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1.
Zhongguo Dang Dai Er Ke Za Zhi ; 23(8): 802-808, 2021 Aug 15.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34511169

RESUMO

OBJECTIVES: To study the association of methylenetetrahydrofolate reductase (MTHFR) gene polymorphism with susceptibility to bronchial asthma and glucocorticoid (GC) efficacy in children. METHODS: A total of 173 children with bronchial asthma who were hospitalized between June 2018 and December 2020 were selected as the observation group. The children received aerosol inhalation of GC for three consecutive months. A total of 178 healthy children who underwent physical examination during the same period were selected as the control group. PCR was used to detect the genotypes of the MTHFR C677T for the two groups. The differences in genotype distribution between the two groups were analyzed. Children with different genotypes in the observation group were compared in terms of immunoglobulin E (IgE), interleukin-8 (IL-8), leukotriene B4 (LTB4), lung function, and clinical outcome before and after treatment. RESULTS: TT genotype and T allele were significantly more frequent in the observation group than in the control group (P<0.001). TT/CT genotypes and T allele were independent risk factors for bronchial asthma (OR=6.615 and 7.055 respectively; P<0.001). After GC treatment, the children with CC, CT or TT genotypes experienced significantly decreased levels of IgE, IL-8, and LTB4 and significantly increased forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio (P<0.001). The children with TT genotype showed significantly lower levels of IL-8 and LTB4 than those with CC genotype, a significantly lower level of LTB4 than those with CT genotype, significantly higher FVC than those with CT genotype, and a significantly higher FEV1/FVC ratio than those with CC genotype (P<0.05). The children with TT genotype had better GC efficacy compared with those with CC genotype (P<0.05). TT genotype was an independent factor for good GC efficacy (OR=2.111, P=0.018). CONCLUSIONS: MTHFR gene polymorphism is associated with asthma susceptibility and GC efficacy in children. Children carrying TT/CT genotypes have a higher risk of developing asthma, and those with TT genotype are more sensitive to GC treatment.


Assuntos
Asma , Glucocorticoides , Alelos , Asma/tratamento farmacológico , Asma/genética , Criança , Predisposição Genética para Doença , Genótipo , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo Genético
2.
Nutrients ; 13(7)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34371949

RESUMO

Homocysteine (Hcy) is well known to be increased in the metabolic syndrome (MetS) incidence. However, it remains unclear whether the relationship is causal or not. Recently, Mendelian Randomization (MR) has been popularly used to assess the causal influence. In this study, we adopted MR to investigate the causal influence of Hcy on MetS in adults using three independent cohorts. We considered one-sample MR and two-sample MR. We analyzed one-sample MR in 5902 individuals (2090 MetS cases and 3812 controls) from the KARE and two-sample MR from the HEXA (676 cases and 3017 controls) and CAVAS (1052 cases and 764 controls) datasets to evaluate whether genetically increased Hcy level influences the risk of MetS. In observation studies, the odds of MetS increased with higher Hcy concentrations (odds ratio (OR) 1.17, 95%CI 1.12-1.22, p < 0.01). One-sample MR was performed using two-stage least-squares regression, with an MTHFR C677T and weighted Hcy generic risk score as an instrument. Two-sample MR was performed with five genetic variants (rs12567136, rs1801133, rs2336377, rs1624230, and rs1836883) by GWAS data as the instrumental variables. For sensitivity analysis, weighted median and MR-Egger regression were used. Using one-sample MR, we found an increased risk of MetS (OR 2.07 per 1-SD Hcy increase). Two-sample MR supported that increased Hcy was significantly associated with increased MetS risk by using the inverse variance weighted (IVW) method (beta 0.723, SE 0.119, and p < 0.001), the weighted median regression method (beta 0.734, SE 0.097, and p < 0.001), and the MR-Egger method (beta 2.073, SE 0.843, and p = 0.014) in meta-analysis. The MR-Egger slope showed no evidence of pleiotropic effects (intercept -0.097, p = 0.107). In conclusion, this study represented the MR approach and elucidates the significant relationship between Hcy and the risk of MetS in the Korean population.


