Association of genetic and epigenetic modification in MTHFR gene with coronary artery disease patients in North Indian population

Background: Methylene tetra hydro folate reductase (MTHFR) gene polymorphism C677T (rs180113) and DNA methylation in promoter region of MTHFR gene may contribute to the development of coronary artery disease however the results have been inconsistent across studies with different populations, so the aim of our study is to explore the association of polymorphism in MTHFR gene and methylation in promoter region with coronary artery disease (CAD) and other risk factor (lipid profile, homocysteine, vitamin B12 and folic acid levels) leading to CAD in of north Indian population. Methods: Total 100 CAD patients and 100 healthy controls were enrolled in the study. Genotyping of rs1801133 SNP (C677T) is done by PCR-RFLP and DNA methylation study in promoter region by methylation specific PCR. Lipid profile analysis by automated chemistry analyzers, serum homocysteine, folic acid and vitamin B12 was assayed by ELISA. Results: As per our finding the T allele (OR=3.03, 95% CI=1.74-5.27) and hyper methylation in promoter region of MTHFR increases the odds of coronary artery disease, (OR=3.05, 95% CI=1.7-5.6). Study participants with CT and TT genotype had significantly higher homocysteine (Hcy) (p=0.001), lower folic acid level (p=0.0), and HDL levels (p<0.0001) than those with CC genotype. The study subjects with hyper methylated promoter region have a significantly high homocystenemia levels (p=0.001). Conclusions: The TT genotype of the MTHFR C677T gene polymorphism and hyper methylation in promoter region of MTHFR, is associated with CAD and can be useful in identification of new biomarkers, development of preventive and therapeutic strategies for CAD.

Association of methylene tetrahydrofolate reductase gene mutation in unexplained recurrent pregnancy loss

Background: Recurrent pregnancy loss (RPL) without apparent causative factor which may be identified in about 50% of cases known as unexplained recurrent pregnancy loss. RPL is very distressing and can be heartbreaking for the couple. Among the many causes of RPL Methylene Tetrahydrofolate Reductase (MTHFR) gene mutation have been postulated as a possible cause. Aim of the study was to assess the association of methylene tetrahydrofolate reductase gene mutation (C677T and A1298C) in unexplained recurrent pregnancy loss.Methods: This was a case-control study conducted at the Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from May 2020 to April 2021. A total of 34 patients with unexplained recurrent pregnancy loss (RPL) and 34 age and BMI-matched controls were selected as study subjects. Data was analyzed using SPSS software, version 22.0.Results: The frequency of heterozygous mutant genotype of MTHFR C677T and A1298C was statistically significantly higher in the case group than the control (38.2% vs 5.9%, p=0.001 and 55.9% vs 11.8%, p=0.000 respectively). No homozygous mutation for MTHFR C677T and only 1 for A1298C in the case group was found. The mutant T allele for MTHFR C677T and Mutant C allele for A1298C were found more frequently in cases compared to the controls (19.1% vs. 2.9% and 30.9% vs. 5.9%). Both the differences were statistically significant (p=0.003 and 0.000 respectively). Compound heterozygous mutant genotype CT/AC was found in 20.6% of RPL patients and not was found in the control.Conclusions: MTHFR C677T and A1298C mutations pose a risk for unexplained recurrent pregnancy loss (RPL). Individuals with these mutations and a history of recurrent pregnancy loss may benefit from tailored management strategies, including low dose aspirin and low molecular weight heparin, to address potential risks.

Gene polymorphisms of CYP2C19,MTHFR,SLCO1B1 and APOE in acute cerebral infarction patients / 国际检验医学杂志

Objective To explore the distribution of CYP2C19,MTHFR,SLCO1B1,and APOE gene poly-morphisms in patients with acute cerebral infarction,so as to provide theoretical basis for individualized drug treatment.Methods A total of 400 patients with acute cerebral infarction admitted to the hospital from 2020 to 2022 were selected as the research subjects,and the polymorphisms of CYP2C19,MTHFR,SLCO1B1 and APOE genes were tested by PCR fluorescene probe method,and the polymorphism distribution of those genes was analyzed.Results In patients with acute cerebral infarction,44.25％of CYP2C19 gene phenotype were EM type,and 9.75％of CYP2C19 gene phenotype were PM type.The proportion of mutations at the C677T locus of the MTHFR gene(CT type+TT type)was 78.50％,CC type accounted for 21.50％.78.75％of the SLCO1B1 genotypes were type Ⅰ wild type,and 1.50％SLCO1B1 gene phenotypes were type Ⅲ homozygous mutant type.The E2 and E3 types accounted for 84.25％of the APOE gene phenotype,while the E4 type ac-counted for 15.75％.Conclusion The distribution of CYP2C19,MTHFR,SLCO1B1 and APOE gene poly-morphisms in 400 acute cerebral infarction patients is analyzed,providing data support for guiding individual-ized medication in the population of acute cerebral infarction patients and of great significance for achieving safe medication.

