MTHFR 677C>T (rsRS1801133) variant is associated with hyperhomocysteinemia but not with clinical severity in patients with peripheral arterial disease / A variante MTHFR 677C>T (RS1801133) está associada a hiperhomocisteinemia, mas não a gravidade clínica em pacientes com doença arterial periférica

Abstract Background The MTHFR 677C>T variant's involvement with hyperhomocysteinemia and peripheral arterial disease (PAD) is still unclear. Objectives To evaluate associations between the MTHFR 677C>T (rs1801133) variant and susceptibility to and severity of PAD and homocysteine (Hcy) levels. Methods The study enrolled 157 PAD patients and 113 unrelated controls. PAD severity and anatomoradiological categories were assessed using the Fontaine classification and the Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC), respectively. The variant was genotyped using real-time polymerase chain reaction and Hcy levels were determined using chemiluminescence microparticle assay. Results The sample of PAD patients comprised 60 (38.2%) females and 97 (61.8%) males. Patients were older and had higher Hcy than controls (median age of 69 vs. 45 years, p<0.001; and 13.66 µmol/L vs. 9.91 µmol/L, p=0.020, respectively). Hcy levels and the MTHFR 677C>T variant did not differ according to Fontaine or TASC categories. However, Hcy was higher in patients with the CT+TT genotypes than in those with the CC genotype (14.60 µmol/L vs. 12.94 µmol/L, p=0.008). Moreover, patients with the TT genotype had higher Hcy than those with the CC+CT genotypes (16.40 µmol/L vs. 13.22 µmol/L, p=0.019), independently of the major confounding variables. Conclusions The T allele of MTHFR 677C>T variant was associated with higher Hcy levels in PAD patients, but not in controls, suggesting a possible interaction between the MTHFR 677C>T variant and other genetic, epigenetic, or environmental factors associated with PAD, affecting modulation of Hcy metabolism.

Resumo Contexto O envolvimento da variante MTHFR 677C>T na hiperhomocisteinemia e na doença arterial periférica (DAP) ainda não está claro. Objetivos Avaliar a associação da variante MTHFR 677C>T (rs1801133) com suscetibilidade e gravidade da DAP e valores séricos de homocisteína (Hcy). Métodos Este estudo caso-controle envolveu 157 pacientes com DAP e 113 controles não relacionados. A gravidade e as categorias anatomorradiológicas da DAP foram avaliadas pela classificação de Fontaine e pelo Inter-Society Consensus for the Management of Peripheral Arterial Disease, respectivamente. A genotipagem foi realizada por meio de reação em cadeia da polimerase em tempo real, e os valores de Hcy foram determinados por ensaio de micropartículas de quimioluminescência. Resultados Entre os pacientes com DAP, 97 (61,8%) eram homens e 60 (38,2%) eram mulheres, com mediana de idade de 69 anos. Os pacientes com DAP eram mais velhos e apresentaram valores mais elevados de Hcy do que os controles (mediana de 69 vs. 45 anos de idade, p < 0,001; 13,66 µmol/L vs. 9,91 µmol/L, p = 0,020, respectivamente). Os valores de Hcy foram mais elevados em pacientes com os genótipos CT+TT do que aqueles com o genótipo CC (14,60 µmol/L vs. 12,94 µmol/L, p = 0,008). Além disso, os pacientes com o genótipo TT apresentaram valores mais elevados de Hcy do que aqueles com os genótipos CC+CT (16,40 µmol/L vs. 13,22 µmol/L, p = 0,019, respectivamente), independentemente das principais variáveis confundidoras. Conclusões O alelo T da variante MTHFR 677C>T foi associado a valores mais elevados de Hcy nos pacientes com DAP, mas não em controles, sugerindo uma possível interação entre a variante genética MTHFR 677C>T e outros fatores genéticos, epigenéticos ou ambientais associados com a DAP na modulação do metabolismo da Hcy.

