RESUMEN
Folate metabolism is required for important biochemical processes that regulate cell functioning, but its role in female reproductive physiology in cattle during peri- and post-conceptional periods has not been thoroughly explored. Previous studies have shown the presence of folate in bovine oviductal fluid, as well as finely regulated gene expression of folate receptors and transporters in bovine oviduct epithelial cells (BOECs). Additionally, extracellular folic acid (FA) affects the transcriptional levels of genes important for the functioning of BOECs. However, it remains unknown whether the anatomical and cyclic features inherent to the oviduct affect regulation of folate metabolism. The present study aimed to characterize the gene expression pattern of folate cycle enzymes in BOECs from different anatomical regions during the estrous cycle and to determine the transcriptional response of these genes to increasing concentrations of exogenous FA. A first PCR screening showed the presence of transcripts encoding dihydrofolate reductase (DHFR), methylenetetrahydrofolate reductase (MTHFR), and methionine synthase (MTR) in bovine reproductive tissues (ovary, oviduct and uterus), with expression levels in oviductal tissues comparable to, or even higher than, those detected in ovarian and uterine tissues. Moreover, expression analysis through RT-qPCR in BOECs from the ampulla and isthmus during different stages of the estrous cycle demonstrated that folate metabolism-related enzymes exhibited cycle-dependent variations. In both anatomical regions, DHFR was upregulated during the preovulatory stage, while MTHFR and MTR exhibited increased expression levels during the postovulatory stage. Under in vitro culture conditions, ampullary and isthmic cells were cultured in the presence of 10, 50, and 100 µM FA for 24 h. Under these conditions, isthmus epithelial cells exhibited a unique transcriptional response to exogenous FA, showing a pronounced increase in MTR expression levels. Our results suggest that the expression of folate metabolism-related genes in BOECs is differentially regulated during the estrous cycle and may respond to exogenous levels of folate. This offers a new perspective on the transcriptional regulation of genes associated with the folate cycle in oviductal cells and provides groundwork for future studies on their functional and epigenetic implications within the oviductal microenvironment.
Asunto(s)
Ciclo Estral , Ácido Fólico , Animales , Femenino , Bovinos , Ciclo Estral/metabolismo , Ácido Fólico/farmacología , Ácido Fólico/metabolismo , Trompas Uterinas/metabolismo , Trompas Uterinas/efectos de los fármacos , Oviductos/metabolismo , Oviductos/efectos de los fármacos , Tetrahidrofolato Deshidrogenasa/genética , Tetrahidrofolato Deshidrogenasa/metabolismo , Células Epiteliales/metabolismo , Células Epiteliales/efectos de los fármacos , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/metabolismo , 5-Metiltetrahidrofolato-Homocisteína S-Metiltransferasa/metabolismo , 5-Metiltetrahidrofolato-Homocisteína S-Metiltransferasa/genética , Regulación de la Expresión Génica/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica/efectos de los fármacosRESUMEN
BACKGROUND: Interactions between genetic and environmental variables contribute to the autoimmune inflammatory process in multiple sclerosis (MS). Elevated homocysteine levels, and vitamin D, vitamin B12, and folate deficiencies are some of the environmental factors associated with the pathogenesis of MS. Considering that the relationship between MTHFR 677C>T (rs1801133) genetic variant, homocysteine, and folate in patients with MS remains unclear and that their role were not extensively explored in the clinical course of the disease, we investigated whether this variant and plasma homocysteine and folate levels are associated with MS susceptibility, disability, disability progression, and inflammatory biomarkers. METHODS: The case-control study included 163 patients with MS categorized using the Expanded Disability Status Scale (EDSS) as mild (EDSS<3) and moderate/high (EDSS≥3) disability, and 226 healthy controls (HC). Disability progression was evaluated using Multiple Sclerosis Severity Score (MSSS) and the MTHFR 677C>T variant was genotyped using real time polymerase chain reaction. The plasma levels of some inflammatory biomarkers were determined. Two new composed scores were proposed: the first, namely as inflammatory activity index (IAI), was entered as a latent vector extracted from the macrophage M1 + T helper (Th)1 + Th17 + Th2 + T regulatory (Treg) cytokines, + tumor necrosis factor (TNF)-α+ soluble TNF receptor (sTNFR)-1 + sTNFR2. The second score, namely MS-severity index was entered as a latent vector extracted from the EDSS + MSSS scores + MS diagnosis. RESULTS: Patients with MS showed higher homocysteine and folate than controls (p < 0.001); homocysteine, and the M1, Th1, Th17, and Th2 Treg cytokine values were different between the three study groups and increased from HC to MS patients with mild disability and to MS patients with moderate/high disability (p < 0.0001). The levels of TNF-α and their soluble receptors sTNFR1 and sTNFR2 were higher in MS patients with EDSS≥3 than in the two other groups (EDSS<3 and HC) (p < 0.001). There was no association between the MTHFR 677 C > T genotypes and MS susceptibility, disability and disability progression (p > 0.05). Moreover, 21.8 % of the disability variance was explained by age, IAI and C-reactive protein (CRP) (all positively associated); 10.9 % of the disability progression variance was predicted by IAI and CRP (both positively) and 25-hydroxyvitamin D (negatively), whereas 54.4 % of the severity index (MS-EDSS-MSSS) was explained by the regression on age, IAI, homocysteine, folate, and CRP (all positively), and adiponectin, body mass index, and 25-hydroxyvitamin D (all negatively), female sex, and the MTHFR 677 TT genotype. In patients and controls, 16.6 % of the variance in the homocysteine was explained by the MTHFR 677 TT genotype and age (both positively), folate (negatively) and male sex. CONCLUSION: The MTHFR 677C>T variant has an indirect effect on the increase in disability in patients with MS, which also depends on factors such as age, sex, ad folate status.
