Dataset Information

The Frequency of the 677C>T and 1298A>C Polymorphisms in the Methylenetetrahydrofolate Reductase (MTHFR) Gene in the Population.

ABSTRACT:

Background

The gene for 5,10-methylenetetrahydrofolate reductase (NAD(P)H) or MTHFR gene encodes protein methylenetetrahydrofolate reductase (MTHFR), an enzyme important in folate metabolism.

Aim

The aim of this study was to determine the frequencies of 677C>T and 1298A>C polymorphisms in the MTHFR gene of healthy subjects from the population.

Material and methods

The blood samples were collected from 164 unrelated and healthy donors from population consisted of 98 females and 66 males. Both the MTHFR 677C>T and 1298A>C single nucleotide polymorphisms (SNPs) were analyzed by Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Linkage disequilibrium (LD) between pair of SNPs was calculated through Haploview analysis.

Results

The frequency of MTHFR 677T allele in the population (32.62%) was in agreement with the frequency of this allele in most other populations, however, the frequency of MTHFR 1298C allele (38.41%) was higher than that reported for most other populations in the world. Haploview analysis showed a relatively strong LD between 677C>T and 1298A>C SNPs with D' values of 0.87.

Conclusion

Regarding the two MTHFR polymorphisms, three of the nine combined genotypes were present in 87.2% of the population. 33.54% subjects were complex heterozygous (677CT/1298AC genotype), 34.15% subjects had 677CC/1298AC and 19.51% of 677CT/1298AA genotype. The subjects with 677TT genotype had a 1298AA or 1298AC genotype while subjects with 1298CC genotype had only 677CC genotype. The subjects with 677CC/1298AA genotype were only 3.05%. We were not found triple 677CT/1298CC and quadruple 677TT/1298CC mutation suggesting decreased viability of embryos with increased numbers of mutant alleles.

SUBMITTER: Nefic H

PROVIDER: S-EPMC6021155 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The Frequency of the 677C>T and 1298A>C Polymorphisms in the Methylenetetrahydrofolate Reductase (MTHFR) Gene in the Population.

Nefic Hilada H Mackic-Djurovic Mirela M Eminovic Izet I

Medical archives (Sarajevo, Bosnia and Herzegovina) 20180601 3

<h4>Background</h4>The gene for 5,10-methylenetetrahydrofolate reductase (NAD(P)H) or <i>MTHFR</i> gene encodes protein methylenetetrahydrofolate reductase (MTHFR), an enzyme important in folate metabolism.<h4>Aim</h4>The aim of this study was to determine the frequencies of <i>677C>T</i> and <i>1298A>C</i> polymorphisms in the <i>MTHFR</i> gene of healthy subjects from the population.<h4>Material and methods</h4>The blood samples were collected from 164 unrelated and healthy donors from populat ...[more]

PMID: 30061759

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Project description:What is already known about this subject* Numerous clinical studies, including a few prospective ones, have reported conflicting results on the impact of gene polymorphisms related to fluorouracil (FU) and oxaliplatin pharmacodynamics.What this study adds* This prospective study is the first to report that clinical response to FOLFOX is significantly related to methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms (677C-->T and 1298A-->C), with a response rate of 37, 53, 63 and 80% in patients harbouring no, one, two or three favourable MTHFR alleles, respectively. * Only polymorphisms of genes related to oxaliplatin pharmacodynamics (GSTpi 105Ile-->Val and XPD 751Ly-->Gln) influenced progression-free survival. * These results corroborate the observation that response was related to the cumulative FU dose, whereas progression-free survival was related to the cumulative oxaliplatin dose.AimsTo test prospectively the predictive value of germinal gene polymorphisms related to fluorouracil (FU) and oxaliplatin (Oxa) pharmacodynamics on toxicity and responsiveness of colorectal cancer (CRC) patients receiving FOLFOX therapy.MethodsAdvanced CRC patients (n= 117) receiving FOLFOX 7 therapy were enrolled. Gene polymorphisms relevant for FU [thymidylate synthase (TYMS, 28 bp repeats including the G-->C mutation + 6 bp deletion in 3'UTR), methylenetetrahydrofolate reductase (MTHFR, 677C-->T, 1298A-->C), dihydropyrimidine deshydrogenase (IVS14+1G-->A) and Oxa: glutathione S-transferase (GST) pi (105Ile-->Val, 114Ala-->Val), excision repair cross-complementing group 1 (ERCC1) (118AAT-->AAC), ERCC2 (XPD, 751Lys-->Gln) and XRCC1 (399Arg-->Gln)] were determined (blood mononuclear cells).ResultsNone of the genotypes was predictive of toxicity. Response rate (54.7% complete response + partial response) was related to FU pharmacogenetics, with both 677C-->T (P= 0.042) and 1298A-->C (P= 0.004) MTHFR genotypes linked to clinical response. Importantly, the score of favourable MTHFR alleles (677T and 1298C) was positively linked to response, with response rates of 37.1, 53.3, 62.5 and 80.0% in patients bearing no, one, two or three favourable alleles, respectively (P= 0.040). Polymorphisms of genes related to Oxa pharmacodynamics showed an influence on progression-free survival, with a better outcome in patients bearing GSTpi 105 Val/Val genotype or XPD 751Lys-containing genotype (P= 0.054).ConclusionsThese results show that response to FOLFOX therapy in CRC patients may be driven by MTHFR germinal polymorphisms.