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)

Association of methylenetetrahydrofolate reductase ( MTHFR ) gene polymorphisms (C677T and A1298C) with thyroid dysfunction: A meta-analysis and trial sequential analysis

ABSTRACT 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.

Factores congénitos de los trastornos trombóticos arteriales en recién nacidos / Congenital factors of arterial thrombotic disorders in newborns

La trombosis arterial neonatal representa el 5,8% de todos los tipos de trombosis conocidos en recién nacidos, esto convierte a esta enfermedad en un punto de enfoque específico para su diagnóstico oportuno, y descifrar los factores congénitos de mayor recurrencia, se realizó una revisión sistemática PRISMA, donde se evaluaron 20 artículos de tipo observacional transversal, detallando los resultados obtenidos en cuanto al factor congénito más recurrente que en este caso es el sexo masculino, prematuridad y defectos genéticos se han mencionado además los marcadores bioquímicos y moleculares mayormente evaluados en esta muestra, demostrando que en estos casos los marcadores bioquímicos analizados con frecuencia son: antitrombina III, Proteína C y S, anticuerpos antifosfolípidos y homocisteína y como marcadores moleculares se evalúa con mayor recurrencia a: Factor V Leiden y el gen de la protrombina G20210A.

Factores congénitos de los trastornos trombóticos arteriales en recién nacidos / Congenital factors of arterial thrombotic disorders in newborns

La trombosis arterial neonatal representa el 5,8% de todos los tipos de trombosis conocidos en recién nacidos, esto convierte a esta enfermedad en un punto de enfoque específico para su diagnóstico oportuno, y descifrar los factores congénitos de mayor recurrencia, se realizó una revisión sistemática PRISMA, donde se evaluaron 20 artículos de tipo observacional transversal, detallando los resultados obtenidos en cuanto al factor congénito más recurrente que en este caso es el sexo masculino, prematuridad y defectos genéticos se han mencionado además los marcadores bioquímicos y moleculares mayormente evaluados en esta muestra, demostrando que en estos casos los marcadores bioquímicos analizados con frecuencia son: antitrombina III, Proteína C y S, anticuerpos antifosfolípidos y homocisteína y como marcadores moleculares se evalúa con mayor recurrencia a: Factor V Leiden y el gen de la protrombina G20210A.

Neonatal arterial thrombosis represents 5.8% of all known types of thrombosis in newborns, this makes this disease a specific point of focus for its timely diagnosis, and to decipher the congenital factors of greater recurrence, a systematic review PRISMA was performed, where 20 articles of cross-sectional observational type were evaluated, detailing the results obtained in terms of the most recurrent congenital factor which in this case is male sex, prematurity and genetic defects have also been mentioned biochemical and molecular markers mostly evaluated in this sample, showing that in these cases the biochemical markers frequently analyzed are: Antithrombin III, Protein C and S, antiphospholipid antibodies and homocysteine and as molecular markers are evaluated with greater recurrence to: Factor V Leiden and the prothrombin gene G20210A.

DNMT3B (rs2424913) polymorphism is associated with systemic lupus erythematosus alone and with co-existing periodontitis in a Brazilian population

Abstract The association between Periodontitis and Systemic Lupus Erythematosus (SLE) has been primarily based on their similar pathophysiology and both are associated with genetic polymorphisms. Objectives: To investigate an association between the methylation-related gene polymorphisms DNMT3B (rs2424913) and MTHFR (rs1801133) to Systemic Lupus Erythematosus (SLE) and Periodontitis. Methodology: In total, 196 individuals of all genders aged 24 to 60 years old were allocated into four groups based on their systemic and periodontal status, namely: Healthy control (n=60), periodontitis (n=51), SLE (n=47), and SLE + periodontitis (n=38). Individuals with SLE were stratified according to disease activity (SLEDAI) in inactive or active. We performed polymorphism analysis using PCR-RFLP with genomic DNA from mouthwash. We analyzed data using Fisher's Exact, Chi-square test, and regression models. Results: Periodontal status were similar in subjects with periodontitis alone and combined with SLE. SLE patients with periodontitis had a longer SLE diagnosis than SLE only (p=0.001). For DNMT3 B polymorphism, the periodontitis, SLE, and Inactive SLE + periodontitis groups showed a higher frequency of T allele and TT genotypes compared to healthy controls (p<0.05). Regression analyses showed that the TT genotype is a strong risk factor for periodontitis (OR=4.53; CI95%=1.13-18.05) and also for SLE without periodontitis (OR=11.57; CI95%=3.12-42.84) and SLE with periodontitis (OR=5.27; CI95%=1.25-22.11) when compared to control. Conclusion: SLE patients with periodontitis had a longer length of SLE diagnosis. The DNMT3B (rs2424913) polymorphism was associated with periodontitis and SLE alone or combined with periodontitis. Our study contributes to understanding the genetic mechanisms involved in periodontitis and SLE susceptibility.