Asunto(s)
Progresión de la Enfermedad , Predisposición Genética a la Enfermedad , Homocisteína , Metilenotetrahidrofolato Reductasa (NADPH2) , Esclerosis Múltiple , Humanos , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Femenino , Masculino , Adulto , Homocisteína/sangre , Estudios de Casos y Controles , Esclerosis Múltiple/genética , Esclerosis Múltiple/sangre , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Ácido Fólico/sangre , Índice de Severidad de la EnfermedadRESUMEN
Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects women of reproductive age. Many women with PCOS have been found to have an unbalanced diet and deficiencies in essential nutrients. This study aimed to assess the levels of folate and vitamin B12 (B12) and their relationship with metabolic factors in women with PCOS. Anthropometric, clinical, and genetic analyses were conducted to evaluate markers related to one-carbon metabolism in women with PCOS and in a control group. The PCOS group had a higher BMI and HOMA-IR (1.7 vs. 3.1; p < 0.0001). HDL cholesterol levels were 23% lower and triglyceride levels were 74% higher in women with PCOS. Although there were no significant differences in folate and B12 levels between the PCOS and control groups, over 60% of women with PCOS had low B12 levels (<300 pg/mL) and high homocysteine levels. In addition, the MTHFR A1298C and C677T polymorphisms were not associated with PCOS. Moreover, erythrocyte folate levels were positively correlated with fasting glucose, triglycerides, and free androgen index, and negatively correlated with SHBG and LH levels. These results suggest that B vitamins may be associated with the metabolic phenotype in PCOS. This study emphasizes the potential link between folate, vitamin B12, and metabolic and hormonal outcomes in women with PCOS.
Asunto(s)
Ácido Fólico , Síndrome del Ovario Poliquístico , Vitamina B 12 , Humanos , Femenino , Síndrome del Ovario Poliquístico/sangre , Síndrome del Ovario Poliquístico/genética , Vitamina B 12/sangre , Ácido Fólico/sangre , Adulto , Chile/epidemiología , Adulto Joven , Triglicéridos/sangre , Homocisteína/sangre , Índice de Masa Corporal , Glucemia/metabolismo , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Resistencia a la Insulina , HDL-Colesterol/sangre , Estudios de Casos y Controles , Biomarcadores/sangreRESUMEN
Background: Several studies in mothers of infants with Down syndrome (DS) (MoIDS) have suggested that the 677C>T and 1298A>C variants of the 5,10-methylentetrahydrofolate reductase (MTHFR) gene can increase the risk of having a child with DS. Aim: This study aimed to evaluate the MTHFR 677C>T and 1298A>C variants as potential maternal risk factors for DS. Materials and Methods: Using TaqMan allelic discrimination assay, we genotyped 95 MoIDS and 164 control mothers from western Mexico. Data were analyzed using logistic regression analysis. Results: We found that MoIDS had a significantly higher risk for the MTHFR 677TT genotype (adjusted odds ratio [aOR] = 3.4, 95% confidence interval [95% CI]: 1.1-10.6), and the MTHFR 677T allele (aOR = 1.5, 95% CI: 1.0-2.3), particularly in MoIDS <35 years of age. Conclusions: Our findings indicate that the presence of the 677TT genotype and 677T allele of the MTHFR 677C>T variant are maternal risk factors for DS in Mexican MoIDS.