Prevalence of thrombophilia-associated genetic risk factors in blood donors of a regional hospital in southern Brazil

ABSTRACT Introduction: Thromboembolic events occur due to an imbalance in the hemostasis and some factors associated with this condition can be inherited. In order to evaluate the frequency of genotypes considered to be common hereditary risk factors for thrombophilia associated with venous thrombosis (g.1691G>A and g.20210G>A) and hyperhomocysteinemia (g.677C>T and g.1298A>C), samples from voluntary healthy blood donors at the Hospital de Clínicas de Porto Alegre were tested. Methods: We examined 325 blood samples from blood donors collected from October 2017 to July 2018. Blood was collected on filter paper and the DNA was extracted for single nucleotide polymorphisms (SNPs) analysis using the qualitative real time polymerase chain reaction. Results: The calculated frequencies of each genetic variant in heterozygosity were 4% for the FV gene (g.1691G> A), 4% for the F2 gene (g.20210G> A) and 42% and 39% for methylenetetrahydrofolate reductase (MTHFR), g.677C>T and g.1298A>C, respectively. Only the genetic variants of MTHFR were found in homozygosity, with frequencies of 14% and 6% (g.677C>T and g.1298A>C), respectively. Discussion: Altogether, these results describe the frequencies of genetic variants associated with venous thrombosis and hyperhomocysteinemia in the analyzed group and are important to enhance our current knowledge about the genetic profiles of Brazilian blood donors.

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.

Correlation between deep venous thrombosis of lower extremity and methylenetetrahydrofolate reductase C677T / 国际外科学杂志

Objective:To investigate the mechanism of methyltetrahydrofolate reductase ( MTHFR) C677T polymorphism in the pathogenesis of lower extremity deep vein thrombosis (DVT). Methods:Used retrospective controlled study method, a total of 64 DVT patients (DVT group) and 96 healthy people (control group) were enrolled in the Affiliated Hospital of Traditional Chinese Medicine, Xinjiang Medical University from August 2019 to August 2021. Clinical manifestations and related detection, including D-dimer, fibrinogen, prothrombin time, prothrombin activity and prothrombin time-international normalized ratio of the subjects were recorded, and plasma homocysteine (Hcy) and soluble endothelial cell protein C receptor (sEPCR) were detected by enzyme linked immunosorbent assay (ELISA). The polymorphism of C677T locus of MTHFR gene was detected by polymerase chain reaction-restricted fragment length polymor-phism (PCR-RFLP), and the differences of blood indexes and MTHFR genotypes between the two groups were compared. Measurement data with normal distribution were represented as mean ± standard deviation ( ± s), and comprison between groups was conducted using the t-test; the skewness data were expressed by M( Q1, Q3), and rank-sum test was used for inter-group comparison. comprison between groups of count data was conducted using the chi-square test or Fisher exact probability. Results:Compared with the control group, DVT group showed more symptoms of limb skin redness, limb swelling, skin temperature rise, local tenderness, skin rupture, skin tension, pigmentation, limb movement and sensory disturbance, the difference were statistically significant ( P<0.05); the prothrombin time-international normalized ratio [0.98(0.95, 1.04) vs 1.05(1.00, 1.13)], fibrinogen [2.76(2.31, 3.30) mg/L vs 3.36(2.74, 4.35) mg/L], D-dimer [0.52(0.38, 0.62) mg/L vs 4.73(2.44, 12.05) mg/L], Hcy[(1 639.03±390.29)ng/mL vs (2 423.03±631.95) ng/mL] and sEPCR [(108.62±25.07) ng/mL vs (137.79±26.23) ng/mL] in DVT group were significantly higher than those in control group, the difference were statistically significant ( P<0.05); the prothrombin activity [90.70% (75.80%, 100.00%) vs 103.00%(93.00%, 112.50%)] was significantly lower than that of the control group, the difference was statistically significant ( P<0.05). Compared with the control group, CC, CT, TT genotype frequency and allele frequency of MTHFR C677T site in DVT group showed a trend of change, but the difference were not statistically significant ( P>0.05). Conclusion:TT mutation at MTHFR C677T site in patients with DVT has an increasing trend, which may promote the expression level of Hcy, and high expression of Hcy and sEPCR can induce the occurrence and development of DVT.

