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1.
Am J Hum Genet ; 108(7): 1283-1300, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34214447

RESUMO

Most rare clinical missense variants cannot currently be classified as pathogenic or benign. Deficiency in human 5,10-methylenetetrahydrofolate reductase (MTHFR), the most common inherited disorder of folate metabolism, is caused primarily by rare missense variants. Further complicating variant interpretation, variant impacts often depend on environment. An important example of this phenomenon is the MTHFR variant p.Ala222Val (c.665C>T), which is carried by half of all humans and has a phenotypic impact that depends on dietary folate. Here we describe the results of 98,336 variant functional-impact assays, covering nearly all possible MTHFR amino acid substitutions in four folinate environments, each in the presence and absence of p.Ala222Val. The resulting atlas of MTHFR variant effects reveals many complex dependencies on both folinate and p.Ala222Val. MTHFR atlas scores can distinguish pathogenic from benign variants and, among individuals with severe MTHFR deficiency, correlate with age of disease onset. Providing a powerful tool for understanding structure-function relationships, the atlas suggests a role for a disordered loop in retaining cofactor at the active site and identifies variants that enable escape of inhibition by S-adenosylmethionine. Thus, a model based on eight MTHFR variant effect maps illustrates how shifting landscapes of environment- and genetic-background-dependent missense variation can inform our clinical, structural, and functional understanding of MTHFR deficiency.


Assuntos
Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Mutação de Sentido Incorreto , Substituição de Aminoácidos , Análise Mutacional de DNA , Diploide , Biblioteca Gênica , Genótipo , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Metilenotetra-Hidrofolato Redutase (NADPH2)/fisiologia , Saccharomyces cerevisiae/genética
2.
Mutat Res ; 843: 73-80, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31421742

RESUMO

Intake of folate (vitamin B9) is strongly inversely linked with human cancer risk, particularly colon cancer. In general, people with the highest dietary intake of folate or with high blood folate levels are at a reduced risk (approx. 25%) of developing colon cancer. Folate acts in normal cellular metabolism to maintain genomic stability through the provision of nucleotides for DNA replication and DNA repair and by regulating DNA methylation and gene expression. Folate deficiency can accelerate carcinogenesis by inducing misincorporation of uracil into DNA, by increasing DNA strand breakage, by inhibiting DNA base excision repair capacity and by inducing DNA hypomethylation and consequently aberrant gene and protein expression. Conversely, increasing folate intake may improve genomic stability. This review describes key applications of single cell gel electrophoresis (the comet assay) in assessing genomic instability (misincorporated uracil, DNA single strand breakage and DNA repair capacity) in response to folate status (deficient or supplemented) in human cells in vitro, in rodent models and in human case-control and intervention studies. It highlights an adaptation of the SCGE comet assay for measuring genome-wide and gene-specific DNA methylation in human cells and colon tissue.


Assuntos
Monitoramento Biológico/métodos , Neoplasias do Colo/genética , Ensaio Cometa/métodos , Ácido Fólico/farmacologia , Instabilidade Genômica , Análise de Célula Única/métodos , Linhagem Celular , Neoplasias do Colo/epidemiologia , Neoplasias do Colo/prevenção & controle , Quebras de DNA , Metilação de DNA , Reparo do DNA , Replicação do DNA , Ácido Fólico/sangue , Deficiência de Ácido Fólico/sangue , Deficiência de Ácido Fólico/genética , Instabilidade Genômica/efeitos dos fármacos , Instabilidade Genômica/genética , Genótipo , Homocistinúria/sangue , Homocistinúria/genética , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/sangue , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/fisiologia , Espasticidade Muscular/sangue , Espasticidade Muscular/genética , Transtornos Psicóticos/sangue , Transtornos Psicóticos/genética , Risco , Uracila/metabolismo
3.
Per Med ; 16(1): 35-49, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30468411

RESUMO

AIM: 5,10-MTHFR-single nucleotide polymorphisms are important for normal functioning of the enzyme that plays a key role in DNA synthesis, folate metabolism and methylation reactions. Methodology & results: Male infertility association of C665T and A1298C polymorphisms was explored, this topic is still debatable. Infertile men (232) and controls (114) were genotyped and statistically analyzed. Comparison of patients (6180) and controls (5744) of Caucasian populations was performed by meta-analysis. Pooled results showed A1298C minor allele and homozygous genotype to be of a significantly higher frequency in the low-income group. Increase in per capita income has shown an increasing trend in the minor allele frequency in various world populations, potentially due to dietry-folate compensation. CONCLUSION: A1298C seems more relevant marker than C665T for infertility association in Caucasian populations and may be addressed by improving dietary folate.