Asunto(s)
Alelos , Síndrome de Down , Predisposición Genética a la Enfermedad , Genotipo , Metilenotetrahidrofolato Reductasa (NADPH2) , Madres , Polimorfismo de Nucleótido Simple , Humanos , Síndrome de Down/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , México/epidemiología , Femenino , Adulto , Lactante , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Predisposición Genética a la Enfermedad/genética , Estudios de Casos y Controles , Frecuencia de los Genes/genética , Masculino , Embarazo , Oportunidad Relativa , Recién NacidoRESUMEN
Systemic lupus erythematosus (SLE) patients present a high prevalence of cardiometabolic risk, associated with worse clinical manifestations and mortality. Folate, an essential micronutrient that participates in vital immune cellular functions, could positively affect the cardiometabolic and disease risk in SLE, through the methylenetetrahydrofolate reductase (MTHFR) enzyme, which participates in the folate metabolism, where single nucleotide variants (SNVs) have been described as a potential genetic risk factor for SLE. The aim of this study was to determine the association of the c.+677 C>T (rs1801133) and c.+1298 A>C (rs1801131) MTHFR genetic variants with cardiometabolic risk and clinical disease variables in SLE patients. A case-control study was conducted on 394 unrelated Mexican-mestizo women: 199 with SLE according to the 1997 SLE-ACR criteria and 196 control subjects (CS). Folic acid and homocysteine levels were evaluated by immunoassays. Genotyping of MTHFR genetic variants was carried out by allelic discrimination. No significant differences were found for folic acid (p = .15) and homocysteine serum levels (p = .59) between groups. According to the CC c.+677 MTHFR genotype, this was associated with low cardiovascular disease (CVD) risk by the Castelli index (OR = 0.42; p = .03) in SLE patients. The TC (OR = 1.3; p = .03) and the TA (OR = 1.6; p < .01) haplotypes from c.+677 C>T plus c.+1298 MTHFR were associated with SLE risk, while the CC MTHFR haplotype (OR = 0.5; p = .01) was found as a non-risk factor for the disease. In conclusion, the TC and the TA MTHFR haplotypes are associated with disease risk; meanwhile, the CC c.+677 MTHFR genotype confers lower cardiometabolic risk in Mexican-mestizo SLE patients.
Asunto(s)
Ácido Fólico , Predisposición Genética a la Enfermedad , Lupus Eritematoso Sistémico , Metilenotetrahidrofolato Reductasa (NADPH2) , Polimorfismo de Nucleótido Simple , Humanos , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/complicaciones , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Femenino , Estudios Transversales , Estudios de Casos y Controles , Adulto , México/epidemiología , Persona de Mediana Edad , Ácido Fólico/sangre , Homocisteína/sangre , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/epidemiología , Factores de Riesgo Cardiometabólico , Genotipo , Factores de Riesgo , Adulto JovenRESUMEN
BACKGROUND: Previous studies had identified genetic variants associated with Myocardial Infarction, but results are inconclusive. We examined the association between FII G20210A (rs1799963), FV G1691A (rs6025), FXIII 97G > T (rs11466016), ATR1 A1166C (rs5186) and MTHFR A1298C (rs1801131) polymorphisms and ST elevation Myocardial Infarction in young Mexican individuals. METHODS: We included a total of 350 patients with Myocardial Infarction <45 years old and 350 controls matched by age and gender. The polymorphisms were analyzed by PCR-RFLP using specific restriction enzymes. DNA fragments were separated by electrophoresis in 2% gel of agarose and visualized using SYBR green. RESULTS: The A1166C (p = 0.004) but not FXIII 97G > T (p = 0.19), G20210A (p = 0.32), G1691A (p = No significant) and A1298C (p = 0.21) polymorphisms were associated with increased risk for ST elevation Myocardial Infarction. Moreover, dyslipidemia, hypertension, smoking and family history of atherothrombotic disease were associated. CONCLUSIONS: We found that A1166C represented increased risk for ST elevation Myocardial Infarction. However, G20210A, G1691A, 97G > T, and A1298C were not associated. In addition, we had determined that Glu298Asp, PLA1/A2, TAFI Thr325Ile, ACE I/D, AGT M235T and PAI-1 4G/5G polymorphisms represented increased risk in the same group of patients. However, MTHFR C677T, AGT T174M, FV G1691A, TSP-1 N700S, MTHFR C677T and TAFI 174 M polymorphisms were no associated. Our results suggest that in young patients with ST Myocardial Infarction, those polymorphisms could contribute to premature endothelial dysfunction, atherothrombosis, vasoconstriction, increased platelet aggregation, muscle cell migration and proliferation. Further studies are required to try to better assess gene-gene and gene-modifiable factors interaction.
Asunto(s)
Infarto del Miocardio , Infarto del Miocardio con Elevación del ST , Humanos , Persona de Mediana Edad , Polimorfismo Genético , Infarto del Miocardio/genética , Polimorfismo de Longitud del Fragmento de Restricción , Movimiento Celular , Metilenotetrahidrofolato Reductasa (NADPH2)/genéticaRESUMEN
INTRODUCTION: The placenta provides nutrients to the fetus, and it has protective effects against harmful substances. Unhealthy maternal diets and toxic agents might increase free radical (FR) production. Elevated FR levels are associated with a high risk of oxidative stress, which may cause DNA damage. DNA might be oxidized in the placenta, occasionally affecting its methylation profile due to 8-hidroxy-2'-deoxyguanosine formation. METHODS: This study assessed 130 mothers and their children. The maternal's nutritional patterns were determined using the Food Frequency Questionnaire. Information on smoking and alcohol consumption was collected during the medical examination. Data on placental DNA were obtained to determine the MTHFR 677C/T genotype and the proportion of placental DNA methylation (pDNAm). RESULTS: Consumption of vitamins and folic acid was above 85%. The pDNAm was found to be correlated with gestational age and coffee intake. Mothers with a smoking history had a low pDNAm. Placentas with the TT genotype had a higher but not significant pDNAm. In the placentas with the CC/CT genotype, the pDNAm was positively associated with carbohydrate and biotin intake. However, the TT genotype was negatively associated with folate and vegetable intake. DISCUSSION: The pDNAm was positively associated with coffee intake, but not with macro-, and micronutrient intake. However, it was negatively associated with cigarette smoking. The placentas with the CC/CT genotype had a lower pDNAm than those with the TT genotype. In the placentas with the CC/CT or TT genotype, methylation was positively, and negatively associated with micro- or macronutrients, respectively.