Thylenetetrahydrofolate reductase gene polymorphisms and susceptibility to esophageal cancer: a case-control study / Polimorfismos do gene metilenotetrahidrofolato redutase e suscetibilidade ao câncer de esôfago: estudo caso-controle

ABSTRACT 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.

RESUMO RACIONAL: A enzima metilenotetrahidrofolato redutase está envolvida na síntese de DNA através do metabolismo do folato. A inibição da sua atividade aumenta a suscetibilidade a mutações, danos e metilação aberrante do DNA, o que altera a expressão gênica de supressores tumorais e proto-oncogenes, potenciais fatores de risco para câncer de esôfago. OBJETIVOS: Investigar a associação entre os polimorfismos metilenotetrahidrofolato redutase 677C>T e metilenotetrahidrofolato redutase 1298A>C e a suscetibilidade ao câncer de esôfago, avaliando a distribuição de genótipos e haplótipos entre casos e controles, bem como investigar a associação de polimorfismos com características clínicas, epidemiológicas e sobrevida. MÉTODOS: Avaliaram-se 109 pacientes com câncer de esôfago submetidos à esofagectomia, enquanto 102 indivíduos constituaram o grupo controle. O DNA genômico do sangue periférico foi isolado e submetido à amplificação por reação em cadeia da polimerase em tempo real. A associação entre os polimorfismos e o risco de desenvolver câncer de esôfago foi avaliada por regressão logística. RESULTADOS: Não houve associação dos polimorfismos e haplótipos metilenotetrahidrofolato redutase 677C>T e metilenotetrahidrofolato redutase 1298A>C com a suscetibilidade ao câncer de esôfago. Pacientes com câncer de esôfago portadores do polimorfismo metilenotetrahidrofolato redutase 677TT apresentaram maior risco de morte pela doença. Para o genótipo TT homozigoto polimórfico, o risco de morte aumentou significativamente em comparação com os casos do genótipo selvagem metilenotetrahidrofolato redutase 677CC (referência) (p=0,045; RR=2,22, IC95% 1,02-4,83). CONCLUSÕES: Não houve associação entre os polimorfismos metilenotetrahidrofolato redutase 677C>T e metilenotetrahidrofolato redutase 1298A>C e o risco de suscetibilidade ao câncer de esôfago. O genótipo homozigoto polimórfico metilenotetrahidrofolato redutase 677TT associou-se a um maior risco de óbito após tratamento cirúrgico para câncer de esôfago.

Study on the relationship between recurrent spontaneous abortion and methylene tetrahydrofolate reductase, plasminogen activator inhibitor-1 gene polymorphism and serum folate concentration in pregnant women of appropriate age / 中国综合临床

