Gene 677C Research Articles

Association of Methylenetetrahydrofolate Reductase (MTHFR) Polymorphism with Osteosarcoma in a Mexican Population.

The methylenetetrahydrofolate reductase (MTHFR) gene 677C➔T polymorphism is capable of altering folate metabolism and can modify certain neoplasia risk. Reports have suggested that folate can have an influence on bone development and so it is of interest to know if the MTHFR 677C➔T polymorphism is associated with the malignant transformation process of this tissue. The polymorphism was determined in 55 patients with osteosarcoma and in 180 healthy individuals. Compared with C/T+C/C genotypes, a 3.7-fold reduction in osteosarcoma probability is possible with the T/T genotype (OR 0.27, CI 95% 0.07-0.82). Undoubtedly, further studies, utilizing large samples and carried out on different populations, are necessary to confirm these results.

The correlation between methylenetetrahydrofolate reductase gene 677C > T polymorphism and fetal congenital defects: A meta-analysis

Abstract Objective To investigate the correlation between the methylenetetrahydrofolate reductase (MTHFR) gene 677C> T polymorphism and fetal congenital defects. Method Original studies relevant to the MTHFR gene 677C>T single nucleotide polymorphism and fetal congenital defects were systematically searched in the electronic databases of Medline, EMBSE and China National Knowledge Infrastructure (CNKI). All relevant publications were screened for inclusion in the present work. The correlation between the MTHFR gene 677C > T single nucleotide polymorphism and the occurrence of fetal congenital defects was expressed as an odds ratio (OR) and its 95% confidence interval (95% CI). Publication bias was assessed by Begg’s funnel plot and Egger’s line regression test. Results Nineteen case-control studies were ultimately included in the present meta-analysis. The pooled results indicated that the general risk of fetal congenital defects was significantly elevated in subjects with the 677T allele of the MTHFR gene in dominant (OR=1.07,95%CI:1.03-1.12, P<0.05), homozygous (OR=1.17,95%CI:1.06-1.30, P<0.05) and recessive genetic models (OR=1.16,95%CI:1.03-1.31, P<0.05) through the random effect method. However, significant publication bias was identified upon pooling the individual data and evaluating the correlation. Conclusion According to the present evidence, the MTHFR gene 677C>T single nucleotide polymorphism is correlated with poor pregnancy outcomes, and subjects with the T allele have an increased risk of developing general fetal congenital defects.

Association between the methylenetetrahydrofolate reductase (MTHFR) gene 677C>T and 1298A>C polymorphisms and the risk of diabetic nephropathy; a meta-analysis

Methylenetetrahydrofolate reductase (MTHFR) is involved in the homocysteine metabolism. Two common variants of MTHFR gene (677C>T and 1298A>C), have been reported to reduce the MTHFR enzyme activity and leading to plasma hyperhomocysteinemia. There are a number of recent case-control studies that investigated the association between the MTHFR polymorphism and diabetic nephropathy (DN), albeit with inconsistent results. The aim of this meta-analysis is to evaluate the associations between the genetic polymorphisms of MTHFR with susceptibility to DN. A literature search was conducted on PubMed, Embase and Google scholar from inception till March 18, 2019. For MTHFR 677C>T analysis, a total of 23 studies including DM controls (3095 cases and 3187 DM controls) and 12 studies including non-DM controls (1590 cases and 2052 nonDM controls) were taken. For MTHFR 1298A>C analysis, a total of 7 studies using DM controls (959 cases and 1209 DM controls) and 3 studies using non-DM controls (400 cases and 802 nonDM controls) were taken. Meta-analysis showed that mutant genotypes of the 677C>T (OR: 1.58; 95%CI: 1.16-2.14) and 1298A>C (OR: 1.38; 95%CI: 1.16-1.65) polymorphisms in the MTHFR gene were associated with increased risk of DN (diabetic kidney disease). MTHFR 677C>T and 1298A>C polymorphisms revealed significant heterogeneity between studies. Further, there was no evidence for publication bias for these polymorphisms. In conclusion, this meta-analysis provides strong evidence that MTHFR 677C>T and 1298A>C polymorphisms may be associated with increased risks of DN. However, further studies are still needed to accurately determine whether MTHFR genetic polymorphisms are associated with susceptibility to DN.