Asunto(s)
Metilación de ADN , Placenta , Niño , Humanos , Femenino , Embarazo , Café , Dieta , Genotipo , Ácido Fólico , ADN , Fumar/efectos adversos , Metilenotetrahidrofolato Reductasa (NADPH2)/genéticaRESUMEN
BACKGROUND: Several studies around the world support the hypothesis that genetic polymorphisms involved in folate metabolism could be related to the maternal risk for Down syndrome (DS). Most of them investigated the role of MTHFR C677T and/or A1298C polymorphisms as maternal risk factors for DS, but their results are often conflicting and still inconclusive. METHODS: We conducted a systematic review and meta-analysis to clarify the association of MTHFR C677T and/or A1298C polymorphisms with the maternal risk of DS. Our search strategy selected 42 eligible case control studies for a total of 4131 case mothers and 5452 control mothers. The Newcastle-Ottawa Scale was used to assess the methodological quality of the selected studies. To assess the confidence of statistically significant associations we applied false positive report probability test, and we performed the trial sequential analysis to minimize the type I error and random error. RESULTS: We observed significant associations between the MTHFR C677T polymorphism and maternal risk for DS for each of the genetic models investigated (dominant, recessive, codominant, and allelic contrast). Subgroup analysis by region revelated significant association in the Asian population for all the genetic models investigated. Significant associations were also found for certain genetic models in North American, South American, and Middle Eastern populations, while no association was observed in Europeans. The MTHFR A1298C polymorphism did not show any association with the maternal risk of DS, either alone or in combination with the C677T one. The results of false positive report probability to verify the confidence of a significant association suggest that the association between the MTHFR C677T polymorphism and the maternal risk for DS is noteworthy, with high confidence in Asians. CONCLUSION: The results of this meta-analysis support that the MTHFR C677T polymorphism, but not the A1298C one, is associated with the maternal risk for DS. Further studies are required to better characterize the contribution of gene-gene and gene-nutrient interactions as well as those of other regional or ethnic factors that could explain the observed different effect size in different populations.
Asunto(s)
Síndrome de Down , Humanos , Síndrome de Down/genética , Síndrome de Down/metabolismo , Polimorfismo Genético , Alelos , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/metabolismo , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , GenotipoRESUMEN
We report two cases of Brazilian patients (a 22-year-old male and a 48-year-old male) with ischemic stroke, whose arterial vascular study and echocardiographic investigation did not reveal any steno-occlusive arterial disease or typical cardioembolic finding, such as atrial fibrillation or myocardial dysfunction. A transcranial Doppler ultrasound and a transesophageal echocardiogram showed a patent foramen ovale (PFO), and the laboratory screening for coagulation abnormalities showed heterozygosity for MTHFR C677T and A1298C in one of the patients and heterozygosity for factor V Leiden gene mutations in the other patient. The significance of the association of PFO with Methylenetetrahydrofolate (MTHFR) C677T and A1298C variants or factor V Leiden mutation is discussed as a possible cause of ischemic stroke through paradoxical embolism from a venous source. There is a high prevalence of these two mentioned conditions in the general population, so we discuss two cases in which indication for anticoagulant therapy or percutaneous closure of PFO prevails.
Asunto(s)
Foramen Oval Permeable , Accidente Cerebrovascular Isquémico , Personal Militar , Accidente Cerebrovascular , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Foramen Oval Permeable/complicaciones , Foramen Oval Permeable/genética , Foramen Oval Permeable/terapia , Accidente Cerebrovascular Isquémico/complicaciones , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Mutación , Factores de Riesgo , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/prevención & controlRESUMEN
BACKGROUND: Diabetes Mellitus (DM) is directly associated with cardiovascular dysfunctions and microvascular complications, such as diabetic retinopathy (DR). The association between DR and increased risks of developing cardiovascular diseases has been described. The low activity of the Methylenetetrahydrofolate reductase (MTHFR), an enzyme involved in the metabolism of homocysteine, can lead to hyperhomocysteinemia that has already been related to cardiac outcomes and resistance to insulin. The A1298C and C677T polymorphisms in the MTHFR can reduce enzyme activity. OBJECTIVE: The study aims to analyze the association between MTHFR genotypes and cardiac parameters in patients with DR. METHODS: DM patients diagnosed with DR (n=65) were categorized and compared according to MTHFR genotypes A1298C (AA and AC+CC groups) and C677T (CC and CT+TT) groups; biochemical, cardiological, anthropometric, genetic, lifestyle and vitamin B9 and B12 consumption variables. Fischer's exact test and Poisson regression were performed to assess the relationship between variables. RESULTS: Comparing echocardiographic and electrocardiogram parameters within genotypic groups, we found a significant association between left atrial dilation and C677T polymorphism. Left atrium diameter was higher in the T allele carriers (CT+TT group), with a prevalence ratio of 0.912. This association was confirmed in the regression model, including confounding variables. The other cardiac structural and functional parameters studied were not significantly associated with the A1298C or C677T genotypes. CONCLUSION: The MTHFR C677T genotype may contribute to atrial remodeling in RD patients. We found an association between the diameter of the left atrium and the T allele of the MTHFR C677T polymorphism in patients with DR.