Assuntos
Infertilidade Masculina/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Alelos , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Ácido Fólico/metabolismo , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/fisiologia , Paquistão , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Classe Social
4.
Birth Defects Res ; 110(14): 1129-1138, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30120883

RESUMO

BACKGROUND: Worldwide, Neural tube defects (NTDs) are considered as major clinical problems imposing a huge socio-economic burden for both affected individuals and their families. In India, the prevalence of Neural tube defects is significantly high. This study aims to evaluate the association between genetic defects in folate metabolism pathway genes, mainly: Folate hydrolase 1 (FOLH1), Dihydrofolate reductase (DHFR) and Methylenetetrahydrofolate reductase (MTHFR) and neural tube defects from eastern India. METHODS: We enrolled 62 consecutive mothers with NTDs foetuses as cases and their corresponding age matched 73 mothers with healthy babies as controls (genetic power has been calculated). Four single nucleotide polymorphisms (FOLH1: rs202676, DHFR: rs70991108, MTHFR: rs1801133 and rs1801131) have been amplified by polymerase chain reaction (PCR) and sequenced. Statistical analysis has been undertaken to find out association with NTDs. RESULTS: Genotype and allele frequency analysis of these SNPs revealed that, rs1801133 (p.Ala222Val) was significantly associated with NTDs risk (p value = 0.028; odds ratio-2.31; 95% CI 1.08-4.93), whereas rs202676 (p.Tyr60His) showed protective role (p value = 0.0066; odds ratio-0.11; 95% CI 0.01-0.86). Serum homocysteine (Hcy) concentration was respectively higher in subjects carrying 222Ala/Val and 222Val/Val alleles (p value = 0.009; p value ≤ 0.0001). CONCLUSION: In conclusion, it can be stated that, rs1801133 was associated with neural tube defects risk in patients from the eastern part of India and it might be counted as a molecular marker for evaluating the susceptibility of NTDs.


Assuntos
Ácido Fólico/genética , Ácido Fólico/metabolismo , Defeitos do Tubo Neural/genética , Adulto , Alelos , Antígenos de Superfície/genética , Antígenos de Superfície/fisiologia , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Genótipo , Glutamato Carboxipeptidase II/genética , Glutamato Carboxipeptidase II/fisiologia , Homocisteína/análise , Homocisteína/sangue , Humanos , Índia/epidemiologia , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/fisiologia , Pessoa de Meia-Idade , Defeitos do Tubo Neural/epidemiologia , Defeitos do Tubo Neural/fisiopatologia , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Tetra-Hidrofolato Desidrogenase/genética , Tetra-Hidrofolato Desidrogenase/fisiologia
6.
PLoS One ; 13(1): e0190916, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29329322

RESUMO

RATIONALE: Environmental exposures strongly influence the development and progression of asthma. We have previously demonstrated that mice exposed to a diet enriched with methyl donors during vulnerable periods of fetal development can enhance the heritable risk of allergic airway disease through epigenetic changes. There is conflicting evidence on the role of folate (one of the primary methyl donors) in modifying allergic airway disease. OBJECTIVES: We hypothesized that blocking folate metabolism through the loss of methylene-tetrahydrofolate reductase (Mthfr) activity would reduce the allergic airway disease phenotype through epigenetic mechanisms. METHODS: Allergic airway disease was induced in C57BL/6 and C57BL/6Mthfr-/- mice through house dust mite (HDM) exposure. Airway inflammation and airway hyperresponsiveness (AHR) were measured between the two groups. Gene expression and methylation profiles were generated for whole lung tissue. Disease and molecular outcomes were evaluated in C57BL/6 and C57BL/6Mthfr-/- mice supplemented with betaine. MEASUREMENTS AND MAIN RESULTS: Loss of Mthfr alters single carbon metabolite levels in the lung and serum including elevated homocysteine and cystathionine and reduced methionine. HDM-treated C57BL/6Mthfr-/- mice demonstrated significantly less airway hyperreactivity (AHR) compared to HDM-treated C57BL/6 mice. Furthermore, HDM-treated C57BL/6Mthfr-/- mice compared to HDM-treated C57BL/6 mice have reduced whole lung lavage (WLL) cellularity, eosinophilia, and Il-4/Il-5 cytokine concentrations. Betaine supplementation reversed parts of the HDM-induced allergic airway disease that are modified by Mthfr loss. 737 genes are differentially expressed and 146 regions are differentially methylated in lung tissue from HDM-treated C57BL/6Mthfr-/- mice and HDM-treated C57BL/6 mice. Additionally, analysis of methylation/expression relationships identified 503 significant correlations. CONCLUSION: Collectively, these findings indicate that the loss of folate as a methyl donor is a modifier of allergic airway disease, and that epigenetic and expression changes correlate with this modification. Further investigation into the mechanisms that drive this observation is warranted.


