RESUMO
Methionine synthase (MTR) and methylenetetrahydrofolate reductase (MTHFR) enzymes are involved in the metabolism of methyl groups, and thus have an important role in the maintenance of proper DNA methylation level. In our study we aimed to evaluate the effect of the polymorphism A2756G (rs1805087) in the MTR gene on the level of human leukocyte genomic DNA methylation. Since the well-studied polymorphism C677T (rs1801133) in the MTHFR gene has already been shown to affect DNA methylation, we aimed to analyze the effect of MTR A2756G independently of the MTHFR C677T polymorphism. For this purpose, we collected the groups of 80 subjects with the MTR 2756AA genotype and 80 subjects with the MTR 2756GG genotype, having equal numbers of individuals with the MTHFR 677CC and the MTHFR 677TT genotypes, and determined the level of DNA methylation in each group. Individuals homozygous for the mutant MTR 2756G allele showed higher DNA methylation level than those harboring the MTR 2756AA genotype (5.061 ± 1.761% vs. 4.501 ± 1.621%, P=0.0391). Individuals with wild-type MTHFR 677СC genotype displayed higher DNA methylation level than the subjects with mutant MTHFR 677TT genotype (5.103 ± 1.767% vs. 4.323 ± 1.525%, P=0.0034). Our data provide evidence that the MTR A2756G polymorphism increases the level of DNA methylation and confirm the previous reports that the MTHFR C677T polymorphism is associated with DNA hypomethylation.
Assuntos
5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/genética , Metilação de DNA , Leucócitos/metabolismo , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo Genético , Sequência de Bases , Primers do DNA , HumanosRESUMO
It has been suggested that DNA hypomethylation because of poorer effectiveness of the 5,10-methylenetetrahydrofolate reductase (MTHFR) enzyme induces muscular growth. We hypothesised that the common, functional 1298A>C polymorphism in the MTHFR gene is associated with athletic status. To test this hypothesis, we investigated the distribution of the 1298A>C variant in Polish (n = 302) and Russian (n = 842) athletes divided into four groups: endurance, strength-endurance, sprint-strength and strength-endurance, as well as in 1540 control participants. We found different genotypes (the AC heterozygote advantage) and allele distributions among sprint-strength athletes and strength athletes than the groups of sedentary controls for each nationality. In the combined study, the allelic frequencies for the 1298C variant were 35.6% in sprint-strength athletes (OR 1.18 [1.02-1.36], P = 0.024 vs. controls) and 38.6% in strength athletes (OR 1.34 [1.10-1.64], P = 0.003 vs. controls). The results of the initial and repetition studies as well as the combined analysis suggest that the functional 1298A>C polymorphism in the MTHFR gene is associated with athletic status. The presence of the C allele seems to be beneficial in sprint-strength and strength athletes. It needs to be established whether and to what extent this effect is mediated by alteration in DNA methylation status.
Assuntos
Genótipo , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Força Muscular/genética , Polimorfismo de Nucleotídeo Único , Corrida/fisiologia , Esportes , População Branca/genética , Alelos , Atletas , Estudos de Casos e Controles , Feminino , Frequência do Gene , Humanos , Masculino , Razão de Chances , Polônia , Federação Russa , Adulto JovemRESUMO
OBJECTIVE: To investigate the association of polymorphisms in the folate-metabolizing genes with idiopathic male infertility in a Russian population and to perform a meta-analysis. DESIGN: A case-control study. SETTING: Research laboratory. PATIENT(S): 275 men with idiopathic male infertility and a population sample of 349 men. INTERVENTION(S): Determining the genotypes of polymorphisms MTHFR C677T, MTHFR A1298C, MTR A2756G, MTRR A66G, SHMT1 C1420T, MTHFD1 G1958A, and CBS 844ins68. MAIN OUTCOME MEASURE(S): Semen analyses performed according to the World Health Organization guidelines (WHO, 1999) and Kruger strict morphology test. RESULT(S): None of the polymorphisms were significantly associated with idiopathic male infertility after the implementation of Bonferroni correction for multiple testing, although the MTHFD1 G1958A and MTR A2756G polymorphisms showed an association before the Bonferroni correction. Meta-analysis revealed an association by use of fixed-effects model of MTHFR C677T with the risk of azoospermia. CONCLUSION(S): These findings suggest that polymorphisms in folate-metabolizing genes could be involved in the etiology of male infertility. Additional studies performed on larger groups are necessary to investigate the possible associations.