Asunto(s)
Diabetes Mellitus , Retinopatía Diabética , Humanos , Retinopatía Diabética/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Polimorfismo Genético , Genotipo , Alelos , Predisposición Genética a la EnfermedadRESUMEN
BACKGROUND: The enzyme methylenetetrahydrofolate reductase is engaged in DNA synthesis through folate metabolism. Inhibiting the activity of this enzyme increases the susceptibility to mutations, and damage and aberrant DNA methylation, which alters the gene expression of tumor suppressors and proto-oncogenes, potential risk factors for esophageal cancer. AIMS: This study aimed to investigate the association between methylenetetrahydrofolate reductase 677C>T and methylenetetrahydrofolate reductase 1298A>C polymorphisms and susceptibility to esophageal cancer, by assessing the distribution of genotypes and haplotypes between cases and controls, as well as to investigate the association of polymorphisms with clinical and epidemiological characteristics and survival. METHODS: A total of 109 esophageal cancer patients who underwent esophagectomy were evaluated, while 102 subjects constitute the control group. Genomic DNA was isolated from the peripheral blood buffy coat followed by amplification by polymerase chain reaction and real-time analysis. Logistic regression was used to assess associations between polymorphisms and the risk of developing esophageal cancer. RESULTS: There was no association for methylenetetrahydrofolate reductase 677C>T and methylenetetrahydrofolate reductase 1298A>C polymorphisms and haplotypes, with esophageal cancer susceptibility. Esophageal cancer patients carrying methylenetetrahydrofolate reductase 677TT polymorphism had higher risk of death from the disease. For polymorphic homozygote TT genotype, the risk of death significantly increased compared to wild-type genotype methylenetetrahydrofolate reductase 677CC (reference) cases (p=0.045; RR=2.22, 95%CI 1.02-4.83). CONCLUSIONS: There was no association between methylenetetrahydrofolate reductase 677C>T and methylenetetrahydrofolate reductase 1298A>C polymorphisms and esophageal cancer susceptibility risk. Polymorphic homozygote genotype methylenetetrahydrofolate reductase 677TT was associated with higher risk of death after surgical treatment for esophageal cancer.
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Neoplasias Esofágicas , Metilenotetrahidrofolato Reductasa (NADPH2) , Estudios de Casos y Controles , ADN , Neoplasias Esofágicas/genética , Humanos , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Oxidorreductasas/genética , Polimorfismo Genético/genéticaRESUMEN
Recent studies have shown that two common methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms (C677T and A1298C) might correlate with thyroid dysfunction, but the results remain inconsistent. We carried out a meta-analysis aiming to assess the relationship of both polymorphisms with thyroid dysfunction. The PubMed, EMBASE, CNKI (China National Knowledge Infrastructure), CBMdisc (China Biology Medicine disc), WeiPu and Wanfang databases were searched up to September 2021. Case-control and cohort studies on MTHFR polymorphism and thyroid dysfunction were identified. Eight studies from six publications were finally included in our meta-analysis, including 817 patients and 566 controls. After pooled analysis, we found that the MTHFR C677T polymorphism was associated with an increased risk of hypothyroidism (TT vs. CC+CT/recessive model: OR = 2.07, 95% CI: 1.02-4.20, P = 0.04; TT vs. CC/homozygote model: OR = 2.35, 95% CI: 1.13-4.86, P = 0.02), while trial sequential analysis (TSA) revealed that it could be a false positive result. The MTHFR A1298C polymorphism was related to a decreased risk of hypothyroidism (C vs. A/allele model: OR = 0.63, 95% CI: 0.44-0.92, P = 0.02; CC vs. AC+AA/recessive model: OR = 0.42, 95% CI: 0.22-0.79, P = 0.007; CC vs. AA/homozygote model: OR = 0.43, 95% CI: 0.25-0.85, P = 0.02), which was conclusive according to TSA. The results of this meta-analysis suggest that MTHFR A1298C seems to be a protective factor for hypothyroidism, while the MTHFR C677T polymorphism may be a risk factor. However, more well-designed studies with larger sample sizes are needed to obtain more reliable results of the association between the MTHFR C677T polymorphism and hypothyroidism.