Assuntos
Metilenotetra-Hidrofolato Redutase (NADPH2)/fisiologia , Hipersensibilidade Respiratória/enzimologia , Animais , Betaína/administração & dosagem , Metilação de DNA , Expressão Gênica , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Camundongos , Camundongos Endogâmicos C57BL , Locos de Características Quantitativas
7.
Reumatol Clin ; 13(6): 318-325, 2017.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-27751863

RESUMO

OBJECTIVE: To analyze the effect of single nucleotide polymorphisms (SNPs) with well-known functional impact of methylenetetrahydrofolatereductase (MTHFR; rs1801131 and rs1801133), the membrane transporter ABCB1 (rs1045642), the AICAR transformylase/IMP cyclohydrolase (ATIC; rs2372536) and folyl-polyglutamatesynthetase (FPGS; rs1544105), on liver and bone marrow toxicity of methotrexate (MTX). PATIENTS AND METHODS: We analyzed 1415 visits from 350 patients of the PEARL (Princesa Early Arthritis Register Longitudinal) study: (732 with MTX, 683 without MTX). The different SNPs were genotyped using specific TaqMan probes (Applied Biosystems). Multivariate analyzes were performed using generalized linear models in which the dependent variables were the levels of serum alanine aminotransferase (liver toxicity), leukocytes, platelets or hemoglobin (hematologic toxicity) and adjusted for clinical variables (disease activity, etc.), analytical (renal function, etc.), sociodemographic (age, sex, etc.) and genetic variants of MTHFR, ABCB1, ATIC and FPGS. The effect of these variables on the MTX doses prescribed throughout follow-up was also analyzed through multivariate analysis nested by visit and patient. RESULTS: When taking MTX, those patients carrying the CC genotype of rs1045642 in ABCB1 showed significantly higher GPT levels (7.1±2.0 U/L; P<.001). Carrying at least one G allele of rs1544105 in FPGS was associated with lower leukocyte (-0.67±0.32; 0.038), hemoglobin (-0.34±0.11g/dL; P=.002), and platelet (-11.8±4.7; P=.012) levels. The presence of the G allele of rs1544105 in FPGS, and the T allele of rs1801133 in MTHFR, was significantly associated with the use of lower doses of MTX. DISCUSSION: Our data suggest that genotyping functional variants in FGPS and MTHFR enzymes and the transporter ABCB1 could help to identify patients with increased risk of MTX toxicity.


Assuntos
Artrite/genética , Hidroximetil e Formil Transferases/genética , Imunossupressores/uso terapêutico , Metotrexato/uso terapêutico , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Complexos Multienzimáticos/genética , Nucleotídeo Desaminases/genética , Peptídeo Sintases/genética , Polimorfismo de Nucleotídeo Único , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/fisiologia , Adulto , Fatores Etários , Idoso , Alanina Transaminase/sangue , Artrite/sangue , Artrite/tratamento farmacológico , Biotransformação/genética , Creatinina/sangue , Feminino , Hemoglobinas/análise , Humanos , Hidroximetil e Formil Transferases/fisiologia , Imunossupressores/efeitos adversos , Imunossupressores/farmacocinética , Contagem de Leucócitos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Metotrexato/efeitos adversos , Metotrexato/farmacocinética , Metilenotetra-Hidrofolato Redutase (NADPH2)/fisiologia , Pessoa de Meia-Idade , Complexos Multienzimáticos/fisiologia , Nucleotídeo Desaminases/fisiologia , Peptídeo Sintases/fisiologia , Contagem de Plaquetas , Fatores Sexuais
8.
Cancer Prev Res (Phila) ; 6(11): 1171-81, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24169962

RESUMO

An understanding of early genetic/epigenetic changes in colorectal cancer would aid in diagnosis and prognosis. To identify these changes in human preneoplastic tissue, we first studied our mouse model in which Mthfr⁺/⁻ BALB/c mice fed folate-deficient diets develop intestinal tumors in contrast to Mthfr⁺/⁺ BALB/c mice fed control diets. Transcriptome profiling was performed in normal intestine from mice with low or high tumor susceptibility. We identified 12 upregulated and 51 downregulated genes in tumor-prone mice. Affected pathways included retinoid acid synthesis, lipid and glucose metabolism, apoptosis and inflammation. We compared murine candidates from this microarray analysis, and murine candidates from an earlier strain-based comparison, with a set of human genes that we had identified in previous methylome profiling of normal human colonic mucosa, from colorectal cancer patients and controls. From the extensive list of human methylome candidates, our approach uncovered five orthologous genes that had shown changes in murine expression profiles (PDK4, SPRR1A, SPRR2A, NR1H4, and PYCARD). The human orthologs were assayed by bisulfite-pyrosequencing for methylation at 14 CpGs. All CpGs exhibited significant methylation differences in normal mucosa between colorectal cancer patients and controls; expression differences for these genes were also observed. PYCARD and NR1H4 methylation differences showed promise as markers for presence of polyps in controls. We conclude that common pathways are disturbed in preneoplastic intestine in our animal model and morphologically normal mucosa of patients with colorectal cancer, and present an initial version of a DNA methylation-based signature for human preneoplastic colon.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias do Colo/genética , Epigênese Genética , Neoplasias Intestinais/genética , Lesões Pré-Cancerosas/genética , Animais , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Metilação de DNA , Seguimentos , Perfilação da Expressão Gênica , Humanos , Técnicas Imunoenzimáticas , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Neoplasias Intestinais/metabolismo , Neoplasias Intestinais/patologia , Metilenotetra-Hidrofolato Redutase (NADPH2)/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Análise de Sequência com Séries de Oligonucleotídeos , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
9.
Br J Cancer ; 108(12): 2505-15, 2013 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-23736036

