at position 677 and elevated levels of homocystein causes DNA hypomethylation which in turn favours nondisjunction. In this study, we conducted a meta-analysis to establish link between maternal single-nucleotide polymorphism (SNP) and birth of Down’s syndrome (DS) child. A total of 37 case–control studies were selected for analysis including our own, in which we investigated 110 cases and 111 control mothers. Overall, the result of meta-analysis showed significant risk of DS affected by the presence of maternal SNP (MTHFR 677 C–T OR = 0.816, 95% CI = 0.741–0.900, P<0.0001). Heterogeneity of high magnitude was observed among the studies. The chi-square value suggested a highly significant association between homozygous mutant TT genotype and birth of DS child (χ²=23.63, P=0.000). Genetic models suggested that ‘T’ allele possesses high risk for DS whether present in dominant (OR = 1.23, 95% CI = 1.13–1.34); codominant (OR = 1.17, 95% CI = 1.10–1.25) or recessive (OR = 1.21, 95% CI = 1.05–1.38) form. The analysis from all 37 studies combined together suggested that MTHFR 677 C–T is a major risk factor for DS birth.     

Maternal Obesity and Tobacco Use Modify the Impact of Genetic Variants on the Occurrence of Conotruncal Heart Defects

Conotruncal heart defects (CTDs) are among the most severe birth defects worldwide. Studies of CTDs indicate both lifestyle behaviors and genetic variation contribute to the risk of CTDs. Based on a hybrid design using data from 616 case-parental and 1645 control-parental triads recruited for the National Birth Defects Prevention Study between 1997 and 2008, we investigated whether the occurrence of CTDs is associated with interactions between 921 maternal and/or fetal single nucleotide polymorphisms (SNPs) and maternal obesity and tobacco use. The maternal genotypes of the variants in the glutamate-cysteine ligase, catalytic subunit (GCLC) gene and the fetal genotypes of the variants in the glutathione S-transferase alpha 3 (GSTA3) gene were associated with an elevated risk of CTDs among obese mothers. The risk of delivering infants with CTDs among obese mothers carrying AC genotype for a variant in the GCLC gene (rs6458939) was 2.00 times the risk among those carrying CC genotype (95% confidence interval: 1.41, 2.38). The maternal genotypes of several variants in the glutathione-S-transferase (GST) family of genes and the fetal genotypes of the variants in the GCLC gene interacted with tobacco exposures to increase the risk of CTDs. Our study suggests that the genetic basis underlying susceptibility of the developing heart to the adverse effects of maternal obesity and tobacco use involve both maternal and embryonic genetic variants. These results may provide insights into the underlying pathophysiology of CTDs, and ultimately lead to novel prevention strategies.     

Maternal Methylenetetrahydrofolate Reductase C677T Polymorphism and Down Syndrome Risk: A Meta-Analysis from 34 Studies

Background

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme of folate metabolic pathway which catalyzes the irreversible conversion of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. 5-methyltetrahydrofolate donates methyl group for the methylation of homocysteine to methionine. Several studies have investigated maternal MTHFR C677T polymorphism as a risk factor for DS, but the results were controversial and inconclusive. To come into a conclusive estimate, authors performed a meta-analysis.

Aim

A meta-analysis of published case control studies was performed to investigate the association between maternal MTHFR C677T polymorphism and Down syndrome.

Methods

PubMed, Google Scholar, Elsevier, Springer Link databases were searched to select the eligible case control studies using appropriate keywords. The pooled odds ratio (OR) with 95%confidence interval were calculated for risk assessment.

Results

Thirty four studies with 3,098 DS case mothers and 4,852 control mothers were included in the present meta-analysis. The pooled OR was estimated under five genetic models and significant association was found between maternal MTHFR 677C>T polymorphism and Down syndrome under four genetic models except recessive model (for T vs. C, OR = 1.26, 95% CI = 1.09–1.46, p = 0.001; for TT vs. CC, OR = 1.49, 95% CI = 1.13–1.97, p = 0.008; for CT vs. CC, OR = 1.29, 95% CI = 1.10–1.51, p = 0.001; for TT+CT vs. CC, OR = 1.35, 95% CI = 1.13–1.60, p = 0.0008; for TT vs. CT+CC, OR = 0.76, 95% CI = 0.60–0.94, p = 0.01).

Conclusion

The results of the present meta-analysis support that maternal MTHFR C677T polymorphism is a risk factor for DS- affected pregnancy.     