Objective:To investigate the association between recurrent spontaneous abortion (RSA) and methylenetetrahydrofolate reductase (MTHFR) and plasminogen activator inhibitor-1 (PAI-1) gene polymorphism in pregnant women of appropriate age, and to observe the difference of the serum concentration of patients with different MTHFR genotypes after taking different does of folic acid.Methods:A prospective case-control study was conducted, one handred and eleven pregnant women with a history of unexplained RSA and gestation less than 12 weeks who visited the Department of Obstetrics and Gynecology of Xuancheng People's Hospital of Anhui Province from January 2019 to June 2021 were enrolled into the RSA group, and 100 normal women of childbearing age in the same area with no history of abortion were included in the control group. After venous blood was extracted, the polymorphisms of MTHFR gene C677T, A1298C PAI-1 and the serum folic acid concentration were detected.The comparison between the measurement data groups with normal distribution adopts t-test, and the counting data adopts t-test χ 2 test, Logistic regression analysis was used for multivariate analysis. Results:The genotype and allele of MTHFR C677T (CC:21.62%(24/111) and 51.00%(51/100), TT: 28.83%(32/111) and 12%(12/100)) and allele (C: 46.40%(103/222) and 69.50% (139/200), T: 53.60%(119/222) and 30.50%(61/200)) and PAI-1 (5G5G: 22.52%(25/111) and 48.00%(48/100), 4G4G: 44.14%(49/111)and 16.00%(16/100); 5G: 39.19%(87/222) and 66.00%(132/200), 4G: 60.81%(135/222) and 34.00%(68/200)) were significantly different (χ 2 values were 21.82, 22.96 and 23.51, 30.30; all P <0.001) between the RSA group and control group. Logistic analysis showed that MTHFR C677T ( OR=0.477, 95% CI 0.303-0.750) and PAI-1 genotype ( OR=0.451, 95% CI 0.306-0.665) were closely related to recurrent abortion ( P=0.001 and P<0.001). There were no significant differences in genotype and allele of MTHFR A1298C between the two groups ( P values were 0.270 and 0.149).There was no significant difference in serum concentration of folic acid between the two groups ( P=0.355 for 0.4 mg folic acid and P=0.786 for 0.8 mg or more folic acid) at the same dose of folic acid. Conclusion:The occurrence of recurrent spontaneous abortion in women of childbearing age may be related to MTHFR C677T and PAI-1 site mutation, and may not be related to MTHFR A1298C site mutation.

Correlation between Serum Homocysteine Level, MTHFR Gene Polymorphism and Patients with Hematological Diseases Complicated with Coronary Heart Disease / 中国实验血液学杂志

OBJECTIVE@#To observe the expression level of serum homocysteine (Hcy) and methylenetetrahydrofolate reductase (MTHFR) gene polymorphism in patients with hematological diseases complicated with coronary heart disease, and analyze the relationship between serum Hcy level, MTHFR gene polymorphism and coronary heart disease.@*METHODS@#The medical records of 80 patients with coronary heart disease who completed treatment of hematological diseases during the period from March 2018 to March 2020 were selected as observation group. In addition, the medical records of 92 patients with hematological diseases who completed treatment in our hospital during the same period were selected as control group. Venous blood samples of the two groups were collected to detect serum Hcy level and MTHFR gene polymorphism. The serum Hcy levels of the two groups with different MTHFR genotypes were compared, and the effects of the above indicators on hematological diseases complicated with coronary heart disease were analyzed.@*RESULTS@#The detection rates of MTHFR gene TT and TC in the observation group were higher than those in the control group, while the distribution frequency of MTHFR genotype CC was lower (P<0.05). The serum Hcy levels of the patients with MTHFR genotype TT and TC in the observation group was higher than the control group (P<0.05). Binary logistic regression analysis showed that MTHFR gene TC/CC genotype serum Hcy overexpression may be influencing factor which induced coronary heart disease in patients with hematological diseases (OR=2.107/OR=1.634, P<0.05). ROC curves showed that the AUC of serum Hcy level of MTHFR gene TC/CC genotype and hematological disease complicated with coronary heart disease were both > 0.8. When MTHFR gene TC reaching the optimal threshold of 22.165 μmol/L, the sensitivity was 0.950 and the specificity was 0.837, While MTHFR gene CC reached the optimal threshold of 19.630 μmol/L, the sensitivity was 0.938 and the specificity was 0.826, the best predictive value could be obtained.@*CONCLUSION@#The changes of serum Hcy and MTHFR gene polymorphisms may be involved in the pathological process in patients with hematological diseases complicated with coronary heart disease. In the future, early detection of serum Hcy levels and MTHFR gene polymorphisms in patients with hematological diseases can be used to predict the risk of coronary heart disease.