RESUMO

BACKGROUND: Fluoropyrimidine drugs are extensively used for the treatment of solid cancers. However, adverse drug reactions are a major clinical problem, often necessitating treatment discontinuation. The aim of this study was to identify pharmacogenetic markers predicting fluoropyrimidine toxicity. METHODS: Toxicity in the first four cycles of 5-fluorouracil or capecitabine-based chemotherapy were recorded for a series of 430 patients. The association between demographic variables, DPYD, DPYS, TYMS, MTHFR, CDA genotypes, and toxicity were analysed using logistic regression models. RESULTS: Four DPYD sequence variants (c.1905+1G>A, c.2846A>T, c.1601G>A and c.1679T>G) were found in 6% of the cohort and were significantly associated with grade 3-4 toxicity (P<0.0001). The TYMS 3'-untranslated region del/del genotype substantially increased the risk of severe toxicity (P=0.0123, odds ratio (OR)=3.08, 95% confidence interval (CI): 1.38-6.87). For patients treated with capecitabine, a MTHFR c.1298CC homozygous variant genotype predicted hand-foot syndrome (P=4.1 × 10⁻6, OR=9.99, 95% CI: 3.84-27.8). The linked CDA c.-92A>G and CDA c.-451C>T variants predicted grade 2-4 diarrhoea (P=0.0055, OR=2.3, 95% CI: 1.3-4.2 and P=0.0082, OR=2.3, 95% CI: 1.3-4.2, respectively). CONCLUSION: We have identified a panel of clinically useful pharmacogenetic markers predicting toxicity to fluoropyrimidine therapy. Dose reduction should be considered in patients carrying these sequence variants.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Citidina Desaminase/genética , Di-Hidrouracila Desidrogenase (NADP)/genética , Fluoruracila/efeitos adversos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Neoplasias/diagnóstico , Timidilato Sintase/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/uso terapêutico , Citidina Desaminase/fisiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Feminino , Fluoruracila/uso terapêutico , Variação Genética/fisiologia , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/fisiologia , Pessoa de Meia-Idade , Modelos Genéticos , Neoplasias/tratamento farmacológico , Neoplasias/epidemiologia , Neoplasias/genética , Farmacogenética , Prognóstico , Fatores de Risco , Timidilato Sintase/fisiologia , Adulto Jovem
10.
DNA Cell Biol ; 32(5): 260-7, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23578207

RESUMO

Epidemiological studies have investigated that functional polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene may play an essential role in bladder carcinogenesis, but the association between these single-nucleotide polymorphisms in the MTHFR gene and the susceptibility of bladder cancer (BC) was inconsistent in previous studies. The objective of this current study was to conduct an update analysis investigating the association between three polymorphisms in the MTHFR gene and the risk of BC. We performed a meta-analysis of 13 publications involving an association between BC and MTHFR gene three polymorphisms (C677T, A1298C, and G1793A). We assessed the strength of the association, using odds ratios (ORs) with 95% confidence intervals (CIs). On one hand, we found that the C677T polymorphism was associated with increased BC risk among Asians, however, with decreased BC risk among a mixed population. Interestingly, BC patients who carried the T-allele (TT+TC) had a higher percentage than the individuals who carried the CC genotype (OR=1.38, 95% CI=1.13-1.69, p=0.002). On the other hand, the A1298C polymorphism may increase BC risk among Asians and Africans, but played a decreased association among Europeans. Results from the current update analysis suggested that the C677T and A1298C polymorphisms in the MTHFR gene were associated with BC risk and disease progression.