Assuntos
Predisposição Genética para Doença , Homocisteína/sangue , Síndrome Metabólica/genética , Idoso , Feminino , Humanos , Masculino , Análise da Randomização Mendeliana , Síndrome Metabólica/sangue , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único
3.
Medicina (Kaunas) ; 57(7)2021 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-34357004

RESUMO

Background and objectives: ischemic stroke (IS) is among the most frequent causes of death worldwide; thus, it is of paramount relevance to know predisposing factors that may help to identify and treat the high-risk subjects. Materials and Methods:we tested nine variants in genes involved in thrombotic pathway in 282 patients that experienced IS and 87 that had transient ischemic attacks (TIA) in comparison to 430 subjects from the general population (GP) of the same geographic area (southern Italy). We included cases of young and child IS to evaluate the eventual differences in the role of the analyzed variants. Results: we did not observe significant differences between TIA and the GP for any of the variants, while the allele frequencies of methylene-tetrahydrofolate reductase (MTHFR) C677T, beta-fibrinogen -455G>A and factor (FXIII) V34L were significantly higher in patients with IS than in the subjects from the GP. No significant interaction was observed with sex. Conclusions: the present data argue that some gene variants have a role in IS and this appears to be an interesting possibility to be pursued in large population studies to help design specific strategies for IS prevention.


Assuntos
Isquemia Encefálica , Fator XIII/genética , Ataque Isquêmico Transitório , AVC Isquêmico , Metilenotetra-Hidrofolato Redutase (NADPH2) , Acidente Vascular Cerebral , Isquemia Encefálica/genética , Criança , Predisposição Genética para Doença , Humanos , Ataque Isquêmico Transitório/genética , AVC Isquêmico/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo Genético , Fatores de Risco , Acidente Vascular Cerebral/genética
4.
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
5.
Development ; 148(13)2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34128976

RESUMO

5,10-Methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme in the folate metabolic pathway with a key role in generating methyl groups. As MTHFR deficiency impacts male fertility and sperm DNA methylation, there is the potential for epimutations to be passed to the next generation. Here, we assessed whether the impact of MTHFR deficiency on testis morphology and sperm DNA methylation is exacerbated across generations in mouse. Although MTHFR deficiency in F1 fathers has only minor effects on sperm counts and testis weights and histology, F2 generation sons show further deterioration in reproductive parameters. Extensive loss of DNA methylation is observed in both F1 and F2 sperm, with >80% of sites shared between generations, suggestive of regions consistently susceptible to MTHFR deficiency. These regions are generally methylated during late embryonic germ cell development and are enriched in young retrotransposons. As retrotransposons are resistant to reprogramming of DNA methylation in embryonic germ cells, their hypomethylated state in the sperm of F1 males could contribute to the worsening reproductive phenotype observed in F2 MTHFR-deficient males, compatible with the intergenerational passage of epimutations.


Assuntos
Metilação de DNA , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Reprodução/fisiologia , Retroelementos/genética , Animais , Epigenômica , Pai , Feminino , Ácido Fólico/metabolismo , Células Germinativas , Homocistinúria , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Espasticidade Muscular , Transtornos Psicóticos , Espermatozoides/metabolismo
6.
Eur J Obstet Gynecol Reprod Biol ; 263: 72-78, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34167037

RESUMO

OBJECTIVE: The purpose of this study was to evaluate the vitamin B status related to the homocysteine pathway and the prevalence of polymorphisms of the MTHFR gene in infertile women programming homologous or heterologous ART. STUDY DESIGN: We investigated 393 consecutive Caucasian women, referred to the Internal Medicine Clinic at the Center for Assisted Reproductive Technology, in order to be framed for their vascular risk before starting homologous or heterologous (oocyte donation) procedures. Total homocysteine, Vitamin B12, folate and vitamin B6 were measured. The women were divided into quartiles of serum concentration of folate, vitamin B12 and vitamin B6. The C677T and A1298C polymorphisms of the MTHFR gene were genotyped by an electronic microchip technology. RESULTS: Sixty-one women (15.5%) had hyperhomocysteinemia, 22.9% had reduced levels of vitamin B12, 4.1% had reduced levels of serum folate and 0.1% had a deficiency of vitamin B6. Women in the highest quartile of vitamin B12 and folates had lower homocysteine ​​levels than women in the first and second quartiles (p < 0.0001). The homozygosity for MTHFR C677T polymorphism was detected in 33.3% (131), and heterozygosity for MTHFR C677T polymorphism in 45.3% (178) of women. We observed a significant association between hyperhomocysteinemia and 677T allele, but not 1298C, of the MTHFR polymorphisms (p = 0.04). CONCLUSIONS: We found inadequate vitamin B status related to the homocysteine ​​pathway in women planning Assisted Reproductive Technology. Moreover, interesting association was found regarding hyperhomocysteinemia in women carrying T allele of the C677T MTHFR polymorphism. A specific supplementation with 5-MTHF and adequate vitamin B12 concentrations before Assisted Reproductive Technology warrant serious consideration, in particular in women carrying T allele of the C677T MTHFR polymorphism.