Polymorphisms of methylenetetrahydrofolate reductase gene among women of childbearing age from Shiyan area

To assess the association of methylenetetrahydrofolate reductase (MTHFR) gene 677C to T polymorphism with blood homocysteine (Hcy) level among women of childbearing age from Shiyan area. PCR-chip hybridization was used to determine the genotype of MTHFR 677C to T, and a biochemical assay was used to determine the total Hcy level among 428 healthy women of childbearing age. Association of MTHFR 677C to T with total Hcy level was assessed. Heterozygous CT mutation was most common form for the MTHFR 677C to T polymorphisms and amounted for 49.77% among the group, while the CC wild type and homozygous TT mutation respectively accounted for 30.61% and 19.63%. These gave a frequency of 44.51% for the 677T allele. The dominant genotype among different age groups were the CT type. Of note, the proportion of MTHFR 677CC is higher in women above 30 years of age. The distribution of MTHFR 677C to T genotypes has differed significantly among different age groups (P<0.05). Compared with those with wild type alleles, carriers of MTHFR mutations had a higher plasma Hcy level. The genotypic frequencies of MTHFR C677T in Shiyan region differed significantly from those of Sichuan, Hebei, Henan and Shandong (P<0.05) but were similar to those of Jiangsu, Guangdong, Ningxia and Xinjiang. The distribution of MTHFR C677T polymorphism among women of childbearing age in Shiyan area is influenced by age and is geographically specific and associated with plasma Hcy level. Nearly 50% of women have carried the high risk alleles, for whom folic acid supplementation is crucial for the reduction of birth defect rate.

Relationship between methylenetetrahydrofolate reductase gene 677C / T, 1298A / C SNP and lung cancer

Objective To explore the relationship between MTHFR gene polymorphism and lung cancer in Han population of Heilongjiang Province. Methods Two hundred and twenty-five lung cancer patients were selected as the experimental group and the healthy subjects in the outpatient physical examination as the control group, A case-control study was used to analyze the association of MTHFR gene 677C/T, 1298A/C SNP and lung cancer, and the gene typing was detected by Sanger double deoxidization chain termination method. Results In the control group, the frequencies of wild-type CC, mutant heterozygote CT, and homozygous TT genotypes of the MTHFR gene C677T were 34.2%, 55.1%, and 10.7%, respectively.The frequencies of the three genotypes in the experimental group were 26.7%, 50.2%, 23.1%, respectively.The difference in the distribution of C677T SNP genotype frequencies of the experimental group and the control group was statistically significant (P=0.002), in which the mutation homozygous TT carriers were 2.78 times more likely to develop lung cancer than wild-type CC(OR(95%CI): 2.78(1.54~5.02) , P=0.001); AA, AC and CC genotype frequencies of the A1298C locus of the MTHFR gene were 34.2%, 55.1%, and 10.7%, respectively, and the control group was 64.0%.32.0%, 4.0%, there was no significant difference between the two groups (P=0.247). The frequencies of AA, AC and CC genotypes in the A1298C locus of the MTHFR gene were 34.2%, 55.1%, and 10.7%, respectively, and 64.0%, 32.0%, and 4.0% in the control group, respectively.There was no significant difference between the two groups (P). =0.247). The haploid analysis showed that the distribution frequency of TA haplotype in the experimental group was significantly higher than that in the control group (43.1% vs.35.3%). There was a statistically significant difference between the two groups (OR(95%CI): 1.39 (1.06-1.81), P=0.016); while the frequencies of CC haplotypes in the experimental group and the control group were 10.6% and 17.1%, respectively.The difference was statistically significant (OR(95%CI): 0.58 (0.39-0.85). P=0.005). There was a linkage disequilibrium between the two points of MTHFR gene 677 and 1298 (D'=0.48, P=0.003). The gene-environment interaction analysis of the MTHFR gene C677T polymorphism showed that based on the comparison between TT and CC genotype, age over 60 (OR(95%CI): 4.0(1.78-9.32), P=0.001), male (OR (95%CI): 5.55 (2.10-14.67), P=0.000), smoking (OR(95%CI): 8.13 (2.29-28.85), P=0.000) and small cell lung cancer (OR (95%CI) : 1.28 (1.10-1.44), P=0.000) can increase the risk of lung cancer; based on the comparison between CT and CC genotype, women (OR(95%CI): 2.09 (1.05-4.16), P=0.030), non-smoking population (OR(95%CI): 2.43 (1.25-4.74), P=0.008) and small cell lung cancer (OR (95% CI): 0.31 (1.16-1.59), P=0.000) can increase the risk of lung cancer. Conclusion MTHFR gene C677T is a genetic susceptibility gene for lung cancer and is associated with the risk of lung cancer. Key words: Methylenetetrahydrofolate reductase; SNP; Lung cancer