Assuntos
Carcinoma/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Bexiga Urinária/genética , Alanina/genética , Substituição de Aminoácidos/fisiologia , Carcinoma/epidemiologia , Carcinoma/etnologia , Estudos de Casos e Controles , Cisteína/genética , Progressão da Doença , Predisposição Genética para Doença , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/fisiologia , Polimorfismo de Fragmento de Restrição , Polimorfismo de Nucleotídeo Único/fisiologia , Fatores de Risco , Treonina/genética , Neoplasias da Bexiga Urinária/epidemiologia , Neoplasias da Bexiga Urinária/etnologia
11.
Mol Psychiatry ; 17(5): 559-66, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-21358708

RESUMO

High total plasma homocysteine (tHcy) has been associated with cognitive impairment in later life, but it is unclear if this association is causal or is due to confounding. The C677T polymorphism of the 5,10 methylenetetrahydrofolate reductase gene (MTHFR) increases basal tHcy, but its contribution to cognitive impairment has not been established. We designed this study to determine if tHcy is causally related to cognitive impairment in later life by investigating its association with high tHcy and the MTHFR-C677T polymorphism. We recruited 1778 older men from the Health in Men Study cohort and established caseness on the basis of the participants' scores on a Telephone Interview for Cognitive Status score 27 in 2008. Exposure to tHcy, gene status and other variables of interest were obtained from assessments 4-7 years earlier. Multivariate logistic regression showed that the odds of cognitive impairment increased with a doubling of tHcy (adjusted odds ratio, OR 1.36; 95% confidence interval, 95% CI 1.02-1.82). Compared with the wild CC genotype, participants with the MTHFR-TT genotype had 46% greater odds of cognitive impairment (OR 1.46, 95% CI 1.01-2.11, P=0.043). The results of this study are consistent with, but do not prove the hypothesis that high tHcy causes cognitive impairment in later life.


Assuntos
Envelhecimento/genética , Transtornos Cognitivos/genética , Transtornos Cognitivos/fisiopatologia , Predisposição Genética para Doença/genética , Homocisteína/fisiologia , Saúde do Homem , Metilenotetra-Hidrofolato Redutase (NADPH2)/fisiologia , Idoso de 80 Anos ou mais , Envelhecimento/psicologia , Estudos de Casos e Controles , Transtornos Cognitivos/sangue , Genótipo , Homocisteína/sangue , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Razão de Chances , Polimorfismo de Nucleotídeo Único/fisiologia
12.
Genet Test Mol Biomarkers ; 16(1): 30-5, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21861708

RESUMO

Vasculitis, thrombophlebitis, arterial aneurysms, and occlusions occur in about 25% of patients with Behçet's disease (BD). The common inherited gene defects, factor V (FV) 1691A (Leiden), methylene tetrahydrofolate reductase (MTHFR) 677T, and prothrombin 20210A, are known risk factors for thrombosis. The aim of the study was to evaluate the contribution of these mutations to thrombosis in Israeli patients with BD. Fifty-four patients with BD (n=54; 27 men and 27 women) underwent clinical and genetic evaluation. Most patients (n=43; 79.6%) were of Arab descent (31 sporadic and 12 familial cases from 4 families), and 11 patients (20.4%) were of Jewish descent (all sporadic cases). The FV Leiden mutation was identified in five patients (9.2%), and eight patients were MTHFR 677TT homozygotes (14.8%). None had the 20210A mutant prothrombin allele. No statistical differences between carriers and noncarriers with regards to demographic and disease manifestations were calculated. Arabs were diagnosed earlier than Jewish patients (25.8±11.6 compared with 37.2±10.7, p=0.01, respectively), but Jewish patients had, respectively, more events of deep vein thrombosis (DVT) compared with Arabs (3 of 11, 27.3% and 3 of 43, 7%, p=0.09). Thrombotic events in our patients with BD were not associated with variations in thrombophilic genes.


Assuntos
Síndrome de Behçet/genética , Fator V/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Mutação/fisiologia , Protrombina/genética , Trombose/genética , Adolescente , Adulto , Síndrome de Behçet/epidemiologia , Síndrome de Behçet/etnologia , Fator V/fisiologia , Feminino , Genes/fisiologia , Predisposição Genética para Doença , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/fisiologia , Polimorfismo de Nucleotídeo Único/fisiologia , Protrombina/fisiologia , Trombose/epidemiologia , Trombose/etnologia , Doenças Vasculares/epidemiologia , Doenças Vasculares/etnologia , Doenças Vasculares/genética , Adulto Jovem
13.
Genes Brain Behav ; 10(3): 354-64, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21255267

RESUMO

Low blood levels of B vitamins have been implicated in age-associated cognitive impairment. The present study investigated the association between genetic variation in folate metabolism and age-related cognitive decline in the ninth decade of life. Both the 677C>T (rs1801133) polymorphism and the scarcely studied 1298A>C (rs1801131) polymorphism of the MTHFR gene were assessed in relation to cognitive change over 8 years in older community-dwelling individuals. MTHFR genotype was determined in 476 participants of the Lothian Birth Cohort 1921, whose intelligence was measured in childhood in the Scottish Mental Survey of 1932. Cognitive performance on the domains of verbal memory, reasoning and verbal fluency was assessed at mean age of 79 (n = 476) and again at mean ages of 83 (n = 275) and 87 (n = 180). Using linear mixed models, the MTHFR 677C>T and 1298A>C variants were not associated with the rate of cognitive change between 79 and 87 years, neither in the total sample, nor in a subsample of individuals with erythrocyte folate levels below the median. APOE E4 allele carrier status did not interact with MTHFR genotype in affecting change in cognitive performance over 8 years. No significant combined effect of the two polymorphisms was found. In conclusion, MTHFR 677C>T and 1298A>C polymorphisms were not associated with individual change in cognitive functioning in the ninth decade of life. Although polymorphisms in the MTHFR gene may cause disturbances in folate metabolism, they do not appear to be accompanied by changes in cognitive functioning in old age.