Assuntos
Infertilidade Feminina , Complexo Vitamínico B , Feminino , Ácido Fólico , Genótipo , Homocisteína , Humanos , Infertilidade Feminina/genética , Itália/epidemiologia , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Vitamina B 12
7.
J Clin Lab Anal ; 35(7): e23798, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34061414

RESUMO

BACKGROUND: Homocysteine assessment has been proposed as a potential predictive biomarker for the severity of COVID-19 infection. The purpose of this review was to analyze the correlation between the prevalence of MTHFR C677 T gene polymorphism and COVID-19 incidence and mortality worldwide. METHODS: Data regarding MTHFR C677 T gene mutation were obtained from the interrogation of the Genome Aggregation Database (genomAD), which is publicly available from the web"https://gnomad.broadinstitute.org." COVID-19 cases, including prevalence and mortality, were obtained from"https://www.worldometers.info/coronavirus" 27 August 2020. RESULTS: There is a clear trend toward the worldwide prevalence of MTHFR 677 T and COVID-19 incidence and mortality. The prevalence of MTHFR 677 T allele in the Latino population, and the incidence and mortality for COVID-19 was higher for this ethnic group than that reported for most other populations globally. Statistical analysis showed a relatively strong correlation between C677 T and death from coronavirus. CONCLUSIONS: Genetic polymorphism of MTHFR C677 T may modulate the incidence and severity of COVID-19 pandemic infection.


Assuntos
Alelos , COVID-19/enzimologia , COVID-19/epidemiologia , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , COVID-19/genética , COVID-19/mortalidade , Grupos Étnicos/genética , Frequência do Gene , Predisposição Genética para Doença , Humanos , Prevalência
8.
Environ Health ; 20(1): 66, 2021 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-34090432

RESUMO

BACKGROUND: Prenatal exposure to heavy metals is implicated in the etiology of birth defects. We investigated whether concentrations of cadmium (Cd) and lead (Pb) in umbilical cord tissue are associated with risk for neural tube defects (NTDs) and whether selected genetic variants of the fetus modify their associations. METHODS: This study included 166 cases of NTD fetuses/newborns and 166 newborns without congenital malformations. Umbilical cord tissue was collected at birth or elective pregnancy termination. Cd and Pb concentrations were assessed by inductively coupled plasma-mass spectrometry, and 20 single-nucleotide polymorphisms (SNPs) in 9 genes were genotyped. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the risk for NTDs in association with metal concentrations or genotype using logistic regression. Multiplicative-scale interactions between the metals and genotypes on NTD risk were assessed with logistic regression, and additive-scale interactions were estimated with a non-linear mixed effects model. RESULTS: Higher concentrations of Cd were observed in the NTD group than in the control group, but no difference was found for Pb. Concentrations of Cd above the median level showed a risk effect, while the association between Pb and NTD risk was not significant in univariate analyses. The association of Cd was attenuated after adjusting for periconceptional folic acid supplementation. Fetuses with the AG and GG genotypes of rs4880 in SOD2 (superoxide dismutase 2) tended to have a lower risk, but fetuses with the CT and TT genotypes of rs1801133 in MTHFR (5,10-methylenetetrahydrofolatereductase) have a higher risk for NTDs when compared to their respective wild-type. rs4880 and Cd exhibited a multiplicative-scale interaction on NTD risk: the association between higher Cd and the risk for NTDs was increased by over fourfold in fetuses carrying the G allele [OR 4.43 (1.30-15.07)] compared to fetuses with the wild-type genotype. rs1801133 and Cd exposure showed an additive interaction, with a significant relative excess risk of interaction [RERI 0.64 (0.02-1.25)]. CONCLUSIONS: Prenatal exposure to Cd may be a risk factor for NTDs, and the risk effect may be enhanced in fetuses who carry the G allele of rs4880 in SOD2 and T allele of rs1801133 in MTHFR.