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Hipotiroidismo , Metilenotetrahidrofolato Reductasa (NADPH2) , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad/genética , Humanos , Hipotiroidismo/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Polimorfismo Genético/genética , Polimorfismo de Nucleótido Simple/genética , Factores de RiesgoRESUMEN
Background: Homocysteine levels can be impacted by enzymes variations. Aim: To correlate MTHFR, MTR and MTRR variants with homocysteine levels in the blood and follicular fluid and assisted reproduction results. Material & methods:MTHFR (rs2274976, rs1801131, rs1801133), MTR (rs1805087) and MTRR (rs1801394) genotyping was performed by TaqMan assays and compared with homocysteine levels, measured by ELISA, to oocytes retrieved and to the pregnancy status of women with endometriosis and controls. Results: The MTR G allele and GG genotype were more common in patients with endometriosis. They also showed lower levels of homocysteine and more clinical gestations. Epistasis analysis showed a model associated with gestational results, composed of MTHFR+MTR variants (CC+AG). Conclusion: The summation effect of variants in genes participating in folate metabolism was associated with pregnancy status in Brazilian women. MTR variants were more observed in endometriosis patients, as well as lower follicular Hcy levels and increased clinical pregnancy results.
What was the aim of the study? To correlate genetic variants to homocysteine levels in the blood and oocyte surrounding fluid, and the results of assisted reproduction techniques. How was the study done? A total of 152 women with endometriosis and controls with male infertility were evaluated. DNA was extracted from blood for genetic analysis, and homocysteine levels were measured from the blood and oocyte surrounding fluid. Genetic results were correlated to homocysteine levels, oocyte quality and pregnancy status. What were the results? A specific genetic marker occurred more in endometriosis patients. They also showed lower levels of homocysteine and a tendency to more clinical gestations than controls. What do the results of the study mean? Endometriosis patients showed specific genetic markers and different levels of homocysteine compared with controls. These results can be helpful to predict gestational results.
Asunto(s)
5-Metiltetrahidrofolato-Homocisteína S-Metiltransferasa , Endometriosis , Ferredoxina-NADP Reductasa , Homocisteína , Metilenotetrahidrofolato Reductasa (NADPH2) , 5-Metiltetrahidrofolato-Homocisteína S-Metiltransferasa/genética , Alelos , Endometriosis/complicaciones , Endometriosis/genética , Femenino , Ferredoxina-NADP Reductasa/genética , Ácido Fólico/metabolismo , Genotipo , Homocisteína/sangre , Humanos , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Polimorfismo de Nucleótido Simple , EmbarazoRESUMEN
BACKGROUND: Legg-Calvé-Perthes disease (LCPD) is the avascular osteonecrosis of the proximal femoral epiphysis. It is a rare disease of unclear etiology in children, although alterations in coagulation or the collagen gene have been described and could be associated with its etiology. Our objective was to evaluate the following alterations: COL1A1 (rs1107946, rs2412298), COL2A1 (rs121912891 and rs387106558), MTHFR rs1801133, CBS rs115742905, and PT rs1799963 and their relationship with LCPD. METHODS: DNA was obtained and genotyped by real-time PCR with TaqMan probes. Prothrombin (FII) and homocysteine (Hcy) were determined by a coagulometric method. The variables were described as mean and standard deviation or percentages, and genotypic and allelic distributions were analyzed using the Student's t-test. The Hardy-Weinberg equilibrium and OR were also used. RESULTS: We studied 23 patients with LCPD and 46 controls. We did not find any association of the MTHFR, CBS, PT, COL1A1, and COL2A1 genetic variants with LCPD. However, when adjusting the data with the Hcy values for the MTHFR C677T polymorphism, the C/C genotypes showed an association with the recessive model (p = 0.038), with susceptibility to LCPD. CONCLUSION: No association was found with the CBS, PT, COL1A1, and COL2A1 genes. Nevertheless, our results suggest a significant link between moderately elevated Hcy levels and the MTHFR C677T polymorphism in a cohort of Mexican children with LCPD.
