Polimorfismo de proteína 5, 10-metilentetrahidrofolatoreductasa en población venezolana / Polymorphisms proteína 5, 10-metilentetrahidrofolatoreductasa in venezuelan people

El folato es un miembro del grupo de la vitamina B y está relacionado con enfermedades crónicas como anemia megaloblástica, enfermedad cardiovascular, cáncer, disfunción cognitiva y riesgo de defectos del tubo neural. La proteína 5,10-metilentetrahidrofolato reductasa (MTHFR) juega un papel clave en el metabolismo del folato mediante la síntesis de nucleótidos y reacciones de metilación. El gen MTHFR se encuentra en el cromosoma 1 (1p36.3), y se han descrito dos alelos comunes, el alelo C677T (termolábil) y el alelo A1298C.El objetivo de este estudio es evaluar la distribución de los polimorfismos genéticos en MTHFR C677T y A1298C en la población venezolana. METODOS: estudio de tipo transversal, descriptivo, experimental y correlacional Las muestras de sangre se colectaron en 314 donantes no emparentados y sanos de la población. Los polimorfismos de un solo nucleótido(SNP) MTHFR 677C>T y 1298A>C se analizaron mediante polimorfismo de longitud de fragmento de restricción de reacción en cadena de polimerasa (PCR-RFLP). El desequilibrio de ligamiento (LD) entre pares de SNP se calculó mediante la prueba X. usando Prism 5 (GraphPad software, Inc). RESULTADOS: Encontramos mayor frecuencia genotípica de heterocigotos para el polimorfismo MTHFR C677T en la población general venezolana, con excepción del grupo caucásico. El polimorfismo MTHFR A1298C en el 70%de la población de estudio es homocigoto de tipo salvaje, encontrándose una baja frecuencia de homocigoto mutado. CONCLUSIONES: Se encontraron diferencias significativas entre grupos étnicos, destacando la importancia del genotipado racial de estos polimorfismos en la población venezolana(AU)

Folate is a member of the vitamin B and it has also been indicated that may be related to chronic diseases such as megaloblastic anemia, cardiovascular disease, cognitive dysfunction and risk of neural tube. Methylenetetrahydro folatereductase (MTHFR) is a key enzyme of folate pathway by nucleotide synthesis and methylation reactions. Several polymorphisms were reported in MTHFR gene but C677Tand A1298 polymorphism are most studied and these have been reported to be risk factor for several diseases/disorders. The present study was designed to determine the frequency of MTHFR polymorphisms in Venezuelan healthy population. METHODS: The blood samples were collected from 314 unrelated and healthy donors from population. Both the MTHFR 677C>T and 1298A>C single nucleotide polymorphisms (SNPs) were analyzed by Polymerase chainreaction-restriction fragment length polymorphism (PCR-RFLP). Linkage disequilibrium (LD) between pair of SNPs was calculated through the .. test using Prism 5 (GraphPad sftoware, Inc). RESULTS: We find higher genotypic frequency of heterozygotes for the MTHFR C677T polymorphism in the Venezuelan general population, with the exception of the Caucasian group. MTHFR A1298C polymorphism in 70%of the study population is homozygous wild type, finding alow frequency of homozygous mutated. CONCLUSIONS: Significant differences between ethnic groups were found,highlighting the importance of racial genotyping of these polymorphisms in the Venezuelan population(AU)

MTHFR C677T and A1298C Gene Polymorphisms and Ischemic Heart Disease (IHD) in a Sri Lankan Population - A Preliminary Study