Meta-analysis of Methylenetetrahydrofolate reductase maternal gene in Down syndrome: increased susceptibility in women carriers of the MTHFR 677T allele

Because a number of data studies include some controversial results about Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and Down syndrome (DS), we performed a meta-analysis to determine a more precise estimation of this association. Studies were searched on PubMed, EMBASE and Lilacs–Scielo, up to April 2013, and they were eligible if they included case mothers (DSM) that have gave birth to children with DS, and controls mothers (CM) that have gave birth to healthy children without chromosomal abnormality, syndrome or malformation. The combined odds ratio with 95 % confidence intervals was calculated by fixed or random effects models to assess the strength of associations. Potential sources of heterogeneity between studies were evaluated using Q test and the I². Publication bias was estimated using Begg’s test and Egger’s linear regression test. Sensitivity analyses were performed by using allelic, dominant, recessive and codominant genetic models, Hardy–Weinberg equilibrium (HWE) and ethnicity. Twenty-two studies with 2,223 DSM and 2,807 CM were included for MTHFR C677T and 15 studies with 1,601 DSM and 1,849 CM were included for MTHFR A1298C. Overall analysis suggests an association of the MTHFR C677T polymorphism with maternal risk for DS. Moreover, no association between the MTHFR A1298C polymorphism and maternal risk for DS was found. There is also evidence of higher heterogeneity, with I² test values ranging from 8 to 89 %. No evidence of publication bias was found. Taken together, our meta-analysis implied that the T allele carriers might carry an increased maternal risk for DS.     

Genetic polymorphisms involved in folate metabolism and elevated plasma concentrations of homocysteine: maternal risk factors for Down syndrome in Brazil

The aim of the present study was to investigate the effect of polymorphisms C677T and A1298C in the methylenetetrahydrofolate reductase (MTHFR) gene, A2756G in methionine synthase reductase (MTR) gene and A80G in reduced folate carrier 1 (RFC1) gene, and plasma homocysteine (Hcy), on the maternal risk for Down syndrome (DS). Seventy-two DS mothers and 194 mothers who had no children with DS were evaluated. The investigation of the MTHFR C677T, MTR A2756G and RFC1 A80G polymorphisms was performed by polymerase chain reaction and enzyme digestion and the MTHFR A1298C polymorphism by allele-specific polymerase chain reaction. Hcy quantification was carried out by liquid chromatography-tandem mass spectrometry. The median number of polymorphic alleles for the four loci tested was greater in DS mothers compared to the control group, and the presence of three or more polymorphic alleles increased the risk for having a child with DS 1.74 times. Elevated maternal risk for DS was also observed when plasma Hcy concentration was higher than 4.99 micromol/L. In conclusion, the presence of three or more polymorphic alleles for MTHFR C677T, MTHFR A1298C, MTR A2756G, and RFC1 A80G, and plasma Hcy concentrations higher than 4.99 micromol/L are maternal risk factors for DS.     

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。     

Maternal and infant MTHFR gene polymorphisms and non-syndromic oral cleft susceptibility: An updated meta-analysis

Non-syndromic cleft lip with or without cleft palate (NSCLP) is a common craniofacial malformation. Irregular folate metabolism plays a significant role in the etiopathology of NSCLP. In this study, we aim to examine the association of the maternal and cleft child methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms (C677 T and A1298C) with nonsyndromic cleft lip with or without cleft palate (NSCLP) by carefully evaluating established studies. The meta-analysis includes 39 studies that focused on MTHFR C677T and A1298C polymorphisms in cleft children or cleft children’s mothers. All statistical data underwent random or fixed effects model with an odds ratio and 95% confidence intervals as effect measures and was preformed using a web tool MetaGenyo. Statistical analyses showed that the MTHFR C677T is significantly associated with the increased risk of NSCLP in children but not in the mothers. In contrast to this, there is no evidence for association between MTHFR A1298C and NSCLP risk in both children and the mothers. Furthermore, there is no evidence for publication bias for both MTHFR C677T and A1298C polymorphisms in cleft children as well as the mothers of cleft children. In conclusion, we determined that there is a strong association between the MTHFR C677 T polymorphism and NSCLP.     

Study on Environmental Causes and SNPs of MTHFR,MS and CBS Genes Related to Congenital Heart Disease

Purpose

Congenital heart diseases (CHD) are among the most common birth defects in China. Environmental causes and folate metabolism changes may alter susceptibility to CHD. The aim of this study is to evaluate the relevant risk-factors of children with CHD and their mothers.

Methods

138 children with CHD and 207 normal children for controls were recruited. Their mothers were also enlisted in this study and interviewed following a questionnaire about their pregnant history and early pregnancy situation. Five single nucleotide polymorphisms (SNPs) in methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MS) and cystathionine β-synthase (CBS) of mothers and children were genotyped.

Results

There were significant differences in the gender of children, occupation of mothers, family history with CHD, history of abortion, history of adverse pregnancy, early pregnancy health, fetus during pregnancy, pesticide exposure and drug exposure in CHD group and control group ( P < 0.05). Logistic regression analyses showed that after adjustment for above factors, MTHFR rs1801131 were significantly associated with their offspring CHD risk in mothers. Compared with the mothers whose MTHFR were rs1801131 AA and AC genotypes, the mothers who got a mutation of MTHFR rs1801131 CC genotypes had a 267% increase in risk of given birth of a CHD children (OR=3.67,95%CI=1.12-12.05). Meanwhile, MTHFR rs1801131 were significantly associated with CHD susceptibility in children (OR = 1.42, 95% CI = 1.00-2.44 in additive model).

Conclusions

Besides mothers’ social and fertility characteristics, our results suggested that the genetic variants in folate metabolism pathway might be one of the most related risk-factors of CHD. MTHFR rs1801131 were identified as loci in Chinese population that were involved in CHD.     

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.