Association between MTHFR gene polymorphism and primary hypertension in children / 中国当代儿科杂志

OBJECTIVES@#To study the distribution characteristics of methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism in children with primary hypertension, and to explore the association between MTHFR C677T gene polymorphism and H-type hypertension in children.@*METHODS@#A total of 121 children with primary hypertension who were hospitalized in the department of cardiovascular medicine from January to July 2021, newly diagnosed, and untreated were retrospectively selected as the subjects. The children were divided into three groups: CC genotype (19 children), CT genotype (51 children), and TT genotype (51 children). According to the serum homocysteine (Hcy) level, they were divided two groups: H-type hypertension (47 children) and simple hypertension (74 children). The medical data were compared between the groups. The association between MTHFR C677T gene polymorphism and H-type hypertension was evaluated.@*RESULTS@#The mutation frequency of T allele in children with primary hypertension was significantly higher than that in healthy adults in Beijing and Chinese Han adults (P<0.001). The serum Hcy level in the TT genotype group was significantly higher than that in the CC and CT genotype groups (P<0.001). The serum Hcy level in the H-type hypertension group was significantly higher than that in the simple hypertension group (P<0.001), and MTHFR C677T was mostly TT genotype, which was associated with the risk of H-type hypertension (OR=12.71, P<0.001). There was no significant difference in the incidence rate of target organ damage between the H-type hypertension and simple hypertension groups (P>0.05). However, multiple organ involvement was observed in the H-type hypertension group at diagnosis, accounting for 11% (5/47).@*CONCLUSIONS@#The mutation rate of MTHFR C677T T allele in children with primary hypertension is high and associated with the serum Hcy level. TT genotype is an independent risk factor for H-type hypertension in children, and it may be related to the severity of early target organ damage.

Correlation between MTHFR gene C677T polymorphism, homocysteine and early neurological deterioration in Han population with acute ischemic stroke in Chengdu area / 国际脑血管病杂志

Objective:To investigate the correlation between methylenetetrahydrofolate reductase (MTHFR) gene polymorphism and early neurological deterioration (END) in Han population with acute ischemic stroke in Chengdu area, and the interaction with other traditional risk factors.Methods:Consecutive Han patients with acute ischemic stroke admitted to the Department of Neurology, the Third People's Hospital of Chengdu from January 2017 to June 2019 were enrolled prospectively. Using the candidate gene association study method, MTHFR gene C677T polymorphism was used as a genetic marker to analyze the correlation between END and MTHFR gene polymorphism, and analyze the interaction of gene-END traditional risk factors.Results:A total of 434 patients with acute ischemic stroke were enrolled in the study, and 129 had END (29.7%). Multivariate logistic regression analysis showed that hyperglycemia (odds ratio [ OR] 2.410, 95% confidence interval [ CI] 1.436-4.046; P<0.001), hyperhomocysteinemia ( OR 2.570, 95% CI 1.229-5.376; P=0.012) and moderate to severe neurological deficit (baseline National Institutes of Health Stroke Scale score >5) ( OR 2.158, 95% CI 1.337-3.484; P=0.002) at admission were independently correlated with END. There was a correlation between C677T polymorphism and END. TT genotype ( OR 1.710, 95% CI 1.021-2.863; P=0.002) and A allele ( OR 1.583, 95% CI 1.181-2.121; P=0.002) could significantly increase the risk of END. Interaction analysis showed that there was interaction effect between C677T polymorphism and hyperglycemia at admission, alcohol drinking and moderate to severe neurological deficit. Interaction could increase the risk of END, but it did not reach statistical significance ( OR 1.237, 95% CI 0.227-6.734; P=0.806). Conclusion:MTHFR gene C677T polymorphism and hyperhomocysteinemia are associated with END in Han population with acute ischemic stroke in Chengdu area.

Homocisteína y trastornos neurocognitivos. ¿Una luz al final del túnel? / Homocysteine and neurocognitive disorders. A light at the end of the tunnel?