MTHFR A1298C and C677T SNPs are now recognised as important genetic mutations which would give rise to hyperhomocysteinemia. In this study, we analysed the prevalence of these two SNPs in 79 ischemic heart disease (IHD) patients awaiting coronary artery bypass grafting and 79 healthy subjects. MHFR polymorphisms were analysed using polymerase chain reaction followed by a restriction fragment analysis. Prevalence rates for MTHFR C677T polymorphism were 72.8%, 24.7%, and 2.5% for CC, CT, and TT genotypes, respectively, for the whole study population with 677CC genotype being the predominant genotype among both the IHD patients and the controls. The 677TT genotype was detected only among the IHD patients. There was no significant difference in MTHFR 677 genotype variations between IHD patients and the control group. Prevalence rates for the MTHFR A1298C polymorphism were 50%, 37.3%, and 12.7% for the AA, AC, and CC genotypes, respectively, for the whole study population with 1298AA genotype being the predominant genotype among controls and 1298AC the predominant genotype among IHD patients. There was a significant difference (p < 0.01) between IHD patients and controls when the MTHFR 1298 genotype variations were compared. Allele frequencies for the mutant T allele for C677T mutation at 0.149 are the highest reported from Sri Lanka. The frequency of the C for the A1298C mutation was 0.313. Results of this study indicate that MTHFR A1298C SNP is more prevalent in Sri Lankans when compared to C677T SNP and that the mutant forms of the MTHFR A1298C SNP are associated with ischemic heart disease.

Methylene tetrahydrofolate reductase, transforming growth factor-ß1 and lymphotoxin-α genes polymorphisms and susceptibility to rheumatoid arthritis / Polimorfismos dos genes metilenotetrahidrofolato redutase, fator de crescimento transformador β1 e linfotoxina-α e susceptibilidade à artrite reumatoide

ABSTRACT Background: Rheumatoid arthritis is a widely prevalent autoimmune disorder with suggested genetic predisposition. Objectives: The aim of this study is to detect the pattern of genetic polymorphism of methylene tetrahydrofolate reductase (MTHFR C677 T and A1298 C), transforming growth factor-β1 (TGF-β1 T869 C) and lymphotoxin-α (LT-α A252G) in patients having rheumatoid arthritis and correlate these patterns to disease activity and serum levels of tumor necrosis factor-alpha (TNF-α), B-Cell Activating Factor (BAFF), and osteopontin. Methods: A total of 194 subjects, 90 controls and 104 patients with rheumatoid arthritis were genotyped for MTHFR C677 T and A1298 C, TGF-β1 T869 C and LT-α A252G polymorphisms using a methodology based on PCR-RFLP. Also serum levels of TNF-α, osteopontin and BAFF were measured by ELISA kits. Results: The CT genotype and T allele of MTHFR C677 T and GG genotype and G allele of LT-α A252G are associated with the risk of RA and with higher levels of the pro-inflammatory cytokine, TNF-α in patients with rheumatoid arthritis. Conclusion: Our findings suggest that there is association between MTHFR C677 T and LT-α A252G genes polymorphisms and increased risk of RA in this sample of Egyptian population.

RESUMO Antecedentes: A artrite reumatoide é uma doença autoimune amplamente prevalente com sugerida predisposição genética. Objetivos: Detectar o padrão de polimorfismo dos genes metilenotetrahidrofolato redutase (MTHFR C677 T e A1298 C), fator de crescimento transformador β1 (TGF-β1 T869 C) e linfotoxina-α (LT-α A252G) em pacientes com artrite reumatoide e correlacionar esses padrões com a atividade da doença e os níveis séricos de fator de necrose tumoral alfa (TNF-α), fator ativador de linfócitos B (BAFF) e osteopontina. Métodos: Foram genotipados 194 indivíduos – 90 controles e 104 com artrite reumatoide – à procura de polimorfismos dos genes MTHFR C677 T e A1298 C, TGF-β1 T869 C e LT-α A252G com uma metodologia baseada na PCR-RFLP. Mensuraram-se também os níveis séricos de TNF-α, osteopontina e BAFF com kits de Elisa. Resultados: O genótipo CT e o alelo T do MTHFR C677 T e o genótipo GG e alelo G do LT-α A252G estão associados ao risco de AR e a níveis mais elevados da citocina pró-inflamatória TNF-α em pacientes com artrite reumatoide. Conclusão Os achados do presente estudo sugerem que há associação entre os polimorfismos dos genes MTHFR C677 T e LT-α A252G e um risco aumentado de AR nessa amostra da população egípcia.