Thromboelastogram parameters and MTHFR gene polymorphism in the diagnosis of adverse fetal pregnancy outcomes / 中国输血杂志

【Objective】 To retrospectively analyze the situation of patients with adverse fetal outcomes by thromboelastogram (TEG) parameters and, MTHFR gene polymorphism, so as to provide molecular biological diagnosis basis for patients with adverse pregnancy outcomes, and a new scheme for early prevention and treatment of women of childbearing age with MTHFR gene polymorphism. 【Methods】 A total of 100 women with adverse fetal pregnancy outcomes were selected as the adverse pregnancy group, and 100 healthy women of childbearing age with normal pregnancy history were selected as the controls. MTHFR gene C677T and A1298C polymorphisms were detected by polymerase chain reaction (PCR). TEG and blood coagulation were detected in the experimental group. 【Results】 The A1298C gene polymorphism(AA、CC、AC; A、C) was similar in both adverse pregnancy group and the controls. The frequency distribution of C, T allele of MTHFR gene C677T was statistically significant (χ2=4.60, P<0.05, OR =1.645, 95% CI: 1.042~2.595). TT and CT+ CC types showed significant different association with the factors of stillbirth(χ2 =7.49, P<0.05). MA value of TEG in the diagnosis of TT type of C677T genotypes MTHFR in 32 patients with adverse pregnancy outcome was analyzed. The area under the AUC curve of MA value was 0.795. 【Conclusion】 MTHFR C677T polymorphism TT with TEG parameter hypercoagulability is an important risk factor in the occurrence of pregnancy stillbirth in adverse pregnancy outcomes.

Trombosis senovenosa cerebral en un recién nacido con mutación MTHFR C677T tratado con enoxaparina / Cerebral sinovenous thrombosis in a newborn with mutation of MTHFR C677T treated with enoxaparin

Resumen: Introducción: La trombosis senovenosa cerebral neonatal (TSVC), es una patología rara y generalmente grave, de la cual se conoce poco sobre los mecanismos fisiopatológicos responsables y, aunque controvertido, se ha sugerido que la trombofilia genética, puede desempeñar un rol en la patogénesis. Debido a los temores de un sangrado intracraneal el tratamiento anticoagulante con heparina de bajo peso mole cular es controvertido. Objetivo: presentar un recién nacido con una trombosis senovenosa cerebral neonatal, discutir los factores de riesgo trombofílico, y el manejo con heparina de bajo peso molecu lar de la trombosis venosa cerebral. Caso Clínico: Recién nacido de término que debutó a los 8 días de vida con convulsiones clónicas, rechazo al pecho más hipoactividad motora. La neuroimagen con RM mostró una TSVC involucrando múltiples senos venosos, un infarto hemorrágico talámico dere cho y congestión venosa de la sustancia blanca frontal. El estudio de trombofilia puso de relieve una mutación homocigota del gen MTHFR C677T. El tratamiento con heparina de bajo peso molecular se asoció a repermeabilización del seno sagital superior a los 23 días de iniciada la terapia. Conclusio nes: La presentación clínica de la TSVC en el neonato es inespecífica, probablemente en relación con la extensión y gravedad de la lesión y el desarrollo de complicaciones asociadas, como infartos he morrágicos venosos intraparenquimatosos o hemorragia intraventricular. Estas complicaciones son detectables mediante Ecografia o Resonancia Magnética, y deben hacer sospechar una TSVC. En esta experiencia el tratamiento anticoagulante mostró ser seguro y prevenir la extensión de la trombosis.