Assuntos
Envelhecimento/genética , Transtornos Cognitivos/enzimologia , Transtornos Cognitivos/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/fisiologia , Transtornos Cognitivos/fisiopatologia , Estudos de Coortes , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/fisiologia , Testes Neuropsicológicos , Escócia
14.
Acta Diabetol ; 48(2): 95-101, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19937354

RESUMO

The role of hyperhomocysteinemia as a risk factor for diabetic long-term complications has not been sufficiently evaluated in prospective studies, considering specific correlates of homocysteine (tHcy) concentration and traditional cardiovascular disease (CVD) risk factors. Fasting tHcy, vitamin B12 and folate plasma levels, the common methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism, as well as clinical and lifestyle information were assessed in 216 type 2 diabetic patients attending two outpatient clinics, who had a follow-up evaluation at 65 ± 9 months for the incidence of macroangiopathy. At basal evaluation, mild hyperhomocysteinemia (tHcy ≥ 15 µmol/l) was diagnosed in 21.3% of participants. At follow-up, hyperhomocysteinemia and the distribution of MTHFR C677T genotype did not significantly differ according to the incidence of macroangiopathy. Multiple variables adjusted ORs (95% CI) for CVD associated with mild hyperhomocysteinemia were 1.01 (0.37-2.82); P > 0.05; those associated with MTHFR TT genotype were 0.46 (0.15-1.38); P > 0.05. Although the prevalence of hyperhomocysteinemia was higher in diabetic men (26.9%) than in women (16.1%; P > 0.05), similar results were also observed in a separate sex-analysis. At the multivariate analysis, including in the model other potential CVD risk factors, only creatinine clearance was a significant risk factor for the development of macroangiopathy. In this cohort of diabetic subjects, mild hyperhomocysteinemia and the MTHFR TT genotype are not significant risk factors for the development of macroangiopathy; impaired renal function was confirmed as a significant predictor of this complication.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Angiopatias Diabéticas/genética , Hiper-Homocisteinemia/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único , Idoso , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Angiopatias Diabéticas/epidemiologia , Angiopatias Diabéticas/etiologia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Hiper-Homocisteinemia/epidemiologia , Hiper-Homocisteinemia/patologia , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/fisiologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/fisiologia , Prevalência , Estudos Prospectivos , Fatores de Risco , Índice de Gravidade de Doença
15.
PLoS Genet ; 6(5): e1000968, 2010 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-20523748

RESUMO

Computational predictions of the functional impact of genetic variation play a critical role in human genetics research. For nonsynonymous coding variants, most prediction algorithms make use of patterns of amino acid substitutions observed among homologous proteins at a given site. In particular, substitutions observed in orthologous proteins from other species are often assumed to be tolerated in the human protein as well. We examined this assumption by evaluating a panel of nonsynonymous mutants of a prototypical human enzyme, methylenetetrahydrofolate reductase (MTHFR), in a yeast cell-based functional assay. As expected, substitutions in human MTHFR at sites that are well-conserved across distant orthologs result in an impaired enzyme, while substitutions present in recently diverged sequences (including a 9-site mutant that "resurrects" the human-macaque ancestor) result in a functional enzyme. We also interrogated 30 sites with varying degrees of conservation by creating substitutions in the human enzyme that are accepted in at least one ortholog of MTHFR. Quite surprisingly, most of these substitutions were deleterious to the human enzyme. The results suggest that selective constraints vary between phylogenetic lineages such that inclusion of distant orthologs to infer selective pressures on the human enzyme may be misleading. We propose that homologous proteins are best used to reconstruct ancestral sequences and infer amino acid conservation among only direct lineal ancestors of a particular protein. We show that such an "ancestral site preservation" measure outperforms other prediction methods, not only in our selected set for MTHFR, but also in an exhaustive set of E. coli LacI mutants.