Relationship of MTHFR gene 677C → T polymorphism, homocysteine, and estimated glomerular filtration rate levels with the risk of new-onset diabetes.

East Asian patients with diabetes have a higher risk for renal complications and strokes than Europeans. We aimed to evaluate the effect of methylenetetrahydrofolate reductase (MTHFR) gene 677C→T polymorphism, which was associated with a higher stroke risk and was common in the Chinese population, as well as homocysteine and estimated glomerular filtration rate (eGFR) levels on the risk of new-onset diabetes (NOD).A total of 2422 subjects without diabetes were followed-up for 7 years. NOD was defined as fasting plasma glucose ≥7.0 mmol/L or self-reported physician diagnosis of diabetes.Compared with subjects with MTHFR 677CC genotype, those with TT genotype had a higher risk of NOD in females (odds ratio 2.78, 95% confidence interval 1.39–5.56) but not in males (0.80, 0.40–1.61, P for interaction = 0.008). Furthermore, MTHFR 677C→T polymorphism was more strongly associated with the risk of NOD among females with higher body mass index (BMI, ≥23 vs <23 kg/m2, P for interaction = 0.009) or lower high-density lipoprotein-cholesterol (HDL-C, <1.3 vs ≥1.3 mmol/L, P for interaction = 0.015) levels. Hyperhomocysteinemia (≥16 vs <10 μmol/L) was not significantly associated with NOD in males (0.88, 0.42–1.85) or females (1.52, 0.65–3.57). However, mildly decreased eGFR (<90 vs 90–120 mL/min/1.73 m2) was associated with NOD mainly in males (1.96, 1.01–3.78; females, 0.74, 0.32–1.72, P for interaction = 0.134).Females with MTHFR 677TT genotype had a significantly higher risk of NOD, particularly those with higher BMI or low HDL-C levels. The higher risk of NOD associated with mildly decreased eGFR also warrants more investigation. Our results provide insights into the ethnic differences of diabetic complications between East Asian patients and Europeans.

Evaluation of Methyleletetrahydrofolate Reductase 677C>T Polymorphism in Patient with Atrial Fibrillation with Ischemic Stroke

OP-102 Methyleletetrahydrofolate reductase (MTHFR) gene 677C>T mutation in the gene coding for MTHFR, characterized by the replacement of cytosine with thymidine, leads to reduced MTHFR activity and is associated with moderately elevated homocysteine levels. MTHFR polymorphism has been proposed by

Rapid screening for MTHFR gene 677C>T polymorphism in Down syndrome using high resolution melting curve and pyrosequencing