Asunto(s)
Enfermedad de Legg-Calve-Perthes , Niño , Estudios de Cohortes , Genotipo , Homocisteína , Humanos , Enfermedad de Legg-Calve-Perthes/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genéticaRESUMEN
Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide. Environmental and genetic factors are recognized as risk determinants in the onset and development of CVDs. However, the interaction between both factors on CVDs risk is not still completely clarified. Therefore, the objective of this study was to evaluate the effect of the interaction between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and polycyclic aromatic hydrocarbon (PAH) exposure (gene-environment interaction) on cardiovascular risk biomarkers in Mexican women. A cross-sectional study was completed with the participation of 390 healthy women. For all enrolled women, anthropometric measurements, serum biochemical analyses, atherogenic indexes, and serum concentrations of biomolecules used as CVD risk biomarkers were obtained. 1-Hydroxypyrene (1-OHP) was measured in urine, as an exposure biomarker of PAHs. The mean urinary level of 1-OHP in the assessed population was 1.23 ± 1.40 µmol/mol creatinine. The allelic frequency (MTHFR C677T polymorphism) identified in the registered individuals was 68.0% for the mutant allele (T-allele). Significant positive associations were detected between urinary 1-OHP levels and serum asymmetric dimethylarginine (ADMA) concentrations (p < 0.05) and atherogenic index of plasma (AIP) values (p < 0.05). Also, women with the TT genotype of the MTHFR C677T enzyme have the highest serum ADMA levels (p < 0.05) and AIP values (p < 0.05) compared to women grouped as CC genotype and CT genotype. Besides, the findings in this study suggest an interaction between environmental (PAHs exposure) and genetic (MTHFR C677T polymorphism) factors on cardiovascular risk markers (ADMA and AIP). According to the usefulness of AIP and ADMA, an increased cardiovascular risk is notable in highly exposed individuals to PAHs with the polymorphic genotype (TT) of the MTHFR enzyme. Therefore, intervention programs in the target communities are required to diminish the cardiovascular risk of the assessed individuals.
Asunto(s)
Enfermedades Cardiovasculares , Hidrocarburos Policíclicos Aromáticos , Biomarcadores , Enfermedades Cardiovasculares/etiología , Estudios Transversales , Femenino , Genotipo , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Factores de RiesgoRESUMEN
BACKGROUND: Down syndrome (DS) is one of the most common chromosomal abnormalities among live-born babies and one of the best-known intellectual disability disorders in humans. Errors leading to trisomy 21 are primarily arising from defects in chromosomal segregation during maternal meiosis (about 88% of cases), and the focus of many investigations has been to identify maternal risk factors favoring chromosome 21 malsegregation during oogenesis. Maternal polymorphisms of genes required for folate metabolism are the most investigated risk factors for the birth of children with DS. Through this review, we sought to investigate the association of the polymorphisms "C677T" and "A1298C" of the MTHFR gene with maternal risk for DS. METHODS: We will use the databases PubMed, Embase, Scopus and Web of Science to search for case-control studies published from 1999 up to September 2021 without language restriction. Results will be presented as relative risks and 95% confidence intervals for dichotomous outcomes and mean differences, or standardized mean differences along with 95% confidence intervals, for continuous outcomes. The all data synthesis will be analyzed on the Review Manager 5.2 version software. RESULTS: This study will be able to clarify all the doubts we seek and that it will be able to provide accurate data that will be able to describe how these polymorphisms can act to increase the predisposition for the birth of children with DS in different populations and under different dietary conditions. CONCLUSIONS: This study will clarify the relationship between C677T and A1298C polymorphisms MTHFR gene with increased the maternal risk for Down syndrome. REGISTRATION: This systematic review and meta-analysis protocol has been registered on the Prospective Registry of International Systematic Review and Meta-analyses: CRD42021269338.
Asunto(s)
Síndrome de Down/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Polimorfismo Genético , Niño , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Metaanálisis como Asunto , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Revisiones Sistemáticas como AsuntoRESUMEN
OBJECTIVE: The folate pathway is involved in hepatic carcinogenesis and angiogenesis. Polymorphisms in genes related to such processes, including methylene tetrahydrofolate reductase (MTHFR) and vascular endothelial growth factor (VEGF)] may play an important role in the development of hepatocellular carcinoma (HCC). The objective of this study was to evaluate MTHFR and VEGF polymorphisms in Brazilian patients with hepatitis C virus (HCV)-related HCC. METHODS: A total of 119 patients diagnosed with confirmed HCC and HCV were included in the study. SNP genotyping assays were performed using real-time PCR. VEGFA (rs2010963, rs3025039, and rs833061) and MTHFRC677T (rs1801133, rs1801131) polymorphisms were evaluated. RESULTS: The C alleles of MTHFR (rs1801131) and VEGF (rs2010963) were associated with protection against the development of multinodular HCC, while the T allele of MTHFR (rs1801133) was associated with a higher risk of multinodular presentation [p=0.04 OR 1.835 CI (1.022-3.297)]. Multivariate analysis revealed that the GG/GC genotypes of VEGF rs2010963 were independently associated with multinodular tumors at diagnosis (p=0.013; OR 4.78 CI (1.38-16.67)]. CONCLUSION: Our results suggest that these polymorphisms may increase the risk of rapid tumor progression in patients with HCV infection. This subgroup of patients with HCC and who present polymorphism is more likely to be diagnosed with multinodular disease and not be amenable to receiving curative treatments. These data must be validated in larger cohorts, and the screening intervals can be customized based on genetic history.