Assuntos
Cádmio/efeitos adversos , Poluentes Ambientais/efeitos adversos , Exposição Materna/efeitos adversos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Defeitos do Tubo Neural/genética , Superóxido Dismutase/genética , Adulto , Cádmio/análise , Estudos de Casos e Controles , China/epidemiologia , Poluentes Ambientais/análise , Feminino , Feto , Genótipo , Humanos , Recém-Nascido , Chumbo/análise , Troca Materno-Fetal , Defeitos do Tubo Neural/epidemiologia , Polimorfismo de Nucleotídeo Único , Gravidez
9.
Turk Neurosurg ; 31(4): 587-593, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34169999

RESUMO

AIM: To elucidate the association of the MTHFR, MTRR, and RAD54L gene variations with meningioma in Turkish cohort. MATERIAL AND METHODS: DNAs were isolated from 87 retrospective meningioma samples. The MTHFR, MTRR, and RAD54L gene hotspot regions were amplified with specific primers via polymerase chain reaction (PCR), and next-generation sequencing (NGS) was performed. All the detected variations and single-nucleotide polymorphisms (SNPs) were listed and compared with healthy control frequencies in different genomic databases. The histopathological characteristics of meningiomas and genomic variations were compared. Pearson?s chi-squared test was used to detect the statistical differences of SNPs, and correlation analysis was conducted. RESULTS: rs1801131, rs1801133, and rs4846051 on MTHFR, rs1801394 on MTRR, and rs1048771 on RAD54L gene frequencies were found to be significantly altered in the overall cohort of 87 patients with meningioma. The frequency of rs18011031 is 0.09 in the meningioma cohort, which is significantly correlated with WHO tumor grades (p = 0.038). The frequency of rs18011033 is 0.29 in the meningioma cohort, which is significantly correlated with WHO tumor grades (p = 0.045). Furthermore, the frequency of rs4846051 is 0.18 in the meningioma cohort, which is significantly correlated with WHO tumor grades (p = 0.023) and also with low Ki67 proliferation index (p = 0.00455). The frequency of rs1801394 is 0.15 and significantly associated with high Ki67 proliferation index in the meningioma cohort (p = 0.0144). The frequency of rs1048771 is 0.09 in the meningioma cohort and is significantly associated with the non-necrotic histopathological form of the tumor (p = 0.05). CONCLUSION: We reported a significant association between the genetic alterations of folate metabolism (MTHFR, MTRR) and DNA repair mechanism (RAD54L) genes with the histopathological characteristics of meningioma. Five significant SNPs on these genes and four significant correlations of SNPs with histopathological characteristics were identified. This is a preliminary promising study conducted to establish the genetic marker analysis for meningioma diagnosis and prognosis for folate metabolism and DNA repair genes in Turkish cohort.


Assuntos
DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Ferredoxina-NADP Redutase/genética , Neoplasias Meníngeas/genética , Meningioma/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Neoplasias Meníngeas/epidemiologia , Meningioma/epidemiologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Turquia/epidemiologia
10.
Pan Afr Med J ; 38: 287, 2021.
Artigo em Francês | MEDLINE | ID: mdl-34122714

RESUMO

Colorectal cancer (CRC) is a major global public health problem. Folate metabolism is involved in DNA synthesis, repair and methylation. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism. Common MTHFR C677T polymorphism was correlated to CRC. This case-control study was conducted to analyze the association between this polymorphism and the risk of sporadic CRC in a Moroccan population. The study involved 76 patients with sporadic colorectal cancer confirmed histologically and 182 patients (control group) without a history of cancer. Deoxyribonucleic acid (DNA) was isolated from peripheral blood and genotypes were determined using PCR-RFLP. The risk of association was estimated using odds ratio (OR) with 95% confidence interval. Genotype frequency of MTHFR in patients and in the control group was CC 34.1%, CT 56.6%, TT 9.21%, CC 51.6%, CT 42.8% and TT 6% respectively. CT genotype and its combination with TT genotype and allele T were associated with an increased risk of CRC and with an OR of 2.02 (with 95% confidence interval [CI]: 1.14-3.58, p = 0.01), 2.05 (95 % CI: 1.18-3.58, p= 0.01) and 1.61 (95% CI: 1.07-2.40, p=0.02). Homozygous TT weren´t a protection factor in our study, with an OR of 2.30 (95% CI: 0.81-6.52, p = 0.11). There was a statistically significant association between the MTHFR C677T variant and the risk of occurrence of sporadic colorectal cancer in the studied population.


Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Adulto , Alelos , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Marrocos , Reação em Cadeia da Polimerase , Polimorfismo Genético , Polimorfismo de Fragmento de Restrição
11.
Clin Chim Acta ; 519: 247-254, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34015304