Abstract: Introduction: Neonatal cerebral sinovenous thrombosis (CSNT) is a rare and generally serious con dition about which there is little knowledge of the responsible pathophysiological mechanisms and, although controversial, it has been suggested that genetic thrombophilia may play a role in its patho genesis. Out of concern for intracranial bleeding, the anticoagulant treatment with low-molecular- weight heparin is controversial. Objective: To present a case of a newborn with neonatal CSNT, to analyze the thrombophilic risk factors, and the management of cerebral venous thrombosis with low-molecular-weight heparin. Clinical Case: Full-term newborn who presented at eight days of life breastfeeding rejection, clonic seizures, and locomotor hypoactivity. The MRI neuroimaging showed a CSNT involving multiple venous sinuses, a right thalamic hemorrhagic infarction, and venous congestion in frontal white matter. Thrombophilia study highlighted a homozygous MTHFR C677T mutation. Treatment with low-molecular-weight heparin was associated with repermeabilization of the superior sagittal sinus after 23 days of starting therapy. Conclusions: The clinical presentation of CSNT in the neonate is nonspecific, probably related to the extent and severity of the injury and the development of associated complications, such as venous hemorrhagic infarctions and intraparenchymal or intraventricular hemorrhage. These complications are detected through ultrasound or MRI, and they should make us suspect a CSNT. In this experience, the anticoagulant treatment proved to be safe and prevents thrombus propagation.

Frecuencias genotípicas en Niños con Leucemia Linfoblástica Aguda en dos centros Oncológicos / Genotypic frequencies in Children with Acute Lymphoblastic Leukemia in two Oncology centers

Introducción: La leucemia linfoblásticaaguda (LLA) es una de las oncopatologías más frecuentes a nivel infantil, ocupando el primer lugar de los cincos tipos de cáncer con mayor incidencia en Ecuador. El objetivodel estudio fue determinar las frecuencias genotípicas y alélicas delos polimorfismos genéticos de MTHFR 677C>T (rs1801133) y MTHFR 1298A>C(rs1801131) en niños con leucemia linfoblástica aguda de SOLCA ­Loja y SOLCA ­Cuenca. Métodos:Es un estudio transversal, donde se evaluó a 160 pacientes pediátricosdiagnosticados con LLA. La detección de lospolimorfismos MTHFR 677C>T y 1298A>C se realizó mediante la técnica PCR entiempo real. El análisis estadístico descriptivo se desarrolló a través del software IBM SPSS (versión 22) y el programa bioinformático SNPStats. Resultados: Se determinóque las frecuencias genotípicas para el SNP MTHFR 677C>T fueron 25% C/C y 75%C/T con una frecuencia alélica del 38% para el alelo mutado (T). Para el SNP MTHFR1298 A>C se encontró una frecuencia genotípica de 2% A/A, 16% A/C y 82% C/C, entanto que su frecuencia alélica fue del 90% para el alelo mutado (C). No se encontróasociación genotípica ni alélica con ninguna de las variables intervinientes (p>0.05),así como tampoco se manifestó una correlación estadísticamente significativa de lospolimorfismos en mención y el tipo de riesgo de LLA. Conclusión:En la población estudiada con LLA, se evidenció para el SNP de MTHFR 677C>T una frecuencia genotípica del 75% para el heterocigoto C/T. Para el SNP MTHFR 1298A>C se encontró una frecuencia genotípica del 82% para el homocigoto mutado C/C. La distribución de la frecuencia alélica se mostró de la siguiente manera: para MTHFR 677C>T se obtuvo 38% para el alelo mutado T y en cuanto a MTHFR 1298 A>C, 90% correspondió para el alelo mutado C. En el análisis estadístico no se encontró asociación genotípica ni alélica con las variablesdemográficas y clínicas

Introduction:Acute lymphoblastic leukemia (ALL) is one of the most frequent oncopathologiesin childhood, occupying the first place of the five types of cancer with the highest incidence in Ecuador. The objective of the study was to determine the genotypic and allelic frequencies of the genetic polymorphisms of MTHFR 677C> T (rs1801133) and MTHFR 1298A> C (rs1801131) in children with acute lymphoblastic leukemia from SOLCA -Loja and SOLCA -Cuenca. Methods: It is a cross-sectional study, where 160 pediatric patients diagnosed with ALL were evaluated. The detection of MTHFR 677C> T and 1298A> C polymorphisms was performed using the real-time PCR technique. The descriptive statistical analysis was developed using the IBM SPSS software (version 22) and the SNPStats bioinformatics program. Results: It was determined that the genotype frequencies for the SNP MTHFR 677C> T were 25% C / C and 75% C / T with an allele frequency of 38% for the mutated allele (T). For the SNP MTHFR 1298 A> C, a genotype frequency of 2% A / A, 16% A / C and 82% C / C was found, while its allelic frequency was 90% for the mutated allele (C). No genotypic or allelic association was found with any of the intervening variables (p> 0.05), as well as no statistically significant correlation of the mentioned polymorphisms and the type of risk of ALL. Conclusion: In the population studied with ALL, a genotypic frequency of 75% was evidenced for the MTHFR 677C> T SNP for the heterozygous C / T. For the SNP MTHFR 1298A> C, a genotypic frequency of 82% was found for the homozygous mutated C / C. The allelic frequency distribution was shown as follows: for MTHFR 677C> T, 38% was obtained for the mutated allele T and for MTHFR 1298 A> C, 90% corresponded to the mutated allele C. In the statistical analysis No genotypic or allelic association was found with demographic and clinical variables