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Carcinoma Hepatocelular , Hepatitis C , Neoplasias Hepáticas , Carcinoma Hepatocelular/genética , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Genotipo , Hepacivirus , Humanos , Neoplasias Hepáticas/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Polimorfismo de Nucleótido Simple , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
BACKGROUND: Fluoropyrimidine plus platinum chemotherapy remains the standard first line treatment for gastric cancer (GC). Guidelines exist for the clinical interpretation of four DPYD genotypes related to severe fluoropyrimidine toxicity within European populations. However, the frequency of these single nucleotide polymorphisms (SNPs) in the Latin American population is low (< 0.7%). No guidelines have been development for platinum. Herein, we present association between clinical factors and common SNPs in the development of grade 3-4 toxicity. METHODS: Retrospectively, 224 clinical records of GC patient were screened, of which 93 patients were incorporated into the study. Eleven SNPs with minor allelic frequency above 5% in GSTP1, ERCC2, ERCC1, TP53, UMPS, SHMT1, MTHFR, ABCC2 and DPYD were assessed. Association between patient clinical characteristics and toxicity was estimated using logistic regression models and classification algorithms. RESULTS: Reported grade ≤ 2 and 3-4 toxicities were 64.6% (61/93) and 34.4% (32/93) respectively. Selected DPYD SNPs were associated with higher toxicity (rs1801265; OR = 4.20; 95% CI = 1.70-10.95, p = 0.002), while others displayed a trend towards lower toxicity (rs1801159; OR = 0.45; 95% CI = 0.19-1.08; p = 0.071). Combination of paired SNPs demonstrated significant associations in DPYD (rs1801265), UMPS (rs1801019), ABCC2 (rs717620) and SHMT1 (rs1979277). Using multivariate logistic regression that combined age, sex, peri-operative chemotherapy, 5-FU regimen, the binary combination of the SNPs DPYD (rs1801265) + ABCC2 (rs717620), and DPYD (rs1801159) displayed the best predictive performance. A nomogram was constructed to assess the risk of developing overall toxicity. CONCLUSION: Pending further validation, this model could predict chemotherapy associated toxicity and improve GC patient quality of life.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Compuestos de Platino/administración & dosificación , Polimorfismo de Nucleótido Simple , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Anciano , Capecitabina/efectos adversos , Estudios de Casos y Controles , Intervalos de Confianza , Proteínas de Unión al ADN/genética , Dihidrouracilo Deshidrogenasa (NADP)/genética , Endonucleasas/genética , Femenino , Fluorouracilo/efectos adversos , Frecuencia de los Genes , Genes p53 , Genotipo , Gutatión-S-Transferasa pi/genética , Glicina Hidroximetiltransferasa/genética , Humanos , Leucovorina/efectos adversos , Modelos Logísticos , Masculino , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Persona de Mediana Edad , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Complejos Multienzimáticos/genética , Nomogramas , Oportunidad Relativa , Compuestos Organoplatinos/efectos adversos , Orotato Fosforribosiltransferasa/genética , Orotidina-5'-Fosfato Descarboxilasa/genética , Pirimidinas , Calidad de Vida , Estudios Retrospectivos , Neoplasias Gástricas/patología , Proteína de la Xerodermia Pigmentosa del Grupo D/genéticaRESUMEN
PURPOSE: Fluoropyrimidines are one of the most used drug class to treat cancer patients, although they show high levels of associated toxicity. This study analyzed 33 polymorphisms in 17 pharmacogenes involved with the pharmacogenomics of fluoropyrimidines, in gastrointestinal cancer patients undergoing fluoropyrimidine-based treatment in the Brazilian Amazon. METHODS: The study population was composed of 216 patients, 92 of whom have an anatomopathological diagnosis of gastric cancer and 124 of colorectal cancer. The single nucleotide polymorphisms (SNP) were genotyped by allelic discrimination using the TaqMan OpenArray Genotyping technology, with a panel of 32 customized assays, run in a QuantStudio ™ 12K Flex Real-Time PCR System (Applied Biosystems, Life Technologies, Carlsbad USA). Ancestry analysis was performed using 61 autosomal ancestry informative markers (AIMs). RESULTS: The study population show mean values of 48.1% European, 31.1% Amerindian, and 20.8% African ancestries. A significant risk association for general and severe toxicity was found in the rs4451422 of FPGS (p = 0.001; OR 3.40; CI 95% 1.65-7.00 and p = 0.006; OR 4.63; CI 95% 1.56-13.72, respectively) and the rs9524885 of ABCC4 (p = 0.023; OR 2.74; CI 95% 1.14-6.65 and p = 0.024; OR 5.36; IC 95% 1.24-23.11, respectively) genes. The rs760370 in the SLC29A1 gene (p = 0.009; OR 6.71; CI 95% 1.16-8.21) and the rs1801133 in the MTHFR toxicity (p = 0.023; OR 3.09; CI 95% 1.16-8.21) gene also demonstrated to be significant, although only for severe toxicity. The results found in this study did not have statistics analysis correction. CONCLUSION: Four polymorphisms of the ABCC4, FPGS, SLC29A1, and MTHFR genes are likely to be potential predictive biomarkers for precision medicine in fluoropyrimidine-based treatments in the population of the Brazilian Amazon, which is constituted by a unique genetic background.