Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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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.
Genet Mol Res 2008 Jan 22
PMID:Genetic polymorphisms involved in folate metabolism and elevated plasma concentrations of homocysteine: maternal risk factors for Down syndrome in Brazil. 1827 17

Single point mutations in the genes coding for hemostatic factors were shown to be major inherited predisposing factors for venous thromboembolism. However, their contribution in the development of non-diabetic coronary artery disease [nDCAD] remains controversial. Angiographically demonstrated nDCAD patients (n = 86) and healthy controls (n = 90) were included in the study. Genotype analysis of hemostatic gene polymorphisms were assessed by using CVD strip assay, based on allele specific oligonucleotide probes. The carrier frequency of factor V (FV) H1299R, prothrombin G20210A, glycoprotein (Gp) IIIa L33P, plasminogen activator inhibitor-I (PAI-1) 4G/5G, 4G/4G, 5G/5G, methylenetetrahydrofolate reductase (MTHFR) A1298C and beta-fibrinogen -455 G > A were similar between patients and controls. In contrast, frequency of FV Leiden was significantly higher among patients (12.5%) than controls (5%, OR: 7.94; 95%CI: 1.9-49.6) and FXIII V34L was significantly lower among patients (23.7%) than controls (40%, OR: 0.24; 95%CI: 0.1-0.89). In addition, the frequency of the MTHFR C677T polymorphism was 32.5% among patients compared with 42.5% in controls, of which the T/T genotype was significantly lower among patients (5%) than controls (17.5%, OR: 0.06; 95%CI: 0.01-0.58). No difference was observed in prevalence of prothrombin G20210A, FV H1299R, Gp IIIa L33P, PAI-1 4G5G, MTHFR A1298C, beta fibrinogen 455 G > A mutations between patients and controls. However, lower frequency of FXIII Val34Leu and MTHFR C677T polymorphisms may decrease, while FV Leiden polymorphism may increase development of nDCAD.
Mol Biol Rep 2009 Nov
PMID:Impact of hemostatic gene single point mutations in patients with non-diabetic coronary artery disease. 1912 42

It has been suggested that the allele frequency of thrombophilic mutations is affected by glucose-6-phosphate dehydrogenase (G6PD) deficiency. The prevalence of thrombophilic mutations were studied in sixty G6PD deficient individuals including 57 males and three females with the mean age of 15 +/- 3.08 and 110 age and sex matched healthy individuals consisted of 95 males and 15 females with the mean age of 16.19 +/- 2.17 from the Kermanshah Province of Iran. Using a combination of PCR-RFLP technique, single strand conformation polymorphism (SSCP) analysis and DNA sequencing polymorphic G6PD mutations were identified. The factor V Leiden, prothrombin G20210A and methylenetetrahydrofolate reductase (MTHFR) C677T were detected by PCR-RFLP method using MnlI, HindIII and HinfI restriction enzymes, respectively. Three mutations, G6PD Mediterranean, G6PD Chatham and G6PD Cosenza were identified in 60 G6PD deficient individuals with highest prevalence of G6PD Mediterranean (91.6%). In G6PD deficient individuals the prevalence of factor V Leiden tended to be higher (5%) compared to healthy individuals (2.7%). The prevalence of prothrombin G20210A mutation in G6PD deficient individuals was 1.7%. However, in normal subjects the prevalence of this mutation was 2.7%. The frequency of T allele in G6PD deficient individuals were insignificantly higher (29.16%) than those in healthy individuals (26.8%). Our finding indicates that the prevalence of factor V Leiden, prothrombin G20210A and MTHFR C677T in G6PD deficient individuals is not statistically different compared to normal subjects and G6PD deficiency is not associated with these thrombophilic mutations in Western Iran.
Mol Biol Rep 2009 Nov
PMID:The prevalence of factor V Leiden, prothrombin G20210A and methylenetetrahydrofolate reductase polymorphism C677T among G6PD deficient individuals from Western Iran. 1921 40