Assuntos
Substituição de Aminoácidos , Proteínas/fisiologia , Alelos , Animais , Teste de Complementação Genética , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/química , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/fisiologia , Filogenia , Proteínas/química , Proteínas/genética
16.
Pediatr Hematol Oncol ; 27(1): 46-52, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20121554

RESUMO

From as early as the 1970s methotrexate has been associated with disseminated necrotizing leukoencephalopathy and other neurotoxic sequelae. Yet, a clear mechanism for methotrexate-induced neurotoxicity has not been established. The authors describe the case of a 12-year-old male with acute lymphoblastic leukemia and a homozygous methylenetetrahydrofolate reductase C677T mutation, who developed subacute methotrexate-induced toxicity and cerebral venous thrombosis after receiving intrathecal methotrexate. The role of homocysteine as a possible mediator in methotrexate-induced neurotoxicity via direct endothelial injury is discussed.


Assuntos
Endotélio Vascular/efeitos dos fármacos , Hiper-Homocisteinemia/complicações , Leucoencefalopatias/induzido quimicamente , Metotrexato/efeitos adversos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras B/complicações , Trombose dos Seios Intracranianos/etiologia , Substituição de Aminoácidos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Asparaginase/uso terapêutico , Criança , Citarabina/uso terapêutico , Daunorrubicina/uso terapêutico , Endotélio Vascular/lesões , Epilepsia Tônico-Clônica/induzido quimicamente , Predisposição Genética para Doença , Humanos , Hiper-Homocisteinemia/genética , Injeções Espinhais , Masculino , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Metilenotetra-Hidrofolato Redutase (NADPH2)/fisiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Prednisona/uso terapêutico , Indução de Remissão , Trombose dos Seios Intracranianos/induzido quimicamente , Trombose dos Seios Intracranianos/genética , Vincristina/uso terapêutico
17.
Fertil Steril ; 94(1): 130-7, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19324355

RESUMO

OBJECTIVE: To investigate associations between folate-metabolizing gene variations, folate status, and unexplained female infertility. DESIGN: An association study. SETTING: Hospital-based IVF unit and university-affiliated reproductive research laboratories. PATIENT(S): Seventy-one female patients with unexplained infertility. INTERVENTION(S): Blood samples for polymorphism genotyping and homocysteine, vitamin B12, and folate measurements. MAIN OUTCOME MEASURE(S): Allele and genotype frequencies of the following polymorphisms: 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C/T, 1298A/C, and 1793G/A, folate receptor 1 (FOLR1) 1314G/A, 1816delC, 1841G/A, and 1928C/T, transcobalamin II (TCN2) 776C/G, cystathionase (CTH) 1208G/T and solute carrier family 19, member 1 (SLC19A1) 80G/A, and concentrations of plasma homocysteine, vitamin B12, and serum folate. RESULT(S): MTHFR genotypes 677CT and 1793GA, as well as 1793 allele A were significantly more frequent among controls than in patients. The common MTHFR wild-type haplotype (677, 1298, 1793) CAG was less prevalent, whereas the rare haplotype CCA was more frequent in the general population than among infertility patients. The frequency of SLC19A1 80G/A genotypes differed significantly between controls and patients and the A allele was more common in the general population than in infertile women. Plasma homocysteine concentrations were influenced by CTH 1208G/T polymorphism among infertile women. CONCLUSION(S): Polymorphisms in folate pathway genes could be one reason for fertility complications in some women with unexplained infertility.


Assuntos
Ácido Fólico/genética , Estudos de Associação Genética , Variação Genética/genética , Infertilidade Feminina/diagnóstico , Infertilidade Feminina/genética , Transdução de Sinais/genética , Adulto , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proteínas de Transporte/fisiologia , Estudos Transversais , Cistationina gama-Liase/genética , Cistationina gama-Liase/fisiologia , Feminino , Receptor 1 de Folato , Receptores de Folato com Âncoras de GPI , Ácido Fólico/sangue , Ácido Fólico/fisiologia , Homocisteína/sangue , Humanos , Infertilidade Feminina/enzimologia , Proteínas de Membrana Transportadoras/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/fisiologia , Polimorfismo Genético/genética , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Receptores de Superfície Celular/fisiologia , Proteína Carregadora de Folato Reduzido , Transcobalaminas/genética , Transcobalaminas/fisiologia , Vitamina B 12/sangue
18.
Invest Clin ; 50(3): 327-33, 2009 Sep.
Artigo em Espanhol | MEDLINE | ID: mdl-19961055

RESUMO

The pathogenesis of recurrent spontaneous abortion is multifactorial, presumably involving the interaction of several genetic and environmental factors. The methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism has been implicated as risk factor for recurrent spontaneous abortion (RA). The main objective of this research was to investigate the association between the C677T polymorphism of the MTHFR gene as a genetic risk factor for idiopathic RA. Molecular analysis was performed in 80 DNA samples from 30 patients with RA and among 50 healthy control subjects. Using the Polymerase Chain Reaction (PCR), a 198 bp (bases pairs) fragment, was digested with the restriction enzyme Hinf1, which can recognize the C > T substitution responsible for the polymorphism. 677T MTHFR allele frequencies for group with RA and the control group were 35% and 33%, respectively and 677C MTHFR allele frequencies were 65% and 67%, respectively. There was no significant difference in allele frequency between these two groups. The data presented in this study fail to support the relationship between MTHFR C677T polymorphism and risk in women with RA.