Hyperhomocystetenemia, MTHFR Mutation Presenting as Unprovoked Pulmonary Embolism.

Introduction: For MTHFR as with homocysteine testing,no official guidelines exist as to who should be tested.Homozygosity for the MTHFR C677T mutation has beenassociated with an increase in blood clotting together withplasma homocysteine increase and DVT occurrence risk.Case report: A 28 year young male patient presented withcomplaints of sudden onset breathlessness for 5 days. Theepisodes of breathlessness were associated with diffuseanterior chest pain. There was no history of leg pain, cough,sputum, hemoptysis, fever. No history of prior hospitalization,trauma, surgery and immobilization could be elicited from thepatient. He was a non smoker with no other comorbidities.On presentation his pulse rate was 120 per minute, respiratoryrate was 22 per minute, blood pressure 146/92 mm Hg,temperature 98.8 ° F, SpO2 of 94% at room air. His generalphysical examination was unremarkable.Conclusion: Although it has been observed that elevatedhomocysteine levels are a common finding in patientswith cardiovascular disease and thrombosis, its role in itspathogenesis is still under evaluation. Homozygosity forthe MTHFR C677T mutation has been associated withincreased homocysteine levels. Testing for this mutation is animportant parameter in thrombophilia workup of patients withunprovoked VTE.

Three Main Causes of Homocystinuria: CBS, cblC and MTHFR Deficiency. What do they Have in Common?

Abstract Genetic homocystinurias are a group of inborn errors of metabolism that result in the massive excretion of homocysteine (Hcy) in the urine due to Hcy accumulation in the body, usually causing neurological and cardiovascular complications. The three most frequent causes are classical homocystinuria [deficiency of cystathionine beta-synthase (CBS)], methylmalonic aciduria with homocystinuria, cblC type (cblC deficiency) and severe methylenetetrahydrofolate reductase (MTHFR) deficiency. In this review, we highlight the similarities and differences among these disorders. Briefly, their joint manifestation is the accumulation of tHcy, however, the other sulfur amino acids show various and even invers profiles. Vascular disease, developmental delay and seizures are found in all homocystinurias, nevertheless, the complications of CNS differ in a wide variety of presentations and severities and are apparently less pronounced in CBS deficiency. Moreover, patients with remethylation defects typically do not present ectopia lentis and bone disturbances, tall stature and osteoporosis. Whereas hematological alterations, such as megaloblastic anemia, thrombocytopenia neutropenia and life-threatening microangiopathy, are specific findings of cblC deficiency.

Correlation between methylenetetrahydrofolate reductase gene C677T polymorphism and plasma homocysteine levels and white matte hyperintensities: a meta-analysis / 国际脑血管病杂志

Objective To investigate the correlation between methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism and plasma homocysteine (Hcy) levels and white matte hyperintensities (WMHs). Methods PubMed, EMbase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Weipu and Wanfang databases were retrieved to search studies on correlation between MTHFR gene C677T polymorphism and plasma Hcy levels and WMHs. The search deadline was October 31, 2018. Stata 14.0 software was used for statistical analysis. Results Six eligible literatures on the correlation between MTHFR gene and WMHs were included. The results of meta-analysis showed that there was no significant correlation between MTHFR C677T gene polymorphism and WMHs in 5 genetic models (T allele vs. C allele, TC vs. CC genotype, TT vs. CC genotype, TT+TC vs. CC genotype, and TT vs. TC+CC genotype). A total of 22 eligible literatures on the correlation between plasma Hcy level and WMHs were included. The results of meta-analysis showed that the plasma Hcy levels in patients with WMHs were significantly higher than those in the control group (weighted mean difference 3.48, 95% confidence interval 2.36-4.60; Z=6.03, P<0.01). Conclusions There was no significant correlation between MTHFR gene C677T polymorphism and WMHs, and the elevated plasma Hcy levels may be a risk factor for WMHs.