To establish a rapid method for detecting MTHFR gene 677C>T polymorphisms with high-resolution melting curve method (HRM) and pyrosequencing. Peripheral blood samples were collected from 155 Down syndrome patients and 182 normal controls from Children's Hospital of Shanghai. The accuracy of three methods including regular HRM, internal control HRM and artificial heterozygosity HRM was compared. Meanwhile, allele frequencies in 10, 30 and 50 mixed samples were measured with pyrosequencing, and the results were compared with that of HRM. Heterozygosity of 677C>T polymorphism could be distinguished by various HRM methods. However, homozygotes CC and TT were only identifiable by internal control HRM and artificial heterozygosity HRM. The accuracy of pyrosequencing for allele frequency has improved with increased sample number. When the number of mixed samples has exceeded 30, the difference between pyrosequencing results and actual values became less than 4%. TT genotype was more frequent in Down syndrome patients than controls (25.2% vs. 14.3%). No significant difference was found in T allele frequency between the two groups (44.9% vs. 40.1%). Respectively, internal control HRM and pyrosequencing may be ideal methods for determination of genotypic and allelic frequencies.

Association of Methylenetetrahydrofolate Reductase Gene 677C>T Polymorphism with Hypertension in Older Women in a Population of Buenos Aires City

We examined the relationship between the 677C >T polymorphism in the MTHFR gene and tHcy in normotensive (NT) and hypertensive (HT) subjects and the influence of sex and age in a cross-sectional study. Smoking habits, history of vascular disease, diabetes, and tHcy were significantly associated with T allele as hypertension risk factors. The T allele was significantly related with higher tHcy in (i) men versus women (P < .01), (ii) men and women older than 47 years versus the younger ones (P < .05 and P < .001, respectively), (iii) HT women versus NT women (P < .01), and (iv) older HT women versus older NT women (P < .01). We found an association between the 677C>T MTHFR polymorphism and tHcy with hypertension that in women is manifested with age.

Strong Association of 677 C&gt;T Substitution in the MTHFR Gene with Male Infertility - A Study on an Indian Population and a Meta-Analysis

BackgroundMethylenetetrahydrofolate reductase (MTHFR) is an important enzyme of folate and methionine metabolism, making it crucial for DNA synthesis and methylation. The objective of this study was to analyze MTHFR gene 677C>T polymorphism in infertile male individuals from North India, followed by a meta-analysis on our data and published studies.Methodology/Principal FindingsWe undertook genotyping on a total of 837 individuals including well characterized infertile (N = 522) and confirmed fertile (N = 315) individuals. The SNP was typed by direct DNA sequencing. Chi square test was done for statistical analysis. Published studies were searched using appropriate keywords. Source of data collection for meta-analysis included ‘Pubmed’, ‘Ovid’ and ‘Google Scholar’. Those studies analyzing 677C>T polymorphism in male infertility and presenting all relevant data were included in meta-analysis. The genotype data for infertile subjects and fertile controls was extracted from each study. Chi square test was done to obtain odds ratio (OR) and p-value. Meta-analysis was performed using Comprehensive Meta-analysis software (Version 2). The frequency of mutant (T) allele (p = 0.0025) and genotypes (CT+TT) (p = 0.0187) was significantly higher in infertile individuals in comparison to fertile controls in our case-control study. The overall summary estimate (OR) for allele and genotype meta-analysis were 1.304 (p = 0.000), 1.310 (p = 0.000), respectively, establishing significant association of 677C>T polymorphism with male infertility.Conclusions/Significance677C>T substitution associated strongly with male infertility in Indian population. Allele and genotype meta-analysis also supported its strong correlation with male infertility, thus establishing it as a risk factor.

Association of polymorphism in the thermolabile 5, 10-methylene tetrahydrofolate reductase gene and hyperhomocysteinemia with coronary artery disease