Hyperhomocysteinemia (HHcy) can result from genetic or nutritional disturbances in folate metabolism. The most common genetic cause of mild HHcy is methylenetetrahydrofolate reductase (MTHFR) deficiency. To explore interactions between HHcy and lipid metabolism in atherogenesis, we measured plasma homocysteine (Hcy), triglycerides and cholesterol in Mthfr(+/+) and Mthfr(+/-) mice on C57BL/6 and BALB/c backgrounds, fed control or folate-deficient diets. We also crossed ApoE(C57)(-/-) mice with Mthfr(C57)(+/-) and Mthfr(BALB/c)(+/-) mice, and examined the same plasma variables as well as lipid accumulation in aortic sinus and whole aorta. Mthfr(+/-) mice had significantly higher plasma Hcy and plasma triglycerides relative to Mthfr(+/+) mice. A significant positive correlation was observed between plasma Hcy and plasma triglycerides in all mice. Mthfr(+/-) mice had lower plasma ApoA-IV protein levels which could reduce clearance of triglyceride-rich lipoproteins from the circulation. In the double mutant experiments, plasma Hcy was higher in Mthfr(+/-) compared with Mthfr(+/+) in ApoE(C57)(-/-)/Mthfr(C57) and ApoE(C57)(-/-)/Mthfr(BALB/c) mice. Triglycerides in female ApoE(C57)(-/-)/Mthfr(BALB/c)(+/-) mice were higher than those in ApoE(C57)(-/-)/Mthfr(BALB/c)(+/-) mice and correlated positively with Hcy. ApoE(C57)(-/-)/Mthfr(C57)(+/-) male mice had more lipid deposition in aortic sinus and whole aorta compared with ApoE(C57)(-/-)/Mthfr(c57)(+/+) mice. Our results suggest that HHcy is associated with hypertriglyceridemia and that MTHFR deficiency may exacerbate lipid accumulation in ApoE deficiency.
Mol Genet Metab
PMID:Hyperhomocysteinemia is associated with hypertriglyceridemia in mice with methylenetetrahydrofolate reductase deficiency. 1956 Sep 54

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 beta-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.
Mol Genet Metab
PMID:Polygenic association with total homocysteine in the post-folic acid fortification era: the CARDIA study. 1957 40

Methylenetetrahydrofolate reductase is an important enzyme in metabolism of homocysteine, and a mutation in the gene predisposes individuals to several disorders related to homocysteine levels. Polymorphism at C677T shows marked heterogeneity based upon ethnicity and geographical location. Pakistani population consists of various ethnic groups confined to different regions of the country where congenital and genetic defects are a major health concern. We have analyzed the distribution of C677T alleles in different Pakistani ethnic groups. A cross-sectional study was conducted from all the four provinces of the country with samples representing the 14 different ethnic clans. A questionnaire with details of their ethnic origin was used, and informed consent was obtained. Blood samples from 701 individuals were collected for DNA isolation and subsequent C677T single-nucleotide polymorphism determination. The data were statistically analyzed. The study revealed that genotypic frequency for CC varied from 0.89 (Mohanna) to 0.38 (Hazara), CT from 0.56 (Hazara) to 0.11 (Mohanna), and TT from 0.06 to 0. Our data revealed a varied distribution of C677T mutation. This information could be helpful for designing future public health strategies, as it can be used to predict the prevalence of several disorders associated with genetic predisposition due to methylenetetrahydrofolate reductase C677T alleles.
Genet Test Mol Biomarkers 2009 Aug
PMID:Prevalence of the C677T single-nucleotide polymorphism in the methylenetetrahydrofolate reductase gene among Pakistani ethnic groups. 1959 69

The 5,10-methylenetetrahydrofolate reductase gene (MTHFR) 677C>T polymorphism produces an elevation in plasma homocysteine concentrations when present in the homozygous state. Increased homocysteine levels have been associated with a greater risk for vascular diseases, including cardiovascular disease and ischemic stroke. In this study, we genotyped 42 nucleic acid samples for the C677T allele from our database of Middle Eastern patients as routine validation of the MTHFR 677C>T assay. Our study is the first to evaluate MTHFR C677T genotype frequency in a population of Middle Eastern patients residing in the United States. Among the patients, 47.6% were wild type, 40.5% were heterozygous, and 11.9% were homozygous for the C677T variant. Although C677T genotype frequency in our patient population is slightly higher than that reported by Golbahar et al. (2005), statistical analysis showed no statistically significant difference beyond chance in genotype profiles (chi(2) = 1.54, df = 2, p = 0.1675). However, our findings implicate the need for a larger sample size to explore the need to implement standard clinical screening of MTHFR 677C>T. We also highlight the robust, reliable, and reproducible assay afforded by the use of anchor and sensor hybridization probes within the LightCycler platform to perform amplification and melting curve analysis protocols. Melting curve profiles that are produced display distinct and robust T(m) peaks based on the degree of anchor and sensor hybridization to amplicons produced from template DNA that is either wild-type, heterozygous, or a homozygous variant at the MTHFR 677C>T locus. A 10 degrees C gap between T(m) peaks allows for rapid and accurate qualitative identification of genotype.
Genet Test Mol Biomarkers 2009 Aug
PMID:MTHFR C677T genotype frequency in patients of Middle Eastern descent as determined by real-time PCR and melting curve analysis. 1959 72