RESUMO

BACKGROUND: Thrombophilia is a substantial source of indisposition and mortality in several countries, including Arab populations. Deep venous thrombosis (DVT) with or without pulmonary embolism (PE) is the prevalent clinical manifestation of thrombophilia. While many genetic risk factors for DVT are known, almost all associated with hemostasis, many genetic factors remain unexplained. Nowadays, Next Generation Sequencing (NGS) offers a potential solution that allows several candidate genes to be analyzed simultaneously at a reasonable expense. METHODS: We performed variant screening in the thrombophilia associated genes in Factor V Leiden (FVL) mutation-negative patients using Ion Torrent Next-generation sequencing (NGS). Ion AmpliSeq panel for 18 genes was designed. Twenty-nine unrelated patients with idiopathic VTE were recruited for NGS. RESULTS: We were able to identify 19 variants (1 novel and 18 previously reported) in 10 out of 18 targeted genes. Pathogenic variants were identified in 22 patients demonstrating mutation detection rates of 76%. Previously reported variants in the F5, MTHFR, PROS1, PROC, F8, F9, SERPINA10, SERPIND1, and HRG genes were recognized in 21 patients. More than one variant in the targeted genes was detected in some of the patients with VTE. We identified SERPINA10 recurrent variant p.(R88*) in seven patients representing 32% of VTE cases. Additionally, we report one novel variant c.356G > T, p.(G119V) in the F7 gene, considered to be pathogenic in this study. CONCLUSIONS: Our studies finding illustrates the ability of targeted next-generation sequencing to uncover uncommon/unknown genetic variants that may predispose to thrombophilia. The finding of the novel variant in the F7 gene extends the spectrum of variants affecting thrombosis. While a comparatively small number of subjects have been included in our cohort, the findings summarize the possible genetic features of thrombophilia.


Assuntos
Trombofilia , Tromboembolia Venosa , Fator V/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Arábia Saudita , Trombofilia/genética , Tromboembolia Venosa/genética
12.
Medicine (Baltimore) ; 100(15): e24523, 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33847607

RESUMO

BACKGROUND: Infertility affects childbearing age couples all over the world. One of the important reasons for infertility is genetic factors. Our study evaluated the association between methylenetetrahydrofolate reductase (MTHFR) and azoospermia. METHODS: Multiple databases like MEDLINE, EMBASE, Cochrane library, and China journal full-text database were used to search for relevant studies, and full-text articles involved in the evaluation of MTHFR and azoospermia. The results were evaluated using STATA 12.0. Heterogeneity analysis, sensitivity analysis, and bias analysis were also performed on the data. RESULTS: Thirteen related studies eventually met the inclusion criteria. Significant association between C677T polymorphism and azoospermia (relative risk [RR] = 0.94 [0.90, 0.99], I2 = 60.9%, P = .002), and between A1298C polymorphism and azoospermia (RR = 0.98 [0.94, 1.02], I2 = 56.3%, P = .011) was observed. Meanwhile, in subgroup analysis, Caucasians had higher risk than Mongolians in association between MTHFR and azoospermia. CONCLUSION: There was association between MTHFR polymorphism and azoospermia. Caucasian populations had higher risk than Mongolian populations in association between MTHFR and azoospermia.


Assuntos
Azoospermia/genética , Predisposição Genética para Doença/etnologia , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Fatores de Risco
13.
Aging (Albany NY) ; 13(8): 11352-11362, 2021 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-33833133

RESUMO

BACKGROUND: Three polymorphisms in the Methylenetetrahydrofolate reductase (MTHFR) gene (C677T, A1298C, and A1793G) were reported associated with AD. However, their genotype distributions and associations with age at onset (AAO), homocysteine, and white matter lesions (WML) were unclear in the Chinese AD population. METHOD: We determined the presence of C677T, A1298C, and A1793G polymorphisms in the MTHFR gene using Sanger sequencing in a Chinese cohort comprising 721 AD patients (318 early-onset AD patients (EOAD) and 403 late-onset AD patients (LOAD)) and 365 elderly controls. Additionally, the homocysteine level and WML were evaluated in 121 AD patients. RESULTS: The frequency of allele T of C677T polymorphism was significantly higher in AD patients than in controls (P = 0.040), while no statistical difference was observed in A1298C and A1793G (P > 0.05). Besides, genotype distributions of C677T and A1298C polymorphisms statistically varied between AD patients and controls (P = 0.021, P = 0.012). Moreover, the AAO was significantly lower in CT/TT (C677T) genotypes carriers (P = 0.042) and higher in AC/CC (A1298C) and AG/GG (A1793G) genotypes carriers (P = 0.034, P = 0.009) in patients with LOAD. We also found that patients with CT/TT (C677T) genotypes were prone to present an increased homocysteine level (P = 0.036) and higher Fazekas score (P = 0.024). In comparison, patients with AG/GG genotypes (A1793G) had a significantly lower Fazekas score (P = 0.013). CONCLUSIONS: The genotype distributions of C677T and A1298C polymorphisms are associated with AD in the Chinese population. Moreover, AD patients with C677T polymorphism are prone to present an earlier onset, higher homocysteine level, and more severe WML.