To determine the incidence of methylene tetrahydrofolate reductase (MTHFR) gene 677C-->T polymorphism and plasma homocysteine (Hcy) levels in a group of subjects who underwent coronary angiography, in an attempt to establish a correlation between these parameters and the severity of coronary artery disease (CAD) and to investigate the correlation between hyperhomocysteinemia (HHcy) and the presence of 677C-->T polymorphism. Elevated plasma Hcy level is an independent risk factor for CAD. A common mutation (677C-->T) in the gene coding for MTHFR has been reported to reduce the enzymatic activity and is associated with elevated levels of Hcy, especially in subjects with low folate intake. The study group comprised of 84 patients with CAD and 100 age-and-sex matched controls who had no history or clinical evidence of CAD and/or MI. DNA was extracted from peripheral blood and genotypes were determined by polymerase chain reaction, restriction mapping with Hinf1, and gel electrophoresis. Conventional risk factors for CAD were prospectively documented. Allele and genotype frequencies in cases and control subjects were compatible with Hardy-Weinberg equilibrium. The frequencies of TT, CT, and CC genotypes among CAD patients were 4.8, 27.4, and 67.8% and in controls were 1.0, 19.0, and 80%. Hcy levels were higher in patients with triple-vessel disease compared to single and double vessel disease (P = 0.002). Multivariate analyses identified HHcy, diabetes mellitus, and hypertension as the independent predictors of CAD. HHcy appears to have a graded effect on the risk of CAD as well as the severity and extent of coronary atherosclerosis. Our findings support that homozygous genotype of MTHFR is a genetic risk factor for CAD. A further study with larger sample size including assessment of vitamin status is needed to better clarify the relationship between MTHFR genotypes and CAD.

MTHFR 677 TT genotype in a mother and her child with Down syndrome, atrioventricular canal and exstrophy of the bladder: implications of a mutual genetic risk factor?

Apart from Husmann and Vandersteen [in: Gearhart JP, Matthews R (eds) The Epispadias-Exstrophy Complex. Kluwer, New York, pp 199-206, 1999], we report only the second case of Down syndrome (DS) associated with exstrophy of the bladder (EB). Besides the appearance of DS, the newborn exhibited a complete atrioventricular canal (CAVC) and classical EB, including diastases of the symphysis, an epispadic penis and an open bladder plate. Despite current recommendations, the mother had not supplemented her intake of folic acid during the periconceptional period. In a comparable case, Al-Gazali et al. (Am J Med Genet 103:128-132, 2001) found the homozygous 677T allele of the methylenetetrahydrofolate (MTHFR) gene 677C-->T polymorphism in a mother and her child with DS and cervical meningomyelocele. They found that the mother, who also had not supplemented her folic acid intake, had a secondarily altered folate status with an increased homocysteine level, suggesting that the homozygous TT mutation in the MTHFR gene in both mother and her child had contributed to the presentation of DS and a neural tube defect. The combined clinical findings of the present case and the observations of Al-Gazali et al. led us to investigate the 677C-->T polymorphism in our mother-child pair. Likewise we found that mother and child were homozygous for the mutant 677T allele. Our findings support the suggestion of Al-Gazali et al. that the MTHFR 677TT could be a mutual genetic risk factor for the co-occurrence of trisomy 21 and midline defects, the risk of which may be reduced by periconceptional folic acid supplementation.

Methylenetetrahydrofolate reductase gene A222V polymorphism and risk of ischemic stroke

The 5,10-methylenetetrahydrofolate reductase ( MTHFR ) gene 677C --> T polymorphism causes an A222V amino acid change which affects MTHFR enzyme activity and can increase homocysteine, a vascular disease risk factor. This polymorphism was examined for association with stroke. In a case-control study of 241 ischemic stroke patients and 304 controls in Hong Kong, the V allele increased in stroke [28% vs. 20%, odds ratio (OR) 1.5, p=0.003]. A lack of significance for the increase in the VV genotype (7.5% vs. 4.6%, OR 1.7, p = 0.16) may be due to its rarity in this region. V -allele carriers had more severe strokes (according to the NIH stroke scale). The association of the V allele with stroke occurred mostly in women or older subjects and was due to decreasing V allele frequency with age, as seen in other studies. This V frequency decline with age might be due to a loss of V -carrying controls from a higher risk of cancer, vascular disease, bone fracture, and kidney failure when folate is sparse. Examination of previous studies revealed that the association of VV genotype with stroke appeared stronger in Japan than elsewhere, possibly due to dietary differences. Perhaps folate supplementation for stroke prevention would particularly benefit VV individuals in such high-risk regions.