Unilateral sequential papillophlebitis and central retinal artery occlusion in a young healthy patient.

A 23‑year‑old girl presented to the clinic with metamorphopsia and photopsia in her left eye. After detailed ophthalmic examination, central retinal vein occlusion with optic disc edema was detected in that eye. Three days after diagnosis, the patient returned to our clinic with visual acuity decrease. Central retinal artery occlusion sparing cilioretinal artery was detected. All the laboratory tests were normal except for heterozygous methylenetetrahydrofolate reductase mutation (A1298C genotypes) and an indefinite Lyme disease seropositivity. Symptoms and visual disturbance recovered without any further treatment other than acetylsalicylic acid for prophylaxis.

Homocisteína, polimorfismos MTHFR C677T, A1298C y variables clínico-bioquímicas en población mexicana / Homocysteine, MTHFR C677T and A1298C polymorphisms, and clinical and biochemical variables in the mexican population / Homocisteína, polimorfismos MTHFR C677T, A1298C e variáveis clínico-bioquímicas em população mexicana

El objetivo del trabajo consistió en analizar la relación del nivel sérico de homocisteína (Hcy) con los polimorfismos de la metilentetrahidrofolato reductasa MTHFR C677T y A1298C y variables clínicas y bioquímicas en población mexicana. Se determinó el nivel de Hcy (inmunoensayo) y de polimorfismos (PCR/RFLP) en 102 individuos de la población general. El genotipo 677TT mostró asociación significativa con el peso corporal (r=0,012) y el genotipo 1298CC tuvo tendencia a asociarse con el IMC (r~0,06). Los valores séricos de Hcy en mujeres (51/102) fueron 8,33±1,86 µmol/L y en hombres (51/102) 11,64±4,15 µmol/L. La Hcy mostró asociación positiva con peso corporal (r=0,004) y asociación negativa con Hb y Hto (r=0,001). Se encontró mayor nivel de Hcy en individuos fumadores (r=0,009) y una tendencia hacia hiperhomocisteinemia en alcohólicos y en mujeres menopáusicas. No se evidenció asociación de Hcy con los polimorfismos MTHFR C677T y A1298C, sin embargo, el análisis con el modelo de herencia dominante para el polimorfismo C677T (TT+CT vs. CC) mostró un efecto semidominante (r<0,10). En este estudio, la presencia de los polimorfismos MTHFR C677T y A1298C no representó ser un factor de riesgo significativo para hiperhomocisteinemia, sin embargo, se encontraron diferencias que puntualizan la posible dependencia de los niveles de Hcy en relación con los genotipos modificados con diversos factores ambientales.

The objective of the current work was to analyze the relationship of serum homocysteine (Hcy) with MTHFR C677T and A1298C polymorphisms and clinical and biochemical variables in the Mexican population. Hcy (immunoassay) levels and polymorphism (PCR/RFLP) levels were determined in 102 individuals from the general population. The 677TT genotype showed significant association with body weight (r=0.012) and the 1298CC genotype tended to be associated with BMI (r~0.06). Serum levels of Hcy in women (51/102) were 8.33±1.86 µmol/L and in men (51/102) 11.64± 4.15 µmol/L. The Hcy was positively as-sociated with body weight (r=0.004) and negatively with Hb and Hct (r=0.001). Higher levels of Hcy were found in smokers (r=0.009) and a tendency to hyperhomocysteinemia in alcoholics and in menopausal women. There was no association of Hcy with MTHFR C677T and A1298C polymorphisms, although the analysis with dominant inheritance model for the C677T polymorphism (TT + CT vs. CC) showed a semi-dominant effect (r<0.10). In this study, the presence of MTHFR C677T and A1298C polymorphisms did not represent a significant risk factor for hyperhomocysteinemia; however, those differences may point out the dependence of the relative levels of Hcy modifed genotypes on various environmental factors.