Assuntos
Doença de Alzheimer/genética , Predisposição Genética para Doença , Homocisteína/sangue , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Substância Branca/patologia , Idade de Início , Idoso , Alelos , Doença de Alzheimer/sangue , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/patologia , Apolipoproteínas E/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China/epidemiologia , Feminino , Homocisteína/metabolismo , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
14.
Genes (Basel) ; 12(4)2021 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-33920562

RESUMO

Folate (vitamin B9) is found in some water-soluble foods or as a synthetic form of folic acid and is involved in many essential biochemical processes. Dietary folate is converted into tetrahydrofolate, a vital methyl donor for most methylation reactions, including DNA methylation. 5,10-methylene tetrahydrofolate reductase (MTHFR) is a critical enzyme in the folate metabolism pathway that converts 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate, which produces a methyl donor for the remethylation of homocysteine to methionine. MTHFR polymorphisms result in reduced enzyme activity and altered levels of DNA methylation and synthesis. MTHFR polymorphisms have been linked to increased risks of several pathologies, including cancer. Breast cancer, gliomas and gastric cancer are highly heterogeneous and aggressive diseases associated with high mortality rates. The impact of MTHFR polymorphisms on these tumors remains controversial in the literature. This review discusses the relationship between the MTHFR C677T and A1298C polymorphisms and the increased risk of breast cancer, gliomas, and gastric cancer. Additionally, we highlight the relevance of ethnic and dietary aspects of population-based studies and histological stratification of highly heterogeneous tumors. Finally, this review discusses these aspects as potential factors responsible for the controversial literature concerning MTHFR polymorphisms.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias da Mama/genética , Glioma/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único , Neoplasias Gástricas/genética , Neoplasias Encefálicas/etnologia , Neoplasias Encefálicas/metabolismo , Neoplasias da Mama/etnologia , Neoplasias da Mama/metabolismo , Metilação de DNA , Feminino , Ácido Fólico/metabolismo , Predisposição Genética para Doença , Glioma/etnologia , Glioma/metabolismo , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Neoplasias Gástricas/etnologia , Neoplasias Gástricas/metabolismo
15.
Nutrients ; 13(4)2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33923969

RESUMO

Methylenetetrahydrofolate reductase (MTHFR) has various polymorphisms, and the effects of periconceptional folic acid supplementation for decreasing neural tube defects (NTDs) risk differ depending on the genotypes. This study analyzed the effectiveness of multivitamin supplementation on folate insufficiency and hyperhomocysteinemia, depending on MTHFR polymorphisms. Of 205 women, 72 (35.1%), 100 (48.8%) and 33 (16.1%) had MTHFR CC, CT and TT, respectively. Serum folate and homocysteine levels in women with homozygous mutant TT were significantly lower and higher, respectively, than those in women with CC and CT. In 54 women (26.3% of all women) with a risk of NTDs, multivitamin supplementation containing folic acid and vitamin D for one month increased folate level (5.8 ± 0.9 to 19.2 ± 4.0 ng/mL, p < 0.0001) and decreased the homocysteine level (8.2 ± 3.1 to 5.8 ± 0.8 nmol/mL, p < 0.0001) to minimize the risk of NTDs in all women, regardless of MTHFR genotype. Regardless of MTHFR genotype, multivitamin supplements could control folate and homocysteine levels. Tests for folate and homocysteine levels and optimal multivitamin supplementation in women with risk of NTDs one month or more before pregnancy should be recommended to women who are planning a pregnancy.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Suplementos Nutricionais , Ácido Fólico/sangue , Variação Genética , Homocisteína/sangue , Infertilidade Feminina/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Vitaminas/farmacologia , Adulto , Feminino , Humanos , Infertilidade Feminina/sangue , Infertilidade Feminina/enzimologia , Gravidez , Resultado da Gravidez , Vitamina D/sangue
16.
Medicine (Baltimore) ; 100(17): e25487, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33907097