Assuntos
Infertilidade Masculina/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único/genética , Vigilância da População , Estudos de Casos e Controles , Humanos , Infertilidade Masculina/diagnóstico , Infertilidade Masculina/epidemiologia , Masculino , Vigilância da População/métodos , Fatores de Risco , Federação Russa/epidemiologiaRESUMO
OBJECTIVE: Periconceptional folate supplementation prevents a number of congenital anomalies (CA). The aim of our study was to investigate the association of 11 polymorphisms in the folate-metabolizing genes with the risk of having an offspring with CA in the Russian ethnic group. METHOD: We genotyped 280 mothers having a CA-affected pregnancy and 390 control mothers. The most common malformations among the cases were CA of the nervous, urinary, and cardiovascular systems, and these groups were analyzed separately. RESULTS: In the whole group of CA, we revealed the associations of MTHFR C677T and MTR A2756G loci with increased risk of CA-affected pregnancy. In the group of CA of the cardiovascular system, we observed an association of MTHFR A1298C with decreased risk and an association of MTR A2756G with increased risk of CA. After the Bonferroni correction, only the association between the genotype MTR 2756GG and the risk of having a fetus with CA of the cardiovascular system remained statistically significant (OR = 4.99, P = 0.03). CONCLUSION: These findings indicate that locus A2756G in the MTR gene may play a role in susceptibility to CA of the cardiovascular system in West Siberia, but further research is necessary to confirm the association.
Assuntos
5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/genética , Anormalidades Congênitas/genética , Predisposição Genética para Doença , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único , Adulto , Anormalidades Cardiovasculares/epidemiologia , Anormalidades Cardiovasculares/genética , Anormalidades Cardiovasculares/metabolismo , Estudos de Casos e Controles , Anormalidades Congênitas/metabolismo , Feminino , Genótipo , Humanos , Malformações do Sistema Nervoso/epidemiologia , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/metabolismo , Gravidez , Sibéria/epidemiologia , Anormalidades Urogenitais/epidemiologia , Anormalidades Urogenitais/genética , Anormalidades Urogenitais/metabolismoRESUMO
Alterations in the nucleotide sequences of folate-metabolizing genes can increase the risk of malignant transformation. The aim of our study was to investigate the association of three single-nucleotide polymorphisms (SNPs) in the folate-metabolizing genes - A2756G MTR, A66G MTRR, and 844ins68 CBS - which have putative functional significance in breast cancer risk. The allele and genotype frequencies of the SNPs were determined in a case group (840 women with sporadic breast cancer) and a control group (770 women). No statistically significant association of studied SNPs with breast cancer was revealed. A meta-analysis, which included data obtained from the literature and the present research, did not reveal any statistically significant associations of these SNPs with breast cancer. The results obtained provide evidence that these SNPs are not involved in the development of breast cancer.
Assuntos
5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/genética , Neoplasias da Mama/genética , Cistationina beta-Sintase/genética , Ferredoxina-NADP Redutase/genética , Ácido Fólico/metabolismo , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Polimorfismo de Fragmento de Restrição , Reação em Cadeia da Polimerase em Tempo Real , Fatores de RiscoRESUMO
We investigated the role of single nucleotide polymorphisms (SNPs) in the folate-metabolizing genes MTHFR, MTR, MTRR, MTHFD, CBS and SHMT in regulating genetic susceptibility to Non-Hodgkin's lymphoma (NHL). We determined the allele and genotype frequencies in the case group (146 patients with NHL) and the control group (540 blood donors). A significant association with NHL was observed only for MTHFD1 G1958A (allele G OR=1.382, P=0.05; genotype GA OR=2.316, P=0.01; genotype GG OR=2.153, P=0.03). After additional stratification of case and control groups according to sex and tumor type association of MTHFD1 G1958A with NHL was observed only in high-grade NHL subgroup (allele G OR=1.664, P=0.01) and in women subgroup (allele G OR=2.043, P=0.009). Meta-analysis for SNPs in the MTHFR, MTR, MTRR and SHMT revealed a reducing effect of the MTR 2756G allele on the risk of NHL (OR=0.902; 95% CI 0.821-0.991, P=0.03).