Association study of MTHFR C677T polymorphism and birth body mass with risk of autism / 中华行为医学与脑科学杂志

Objective To explore the association of MTHFR C677T polymorphism and birth body mass with the vulnerability of autism in Chinese Han population. Methods Totally 1 505 children with au-tism have been recruited,using the diagnosis and statistical manual,4th revised version ( DSM-IV-R) diag-nostic criteria for autism. And 1 308 healthy control subjects sex matched with the children with autism were enrolled for the study. All the participants were identified the birth body mass ( kg) according to the birth medical recording. All the subjects were examined the MTHFR C677T genotypes,using the polymerase chain reaction- restrict fragment length polymorphism (PCR-RFLP) methods. The frequencies of genotypes,alleles and birth body mass were compared between autism and healthy control groups using the chi-square and other tests. Results The MTHFR C677T (P=0. 004,OR=1. 18,95% CI=1. 02-1. 29),low birth body mass (<2. 5 kg) (P=0. 001,OR=1. 04,95%CI=1. 02-1. 06),and their interactive effects ( P=0. 0001,OR=2. 18,95%CI=1. 44-3. 32) were associated with the vulnerability of autism. Conclusions The MTHFR C677T polymorphism,low birth body mass and their interactive effects might be associated with susceptibility of autism in Chinese Han population.

Analysis for polymorphism of MTHFR C677T gene in Han population in Beijing / 临床检验杂志

Objective@#To explore the distribution characteristics of MTHFR gene polymorphism of Chinese Han population in Beijing, and analyze the differences of distribution of MTHFR gene polymorphism between Beijing area and the other parts of northern China. @*Methods@#MTHFR C677T gene was detected by PCR-gold magnetic particles chromatography. The distribution characteristics of MTHFR gene polymorphism of 3 945 healthy subjects from September 2014 to May 2018 detected in Peking Union Medical College Hospital were analyzed retrospectively. The distribution of MTHFR gene polymorphism in Chinese Han population in Beijing area was compared with the Han population of the other area from northern China by reviewing domestic and foreign literature databases. @*Results@#The frequencies of CC, CT and TT genotype of MTHFR C677T gene in the male population undergoing physical examination in Beijing were 23.3%, 50.5% and 26.2%, respectively, and the frequencies of C and T allele frequencies were 48.6% and 51.4%, respectively. The frequencies of CC, CT and TT genotype of MTHFR C677T gene in the female population were 22.7%, 49.4% and 27.9%, respectively, and the C and T allele frequencies were 47.4% and 52.6%, respectively. There was no difference in genotype frequency and allele freaaency between male and femal (P＞0.05). The frequencies of CC, CT and TT genotypes and allele frequencies of MTHFR C677T gene in the population of Beijing area were significantly different from those of Heilongjiang, Jilin, Hebei, Shandong and Henan provinces (P＜0.01). @*Conclusion@#There was no significant difference of polymorphism distribution of MTHFR C677T gene between male and female populations in Beijing. The distinct distribution characteristics of MTHFR gene in Beijing area should be presented.

Association of Bone Turnover Levels with MTHFR Gene Polymorphisms among Pregnant Women in Wuhan, China / 华中科技大学学报（医学）（英德文版）

Pregnancy is a critical stimulator of bone mineral resorption.We used to find the MTHFR gene polymorphisms are related with blood lead levels among pregnant women.Pregnancy-stimulated bone turnover may be associated with MTHFR gene polymorphisms too.In this article,we aimed to determine the relationship between MTHFR gene polymorphisms and bone turnover rates among the pregnant women.The participants including pregnant and non-pregnant women were selected and recruited during their routine prenatal or physical examination from July to October in 2012.A total of 1000 participants,including 250 pregnant women in the first,second,and third trimesters and 250 non-pregnant women,were enrolled in the study.Finally,after excluding 27 participants unable to provide blood samples,973 eligible participants (i.e.,234,249,and 248 pregnant women in the first,second,and third trimesters,respectively,and 242 non-pregnant women)were included in the research.The MTHFR gene 1298CC homozygote carriers were more susceptible to yield higher plasma homocysteine levels than the 1298AA/AC carriers,with standardized coefficients of 0.086 (P＜0.05) and 0.104 (P＜0.01) of all the participants and the pregnant women,respectively.The MTHFR gene 1793AA homozygote carriers more likely showed higher plasma osteocalcin levels (standardized β=0.091,P＜0.01) than the 1793GG/GA carriers among all the subjects.Plasma homocysteine levels were positively correlated with blood lead levels among the participants and the pregnant women with standardized coefficients of 0.320 (P＜0.01) and 0.179 (P＜0.01),respectively.Plasma osteocalcin levels were positively associated with blood lead levels among pregnant and non-pregnant women with standardized coefficients of 0.084 (P＜0.05) and 0.125 (P＜0.01),respectively.In conclusion,homocysteine and osteocalcin contents in plasma are associated with the MTHFR gene A1298C polymorphism and blood lead levels among pregnant women.The MTHFR gene A 1298C polymorphism-related homocysteine is a possible risk factor for increased blood lead levels among Chinese women.