RESUMO

BACKGROUD: To analyze the correlation between gene polymorphisms of 5,10- methylenetetrahydrofolate reductase (MTHFR) and risk of unexplained recurrent pregnancy loss (URPL) in Chinese women. METHODS: Eligible studies were searched in Pubmed, Embase, Web of Science, Wanfang, and China National Knowledge Infrastructure (CNKI) databases. Established inclusion criteria were used to screening articles, subsequently evaluate the quality of the included studies, Stata 16.0 PM and RevMan 5.3 software were conducted for meta-analysis. The pooled odds ratio (OR) with 95% confidence interval (CI) was determined to assess the relationship between MTHFR and risk of URPL in Chinese women. RESULTS: For MTHFR C677T, fifty studies were included, involving 6677 URPL cases and 8111 controls. The overall results showed that MTHFR C677T was significantly correlated with URPL risk, especially in the homozygous model (TT vs CC; OR 3.06; 95% CI 2.56-3.66). For MTHFR A1298C, twenty-first studies were included, involving 3439 URPL cases and 3155 controls. The results showed that MTHFR A1298C was also significantly correlated with URPL risk in recessive (CC vs AC + AA; OR 1.55; 95% CI 1.25-1.93) and homozygous (CC vs AA; OR 1.53; 95% CI 1.22-1.91) models. In addition, sub-group results showed that no significant difference between north and south China populations in the MTHFR gene polymorphisms and URPL risk. Of note, the patients carrying MTHFR C677T and MTHFR A1298C joint mutants had no synergistic effect (OR 2.71; 95% CI 0.84-8.70) on the occurrence of URPL compared with the wild-type homozygous genotype (MTHFR 677CC/ MTHFR 1298AA). CONCLUSION: Studies included in this meta-analysis suggested that MTHFR 677T allele and 677TT genotype and MTHFR 1298CC genotype were both associated with URPL; testing MTHFR C677T gene polymorphism was a more appropriate target compared with other mutations in the prediction of URPL.


Assuntos
Aborto Habitual/genética , Predisposição Genética para Doença/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo Genético/genética , Aborto Habitual/etnologia , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China , Feminino , Genótipo , Humanos , Razão de Chances , Gravidez , Fatores de Risco
17.
Crit Rev Oncol Hematol ; 161: 103312, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33794308

RESUMO

Methotrexate (MTX), an important chemotherapeutic agent, is often accompanied with mucositis. The occurrence and severity are unpredictable and show large interindividual variability. In this study, we review and meta-analyze previously studied genetic variants in relation to MTX-induced mucositis. We conducted a systematic search in Medline and Embase. We included genetic association studies of MTX-induced mucositis in cancer patients. A meta-analysis was conducted for single nucleotide polymorphisms (SNPs) for which at least two studies found a statistically significant association. A total of 34 SNPs were associated with mucositis in at least one study of the 57 included studies. Two of the seven SNPs included in our meta-analysis were statistically significantly associated with mucositis: MTHFR c.677C > T (recessive, grade ≥3 vs grade 0-2, OR 2.53, 95 %CI [1.48-4.32], False Discovery Rate[FDR]-corrected p-value 0.011) and MTRR c.66A > G (overdominant, grade ≥1 vs grade 0, OR 2.08, 95 %CI [1.16-3.73], FDR-corrected p-value 0.042).


Assuntos
Mucosite , Neoplasias , Antimetabólitos Antineoplásicos/efeitos adversos , Humanos , Metotrexato/efeitos adversos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Mucosite/induzido quimicamente , Mucosite/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Polimorfismo de Nucleotídeo Único
18.
J Stroke Cerebrovasc Dis ; 30(6): 105744, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33813081

RESUMO

BACKGROUND AND OBJECTIVES: Pseudoxanthoma elasticum (PXE) is a rare autosomal recessive disorder caused by pathogenic variants in the ABCC6 gene. The phenotypic spectrum of PXE is highly variable and includes principally three major features: skin lesions, eye and vascular manifestations, while brain manifestations are less common. To date about 400 different PXE associated variants in ABCC6 gene are described without any evident genotype-phenotype correlation. Herein, we report the clinical and molecular findings of a large PXE family with clinical and genetic intra-familial variability with significant cerebrovascular involvement. METHODS: The analysis of the ABCC6 gene was performed in the proband and her familiars for the definition of genetic background. Then, in order to determine why some affected individuals had more prominent brain involvement, we investigated classic thrombophilic gene variants. RESULTS: Molecular findings disclosed two different ABCC6 mutations, i.e., the recurrent p.(Arg518Gln) and the novel p.(Val1285Met) missense substitution responsible of a pseudo-dominant inheritance. The study of thrombophilic gene variants revealed the presence of 4G/4G SERPINE1 genotype in the proband and in her father, which both developed ischemic stroke. The proband carried also the C677T variant the MTHFR gene. CONCLUSION: We argue, for the first time, that the 4G/4G SERPINE1 genotype could represent an additional risk factor in PXE for developing ischemic stroke, which adds up to the already known predisposing conditions. Therapeutic implications are discussed, we also advise that PXE patients should be adequately screened for cerebral vasculopathy, even more if familial history is suggestive of brain complications.