O objetivo deste trabalho foi analisar a relação do nível sérico de homocisteína (Hcy) com os polimorfismos da metilenotetrahidrofolato redutase MTHFR C677T e A1298C e variáveis clínicas e bioquímicas na po-pulação mexicana. Foi determinado o nível de Hcy (imunoensaio) e de polimorfismos (PCR/RFLP) em 102 indivíduos da população geral. O genótipo 677TT mostrou associação significativa com o peso corporal (r =0,012) e o genótipo 1298CC teve tendência a se associar com o IMC (r~0,06). Os níveis séricos de Hcy em mulheres (51/102) foram 8,33±1,86 µmol/L e em homens (51/102) 11,64±4,15 µmol/L. A Hcy mos-trou associação positiva com o peso corporal (r=0,004) e associação negativa com Hb e Hto (r=0,001). Encontraram-se níveis mais elevados de Hcy em fumantes (p=0,009) e uma tendência para hiperhomo-cisteinemia em alcoólatras e em mulheres na menopausa. Nenhuma associação se mostrou entre Hcy e os polimorfismos MTHFR C677T e A1298C, no entanto, a análise com modelo de herança dominante para o polimorfismo C677T (TT+CT vs. CC) mostrou um efeito semidominantes (r<0,10). Neste estudo, a presença dos polimorfismos MTHFR C677T e A1298C não representou ser um fator de risco significativo para a hiper-homocisteinemia, no entanto, foram encontradas diferenças que apontam a possível dependência dos níveis de Hcy relativos aos genótipos modificados com diversos fatores ambientais.

Predisposing role of heterozygote MTHFR A1298C mutation in venous thrombosis in a pregnant patient: A case report.

Congenital and acquired thrombophilia are associated with an increased risk of pregnancy-associated venous thrombosis (VT). Several genetic mechanisms have been investigated for their possible relationship with VT. Methyl tetrahydrofolate reductase gene polymorphisms are frequently in the MTHFR gene, which leads to a C to T change at position 677, has been suggested to alter the thrombohemostasis process and thrombophilia. Also, it has been found that MTHFR C1298C or MTHFR A1298C have no effect on the risk of VT. Herein, we describe deep VT (DVT) secondary to heterozygous MTHFR A1298C mutation in pregnant woman.

A Case-control Study on the Relationship between Methylenetetrahydrofolate Reductase C677T, A1298C and G1793A Polymorphism and the Risk of Stomach Cancer

PURPOSE: The methylenetetrahydrofolate reductase (MTHFR) play a central role in converting folate to methyl donor for DNA methylation. Genetic variation in folate metabolism are believed to contribute to the risk of acute lymphoblastic leukemia, colon, esophageal and stomach cancer, as well as cardiovascular and cerebrovascular disease. Generally, low folate level is known that it is associated with gastrointestinal neoplasm. Three common single nucleotide polymorphisms (SNPs) resulting in amino-acid changes (C677T/Ala222Val, A1298C/Glu428Ala and G1793A/Arg594Glu) has been described in MTHFR. We studied the relation of MTHFR C677T, A1298C and G1793A polymorphisms derived from stomach cancers and a control group in Korean people. METHODS: We performed a case-control study to examine the relationship between MTHFR C677, A1298C and G1793A polymorphism and the risk of stomach cancer. 124 individuals with stomach cancer and 288 healthy persons were analyzed. Blood sampling of each groups were performed, PCR-RFLP analyzed, as a results, MTHFR polymorphism genotypes of 677C/C, 677C/T, 677T/T, 1298AA, 1298AC, 1298CC, 1793GG, 1793GA and 1793AA were obtained. RESULTS: The genotype frequency of MTHFR C677T polymorphisms were 23.4% (CC), 51.6% (CT), 25.0% (TT), 76.6% (CT+TT) in case patients and 39.2% (CC), 36.8% (CT), 24.0% (TT), 60.8% (CT+TT) in control groups. The genotype frequency of MTHFR A1298C polymorphisms were 38.7% (AA), 54.0% (AC), 7.3% (CC), 61.3% (AC+CC) in case patients and 55.6% (AA), 40.3% (AC), 4.2% (CC), 44.4% (AC+CC) in control groups. The genotype frequency of MTHFR G1793A polymorphisms were 82.3% (GG), 16.9% (GA), 0.8% (AA), 17.7% (GA+AA) in case patients and 85.8% (GG), 11.8% (GA), 2.4% (AA), 14.2% (GA+AA) in control groups. 677TT and 677CT genotype was associated with a significantly increased risk for gastric cancer (adjusted OR=2.15, 95% confidence interval 1.16~3.95 in TT, adjusted OR=2.49, 95% CI 1.47~4.20 in CT) than the 677CC genotype, and 1298CC and 1298 AC genotype also was associated with a significantly increased risk for stomach cancer (adjusted OR=2.87, 95% CI 1.10~|7.49 in CC, adjusted OR= 2.07, 95% CI 1.31~3.26 in AC). But 1793AA and 1793GA genotypes were not association with a significantly increased risk for stomach cancer (adjusted OR=0.29, 95% CI 0.03~|2.47 in AA, adjusted OR=1.55, 95% CI 0.84~2.86 in GA) CONCLUSION: MTHFR C677T and A1298C polymorphism may influence stomach cancer, but MTHFR G1793A polymorphism need careful interpretation and confirmation in larger studies.