Assuntos
Aborto Habitual/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único , Aborto Habitual/epidemiologia , Adulto , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/fisiologia , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Gravidez , Fatores de Risco , Venezuela/epidemiologia , Adulto Jovem
19.
J Inherit Metab Dis ; 31(3): 403-11, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18415702

RESUMO

Severe deficiency of methylenetetrahydrofolate reductase (MTHFR) results in homocystinuria, with a variety of neurological and vascular complications, and sometimes death in the first year of life. MTHFR (EC 1.5.1.20) catalyses the synthesis of 5-methyltetrahydrofolate (5-methylTHF) which is required for homocysteine remethylation to methionine. Mthfr (-/-) mice are a good animal model of severe MTHFR deficiency in humans. They have marked hyperhomocysteinaemia and a high rate of mortality in the neonatal period. We attempted to rescue Mthfr (-/-) mice from postnatal death by treating their Mthfr (+/-) mothers with mefolinate (a synthetic form of 5-methylTHF, dissolved in their drinking water) or with a folic acid-enriched diet throughout pregnancy and lactation. We monitored pups' vitality and body weights until 3 weeks of age. The majority of Mthfr (-/-) pups from the control groups died during the first week of life. Body weights of -/- pups from control groups were significantly less than those of their Mthfr (+/-) and Mthfr ( +/+ ) littermates. Mefolinate treatment significantly improved survival rates (64% survival) in the -/- pups and improved morphology of the cerebellum. Folic acid supplementation did not affect the survival rate or body weights of the -/- pups. Our study suggests that MTHFR is important for postnatal growth and vitality, and that 5-methylTHF deficiency contributes to the high postnatal mortality. Mefolinate may be a good candidate drug for treatment of severe MTHFR deficiency.


Assuntos
Ácido Fólico/uso terapêutico , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Tetra-Hidrofolatos/uso terapêutico , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Feminino , Genótipo , Homocisteína/sangue , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Taxa de Sobrevida
20.
Circulation ; 117(14): 1802-9, 2008 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-18378616

RESUMO

BACKGROUND: Particulate air pollution is associated with cardiovascular mortality and morbidity. To help identify mechanisms of action and protective/susceptibility factors, we evaluated whether the effect of particulate matter <2.5 mum in aerodynamic diameter (PM(2.5)) on heart rate variability was modified by dietary intakes of methyl nutrients (folate, vitamins B(6) and B(12), methionine) and related gene polymorphisms (C677T methylenetetrahydrofolate reductase [MTHFR] and C1420T cytoplasmic serine hydroxymethyltransferase [cSHMT]). METHODS AND RESULTS: Heart rate variability and dietary data were obtained between 2000 and 2005 from 549 elderly men from the Normative Aging Study. In carriers of [CT/TT] MTHFR genotypes, the SD of normal-to-normal intervals was 17.1% (95% CI, 6.5 to 26.4; P=0.002) lower than in CC MTHFR subjects. In the same [CT/TT] MTHFR subjects, each 10-mug/m(3) increase in PM(2.5) in the 48 hours before the examination was associated with a further 8.8% (95% CI, 0.2 to 16.7; P=0.047) decrease in the SDNN. In [CC] cSHMT carriers, PM(2.5) was associated with an 11.8% (95% CI, 1.8 to 20.8; P=0.02) decrease in SDNN. No PM(2.5)-SSDN association was found in subjects with either [CC] MTHFR or [CT/TT] cSHMT genotypes. The negative effects of PM(2.5) were abrogated in subjects with higher intakes (above median levels) of B(6), B(12), or methionine. PM(2.5) was negatively associated with heart rate variability in subjects with lower intakes, but no PM(2.5) effect was found in the higher intake groups. CONCLUSIONS: Genetic and nutritional variations in the methionine cycle affect heart rate variability either independently or by modifying the effects of PM(2.5).


Assuntos
Cardiotônicos/farmacologia , Dieta , Glicina Hidroximetiltransferase/genética , Sistema de Condução Cardíaco/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Material Particulado/toxicidade , Polimorfismo de Nucleotídeo Único , Idoso , Idoso de 80 Anos ou mais , Boston/epidemiologia , Estudos de Casos e Controles , Ácido Fólico , Seguimentos , Predisposição Genética para Doença , Genótipo , Glicina Hidroximetiltransferase/fisiologia , Sistema de Condução Cardíaco/efeitos dos fármacos , Frequência Cardíaca/genética , Humanos , Masculino , Conceitos Meteorológicos , Metionina , Metilenotetra-Hidrofolato Redutase (NADPH2)/fisiologia , Fatores de Risco , Complexo Vitamínico B
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