Association of Bone Turnover Levels with MTHFR Gene Polymorphisms among Pregnant Women in Wuhan, China / 华中科技大学学报（医学）（英德文版）

Pregnancy is a critical stimulator of bone mineral resorption.We used to find the MTHFR gene polymorphisms are related with blood lead levels among pregnant women.Pregnancy-stimulated bone turnover may be associated with MTHFR gene polymorphisms too.In this article,we aimed to determine the relationship between MTHFR gene polymorphisms and bone turnover rates among the pregnant women.The participants including pregnant and non-pregnant women were selected and recruited during their routine prenatal or physical examination from July to October in 2012.A total of 1000 participants,including 250 pregnant women in the first,second,and third trimesters and 250 non-pregnant women,were enrolled in the study.Finally,after excluding 27 participants unable to provide blood samples,973 eligible participants (i.e.,234,249,and 248 pregnant women in the first,second,and third trimesters,respectively,and 242 non-pregnant women)were included in the research.The MTHFR gene 1298CC homozygote carriers were more susceptible to yield higher plasma homocysteine levels than the 1298AA/AC carriers,with standardized coefficients of 0.086 (P＜0.05) and 0.104 (P＜0.01) of all the participants and the pregnant women,respectively.The MTHFR gene 1793AA homozygote carriers more likely showed higher plasma osteocalcin levels (standardized β=0.091,P＜0.01) than the 1793GG/GA carriers among all the subjects.Plasma homocysteine levels were positively correlated with blood lead levels among the participants and the pregnant women with standardized coefficients of 0.320 (P＜0.01) and 0.179 (P＜0.01),respectively.Plasma osteocalcin levels were positively associated with blood lead levels among pregnant and non-pregnant women with standardized coefficients of 0.084 (P＜0.05) and 0.125 (P＜0.01),respectively.In conclusion,homocysteine and osteocalcin contents in plasma are associated with the MTHFR gene A1298C polymorphism and blood lead levels among pregnant women.The MTHFR gene A 1298C polymorphism-related homocysteine is a possible risk factor for increased blood lead levels among Chinese women.

Prevalence of the MTHFR C677T Mutation in Fertile and Infertile Women / Prevalência da mutação MTHFR C677T em mulheres férteis e inférteis

Abstract Introduction The importance of the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene in infertile women remains controversial. Objective To evaluate if the MTHFR C677T mutations are more frequent in infertile women, and if they can be associated with the occurrence of infertility in the Brazilian population. Methods This case-control study included 130 infertile women consulting at a private clinic betweenMarch 2003 andMarch 2005 (data previously published), and 260 fertile women attending the family planning outpatient clinic of our institution between April 2012 and March 2013. Data analysis The Chi-squared and Fisher Exact tests were used to evaluate the association between the presence of the MTHFR C677T mutation and a history of infertility. Results The frequency of the mutation was of 58.5% for the case group (n = 76) and of 49.2% for the fertile controls (n = 128). The mutation was homozygous in 13 women in the case group (10%) and in 23 of the fertile women in the control group (8.8%). These differences were not statistically significant. Conclusions These results suggest that the presence of the MTHFR C677T mutation does not constitute a risk factor for infertility, even when themutation is homozygous. Further studies are needed to confirm whether research on this mutation should be considered unnecessary in women with infertility.