Project description:Background and objectiveMethylenetetrahydrofolate reductase (MTHFR) is a key enzyme involved in folate metabolism and one-carbon metabolism. MTHFR gene polymorphism affects enzyme activity. MTHFR gene polymorphism is closely related to many human diseases, such as cardiocerebrovascular diseases, diabetes, neural tube defects (NTDs), tumors, and so on. In the field of Andrology, MTHFR gene polymorphism may be associated with male infertility and erectile dysfunction (ED), and there is a possibility of treating male infertility and ED by supplementing with folic acid. However, its exact pathophysiologic mechanism is not fully understood. We sought to obtain a robust understanding of the interactions between MTHFR gene polymorphism, oxidative stress, DNA methylation, hyperhomocysteinemia (HHcy), male infertility, and ED.MethodsWe performed a non-systematic literature review using the PubMed database to identify articles specifically related to MTHFR, male infertility and ED.Key content and findingsOur literature review on MTHFR gene polymorphism in male infertility patients indicates a significant association between C677T gene polymorphism and male infertility. There is limited literature on the correlation between ED and MTHFR gene polymorphism, and there are two different conclusions, related and unrelated. More clinical data are needed to clarify the conclusion. There is a possibility of using folic acid supplementation to treat male infertility and ED, especially for patients with thymine-thymine (TT) genotype. Future research is necessary to further understand the relationship between MTHFR gene polymorphism and male infertility and ED.ConclusionsOur literature review on MTHFR gene polymorphism in male infertility patients indicates a significant association between C677T gene polymorphism and male infertility. Folic acid supplementation can improve sperm quality. The correlation between MTHFR gene polymorphisms and ED is questionable and needs to be confirmed by more clinical data. MTHFR gene polymorphisms are associated with homocysteine (Hcy) levels, which affects vascular endothelial function and may be related to the development of vascular ED (VED). Folic acid supplementation improves International Index for Erectile Function (IIEF) questionnaire scores in ED patients in whom phosphodiesterase 5 inhibitor (PDE5i) alone is ineffective.

Project description:BackgroundThe association between the methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphisms and the susceptibility to cervical lesions was unclear. This study was designed to investigate their precise association using a large-scale meta-analysis.MethodsThe previous 16 studies were identified by searching PubMed, Embase and CBM databases. The crude odds ratios and their corresponding 95% confidence intervals (CIs) were used to estimate the association between the MTHFR C677T/A1298C polymorphisms and the susceptibility to the cervical lesions. The subgroup analyses were made on the following: pathological history, geographic region, ethnicity, source of controls and source of DNA for genotyping.ResultsNeither of the polymorphisms had a significant association with the susceptibility to the cervical lesions in all genetic models. Similar results were found in the subgroup analyses. No association was found between the MTHFR C677T polymorphism and the cervical lesions in the Asia or the America populations though a significant inverse association was found in the Europe population (additive model: P = 0.006, OR = 0.83, 95% CI = 0.72-0.95; CT vs. CC: P = 0.05, OR = 0.83, 95% CI = 0.69-1.00; TT vs. CC: P = 0.05, OR = 0.73, 95% CI = 0.53-1.00). Interestingly, women with the MTHFR A1298C polymorphisms had a marginally increased susceptibility to invasive cancer (ICC) when compared with no carriers but no statistically significant difference in the dominant model (P = 0.06, OR = 1.21, 95% CI = 0.99-1.49) and AC vs. AA (P = 0.09, OR = 1.21, 95% CI = 0.97-1.51).ConclusionsThe MTHFR C677T and A1298C polymorphisms may not increase the susceptibility to cervical lesions. However, the meta-analysis reveals a negative association between the MTHFR C677T polymorphisms and the cervical lesions, especially in the European populations. The marginal association between the MTHFR A1298C polymorphisms and the susceptibility to cervical cancer requires a further study.

Dataset Information

The Frequency of the 677C>T and 1298A>C Polymorphisms in the Methylenetetrahydrofolate Reductase (MTHFR) Gene in the Population.

Background

Aim

Material and methods

Results

Conclusion

Publications

The Frequency of the 677C>T and 1298A>C Polymorphisms in the Methylenetetrahydrofolate Reductase (MTHFR) Gene in the Population.

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