Assuntos
Heterogeneidade Genética , AVC Isquêmico/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Inibidor 1 de Ativador de Plasminogênio/genética , Pseudoxantoma Elástico/genética , Trombofilia/genética , Adulto , Feminino , Predisposição Genética para Doença , Hereditariedade , Humanos , AVC Isquêmico/sangue , AVC Isquêmico/diagnóstico , Masculino , Linhagem , Pseudoxantoma Elástico/complicações , Pseudoxantoma Elástico/diagnóstico , Medição de Risco , Fatores de Risco , Trombofilia/sangue , Trombofilia/complicações , Trombofilia/diagnóstico
19.
Nutrients ; 13(3)2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33802362

RESUMO

Identification of causal factors that influence fetal growth and anthropometry at birth is of great importance as they provide information about increased risk of disease throughout life. The association between maternal genetic polymorphism MTHFR(677)C>T and anthropometry at birth has been widely studied because of its key role in the one-carbon cycle. MTHFR(677) CT and TT genotypes have been associated with a greater risk of low birth weight, especially in case of deficient intake of folic acid during pregnancy. This study aimed to analyze the association between the maternal MTHFR(677)C>T genetic polymorphism and anthropometry at birth in a population with adequate folate consumption. We included 694 mother-newborn pairs from a prospective population-based birth cohort in Spain, in the Genetics, Early life enviroNmental Exposures and Infant Development in Andalusia (GENEIDA) project. Women were genotyped for MTHFR(677)C>T SNP by Q-PCR using TaqMan© probes. Relevant maternal and newborn information was obtained from structured questionnaires and medical records. Results showed that maternal MTHFR(677)C>T genotype was associated with newborn anthropometry. Genotypes CT or CT/TT showed statistically significant associations with increased or decreased risk of large-for-gestational-age (LGA) or small-for-gestational-age (SGA) based on weight and height, depending on the newborn's sex, as well as with SGA in premature neonates. The relationships between this maternal genotype and anthropometry at birth remained despite an adequate maternal folate intake.


Assuntos
Peso ao Nascer/genética , Ingestão de Alimentos/genética , Fenômenos Fisiológicos da Nutrição Materna/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo Genético , Adulto , Antropometria , Feminino , Desenvolvimento Fetal/genética , Ácido Fólico/sangue , Genótipo , Humanos , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional , Masculino , Estudos Prospectivos , Espanha
20.
Arab J Gastroenterol ; 22(2): 121-126, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33664006

RESUMO

BACKGROUND AND STUDY AIMS: Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide. In Egypt, 92.5% of HCV infection cases reportedly involve infection with HCV genotype 4. HCV infection may induce liver steatosis directly and indirectly. Host genetic polymorphisms may also contribute to the pathogenesis of steatosis. Folate deficiency indirectly cuase liver damage. Folate status is mostly affected by MTHFR C677T polymorphism. The pathophysiology of thrombocytopenia (TCP) in HCV infection remains unclear. Thus, the present study investigated the roles and consequences of MTHFR C677T SNP and folate status in patients with early HCV genotype 4 infection and their relation with steatosis and thrombocytopenia. PATIENTS AND METHODS: Fifty patients with the HCV genotype 4 and 50 healthy controls were enrolled in the study. All the participants underwent laboratory, demographic, and anthropomorphic examinations. Serum folate level was determined, and genomic analysis of MTHFR C677T SNP was performed. RESULTS: No significant difference in allelic frequency of MTHFR C677T was observed between patients and controls. However, significantly lower serum folate level, hemoglobin level, and platelet count were found in patients than controls (p = 0.014, p = 0.005, and p = 0.001, respectively). The cholesterol, triglyceride, and high-density lipoprotein levels were also significantly lower in patients than controls (p < 0.001, p = 0.001, and p < 0.001, respectively), whereas the low-density lipoprotein level was significantly higher in patients (p < 0.001). Patients harboring the MTHFR CT genotype had a significantly lower serum folate level (p = 0.033) than the controls. Among the patients with HCV infection, those with the TT genotype had the highest body mass index (p = 0.003) and levels of cholesterol, triglyceride, and high-density lipoprotein (p = 0.007, p = 0.025, and p = 0.040, respectively). CONCLUSION: MTHFR C677T SNP may contribute to the development of complications associated with early HCV genotype 4 infection, such as dyslipidemia and decreased folate levels.


Assuntos
Hepacivirus , Metilenotetra-Hidrofolato Redutase (NADPH2) , Egito , Ácido Fólico , Genótipo , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo Genético
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