Resumo Introdução A importância da mutação C677T no gene da metilenotetrahidrofolato redutase (MTHFR) em mulheres com infertilidade permanece controversa. Objetivo Avaliar se a mutação MTHFR C677Témais frequente em mulheres inférteis, e se pode ser associada com a ocorrência de infertilidade na população brasileira. Métodos Estudo de caso-controle, com avaliação de 130 mulheres com infertilidade atendidas em clínica privada no período de março de 2003 a março de 2005 (dados previamente publicados) e 260 mulheres férteis atendidas no ambulatório de planejamento familiar de nossa instituição no período de abril de 2012 a março de 2013. Análise dos dados Foram utilizados os testes de Qui-quadrado e Exato de Fisher para o estudo da associação entre a presença damutação MTHFR C677T e o antecedente de infertilidade. Resultados A frequência da mutação foi de 58,5% nos casos (n = 76) e de 49,2% nos controles (n = 128). Dentre os casos, 13 apresentavam esta mutação em homozigose (10%). Nos controles, a homozigose foi encontrada em 23 mulheres férteis (8,8%). Estas diferenças não foram estatisticamente significativas. Conclusões Este estudo sugere que a presença da mutação MTHFR C677T não constitui fator de risco para infertilidade, mesmo em casos de homozigose. Estudos complementares são necessários para ratificar se a investigação desta mutação deve ser considerada desnecessária em mulheres com infertilidade.

Polimorfismos en los genes MTHFR e IL-10 y factores de riesgo en pacientes con cáncer gástrico del municipio de San José de Cúcuta, Colombia / Polymorphisms in MTHFR and IL-10 Genes and Risk Factors in Patients with Gastric Cancer in the Municipality of San José de Cúcuta, Colombia

Introducción: el cáncer gástrico es una de las neoplasias de mayor interés en el mundo por su incidencia y mortalidad asociada. Se consideran tres factores relacionados con la ocurrencia del carcinoma gástrico: infección por Helicobacter pylori, susceptibilidad genética del huésped y factores ambientales. Objetivo: evaluar los polimorfismos C677T, A592C y T819C y factores de riesgo en pacientes con cáncer gástrico del municipio San José de Cúcuta. Métodos: aplicación de encuestas para detectar factores de riesgo, determinación de infección por Helicobacter pylori, genotipificación de polimorfismos mediante PCR-RFLP y análisis estadístico. Resultados: el análisis de factores de riesgo en los pacientes del grupo de casos mostró un consumo de tabaco, alcohol, y sal en el 68,8%, e infección por Helicobacter pylori de 75%; se determinó que el 68,8% tenían antecedentes familiares de cáncer y el 75% enfermedades gástricas preexistentes. El grupo control presentó un consumo de alcohol y tabaco inferior al de los pacientes del grupo de casos, alto consumo de verduras (64%) y valor similar de infección por Helicobacter pylori (80%). El análisis del polimorfismo C677T mostró mayor frecuencia en los pacientes del grupo de casos y grupo control para el alelo salvaje; los polimorfismos A592C y T819C presentaron mayor frecuencia del alelo mutado en los pacientes del grupo de casos y grupo control. El polimorfismo C677T no evidenció asociación significativa con la probabilidad de cáncer gástrico. Los polimorfismos A592C y T819C no registraron diferencias significativas entre los pacientes del grupo de casos y grupo control. Conclusión: aunque no se observaron diferencias significativas en las variantes genéticas, al evaluar los factores ambientales se detectaron distintos patrones entre los pacientes del grupo de casos y grupo control, lo cual probablemente explicaría la ausencia de la enfermedad en individuos sanos.

Introduction: gastric cancer is one of more concern neoplasms around the world due to its incidence and associated mortality. Helicobacter pylori infection, host genetic susceptibility and environmental factors are considered the causes of gastric carcinoma occurrence. Objective: to evaluate the C677T, A592C and T819C polymorphisms and risk factors in patients with gastric cancer in the municipality of San José de Cúcuta. Methods: application of surveys for determining risk factors, detection of serologic response to H. pylori infection, genotyping of polymorphisms using PCR-RFLP and statistical analysis. Results: the analysis of risk factors in the cases showed consumption of tobacco, alcohol, and salt in 68.8% and H. pylori infection in 75% of cases; 68.8% had a family history of cancer and 75% had preexisting gastric disease. The control population had lower consumption of alcohol and tobacco comparing to the cases group, high consumption of vegetables (64%) and similar value of H. pylori infection (80%). Analysis of the C677T polymorphism revealed predominance of the wild-type allele in both cases and controls with no evidence of association with the developing of gastric cancer; the polymorphisms A592C and T819C presented higher frequency of the mutated allele in both groups, with no significant differences between cases and controls. Conclusions: although no significant differences were observed in the genetic variants, different patterns were detected between cases and controls regarding the evaluation of environmental factors, which would probably explain the absence of the disease in healthy individuals.