Carcinogenesis may result from abnormal methylation of cancer-related genes regulatory sequence. Though, the polymorphic variants of genes encoding enzymes of folate and methionine metabolism may have an effect on DNA methylation. Using PCR-RFLPs, we examined the polymorphism distribution of genes encoding methionine synthase (MTR); 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase (MTHFD1); and methylenetetrahydrofolate reductase (MTHFR) in patients with larynx cancer (n = 131) and controls (n = 250). Patients with MTR 2756AG or GG genotypes displayed a 1.856 -fold increased risk of larynx cancer (95% CI = 1.1860-2.903, P = 0.0076). However, we did not observe an increased risk for the homozygous GG genotype OR = 1.960 (95% CI = 0.6722-5.713, P = 0.2535). Moreover, we did not observe statistical differences in distribution of MTHFR 677C>T, 1298A>C and MTHFD1 1958G>A allele and genotype frequencies in patients and controls. Our findings confirm the significance of the role of the methyl cycle in etiopathogenesis of laryngeal cancer.
Mol Biol Rep 2010 Jan
PMID:Polymorphic variants of folate metabolism genes and the risk of laryngeal cancer. 1964 27

Approximately 50% of patients with venous thromboembolism also present with hereditary predisposition. The most common genetic factors are single nucleotide polymorphisms (SNPs) of factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T. Genotyping these SNPs helps clinicians to correctly diagnose the disease and properly manage patients. In this study, we report a novel method using surface-enhanced laser desorption and ionization time of flight mass spectrometry to rapidly genotype, in a multiplex fashion, 3 SNPs that predispose patients to thrombosis. First, patient DNA samples were subjected to polymerase chain reaction to amplify and extend the DNA products with masses corresponding to specific genotypes. Polymerase chain reaction products were then applied to Q10 anionic protein chips, undergoing on-chip sample enrichment and clean-up. Finally, the genotypes of the SNPs were determined by surface-enhanced laser desorption and ionization time of flight mass spectrometry. This method offers a rapid turnaround time of less than 5 hours from sample collection to result reporting. The analytical accuracy of each SNP genotyping result has been confirmed by DNA sequencing. In addition, the genotype results produced by this method were validated by comparing them with results obtained by the approved method in the clinical reference laboratory. This novel method is fast, accurate, and reproducible, and thus provides an excellent platform to promote personalized medicine in the management of clotting disorders.
Diagn Mol Pathol 2010 Mar
PMID:Rapid multiplexed genotyping for hereditary thrombophilia by SELDI-TOF mass spectrometry. 2018 13

Some studies have suggested that coagulation disorders may be implicated in osteonecrosis of the femoral head (ONFH). The C677T polymorphism of the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene has been postulated to be a genetic risk factor for venous thromboembolism and osteonecrosis in Caucasians, but this relationship has not been established in other populations. In this study, we conducted case-control analysis of whether MTHFR polymorphisms are associated with ONFH in Korean patients. Fifteen single nucleotide polymorphisms (SNPs) were selected and genotyped in 443 ONFH patients and 273 control subjects using the TaqMan 5' allelic discrimination assay. Comparison of ONFH and control subjects using logistic regression models revealed no statistically significant differences in the frequencies of the MTHFR polymorphisms and haplotypes. Further analysis stratified by etiology also showed no association. These results suggest that MTHFR polymorphisms play no significant role in susceptibility to ONFH in the Korean population.
Mol Cells 2010 Apr
PMID:Lack of association of MTHFR gene polymorphisms with the risk of osteonecrosis of the femoral head in a Korean population. 2022 89


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