Methylenetetrahydrofolate Reductase C677T and A1298C Polymorphisms in Colorectal Cancer

PURPOSE: Recently, the role of vitamins, folate in particular, has been emphasized in the maintenance of health. Folate deficiency is known to give rise to developmental delay, pre-mature vascular disease, neural tube defects, acute leukemia, atherosclerotic vascular disease, delivery defects, breast cancers and gastrointestinal neoplasia. Methylenetetrahydrofolate reductase (MTHFR) is an essential enzyme in folate metabolism, and influences DNA synthesis and DNA methylation. Generally, a low folate level is known to be associated with gastrointestinal neoplasms. Also, the amino- acid-changing and enzyme-activity-reducing nucleotide polymorphism (677C-->T/Ala222Val) has been described in the MTHFR polymorphism and it brings about low enzyme activity, which may reduce DNA methylation and uracil misincorporation into DNA. These processes may be critical for the oncogenic transformation of human cells. Two common single nucleotide polymorphisms (SNPs) resulting in amino-acid changes (677C T/Ala222Val and 1298A C/Glu428Ala) have been described in MTHFR. We investigated the relation between the MTHFR C677T and A1298C polymorphisms derived from colorectal cancers and from controls in the Korean population. METHODS: One hundred forty-eight (148) individuals with colorectal cancer and 288 healthy persons were analyzed. Blood sampling of each group was performed by using a PCR- RFLP analysis, and MTHFR polymorphism genotypes of 677C/C, 677C/T, 677T/T, 1298AA, 1298AC, and 1298CC were obtained. RESULTS: The genotype frequencies of MTHFR C677T polymorphisms were 25.0% (CC), 48.0% (CT), 27.0% (TT), and 75.0% (CT+TT), respectively, in case patients and 39.2% (CC), 36.8% (CT), 24.0% (TT), and 60.8% (CT+TT) in controls. The genotype frequencies of MTHFR A1298C polymorphisms were 56.1% (AA), 372% (AC), 6.8% (CC), and 43.9% (AC+CC), respectively, in case patients and 55.6% (AA), 40.3% (AC), 4.2% (CC), and 44.4% (AC+CC) in controls. The 677TT and the 677CT genotypes were associated with significantly increased risks for colorectal cancer (adjusted OR=1.77 and 95% CI=1.02~3.04 in TT; adjusted OR=2.07 and 95% CI=1.28~3.35 in CT) than was the 677CC, genotype but the the 1298CC and 1298 AC genotypes were not associated with significantly increased risks for colorectal cancer (adjusted OR=1.75 and 95% CI= 0.71~4.26 in CC; adjusted OR=0.95 and 95% CI=0.62~1.45 in AC). CONCLUSIONS: The MTHFR C677T polymorphism may be influenced by colorectal cancer, but the role of the MTHFR A1298C polymorphism needs careful interpretation and confirmation in larger studies.