El deterioro cognitivo es uno de los procesos que acompañan al envejecimiento y puede depender de factores nutricionales, genéticos o ambientales. La identificación de factores de riesgo modificables proporciona un enfoque esencial para la prevención de dicho deterioro y de los trastornos neurocognitivos. Uno de los factores de riesgo involucrados es la elevada concentración de homocisteína plasmática, la cual se ha relacionado con hallazgos histopatológicos en demencia senil y enfermedad de Alzheimer. Los diferentes estudios sobre esta asociación revelan inconsistencia o contradicción en los resultados. El propósito de esta revisión es relacionar la posible interacción de tres factores en la instalación y progresión del deterioro neurocognitivo: a) factores de tipo nutricional (homocisteína, ácido fólico y vitamina B12), b) la utilización de pruebas para el diagnóstico de disfunción o deterioro cognitivo como el Mini Examen del Estado Mental, y c) la presencia de variantes genéticas polimórficas de la enzima metilentetrahidrofolato reductasa. Una consecuencia directa de esta triple relación es que el tratamiento con ácido fólico y vitamina B12 logra disminuir las elevadas concentraciones de homocisteína plasmática, asumiendo que una mejoría en los síntomas clínicos de deterioro cognitivo puede retrasar los cambios relacionados con progresión a estados demenciales. La intervención temprana mediante políticas de promoción y prevención de la salud mental puede ser efectiva si se comienza con la administración de ácido fólico y vitamina B12 en los estadios iniciales de la alteración cognitiva, logrando así reducir sus funestas consecuencias. Las políticas de salud pública centradas en la salud mental de ancianos pueden identificar a las personas con disfunción cognitiva inicial a través de la promoción de la salud y medidas preventivas; en esta etapa puede ser posible la administración de vitaminas B para reducir o minimizar la progresión del deterioro cognitivo, que podría conducir a trastornos neurocognitivos como la demencia y la enfermedad de Alzheimer

Cognitive impairment is one of the processes that accompany aging and may depend on nutritional, genetic or environmental factors. The identification of modifiable risk factors provides a crucial approach for the prevention of cognitive decline and neurocognitive disorders. One of the risk factors is the high concentration of plasma homocysteine and it has been associated to histopathological changes in senile dementia and Alzheimer´s disease. Clinical trials about this association has shown inconsistent and contradictory results. The purpose of this review is to describe the possible interaction of three factors related with cognitive impairment: a) nutritional factors (homocysteine, folic acid and vitamin B12), b) the use of mental tests such as the Mini Mental State Examination for the diagnosis of cognitive dysfunction, and c) the presence of polymorphic genetic variants of the methylenetetrahydrofolate reductase enzyme. A direct consequence of this triple relationship is the treatment with folic acid and vitamin B12, which decrease high concentrations of plasma homocysteine, with a potential for improvement of the clinical symptoms of cognitive decline, and possibly a delay in the progression towards neurocognitive disorder. Public health policies focused on mental health of older adults can identify people with initial cognitive dysfunction through health promotion and preventive measures, where it can be possible to administer B vitamins in order to reduce or minimize the progression of cognitive decline, that could lead to mental disturbances such as neurocognitive disorders

Hematotoxicity Correlation of MTHFR Gene Polymorphism with High-dose of Methotrexate in Hematological Neoplasm Patients ：A Meta-analysis / 中国药房

OBJECTIVE：To systematically evaluate the c orrelation of methylenetetra hydrofolate reductase （MTHFR）C677T and A 1298C gene polymorphisms with blood system adverse events induced by high-dose of methotrexate （HDMTX）. METHODS ： Retrieved from Medline ，Embase，Clinical Trials.gov ，CNKI，Wanfang database ，CBM，cohort studies about MTHFR gene polymorphism in hematological neoplasm treated by HDMTX were collected from inceptions to March 2018. After data extraction of included literatures ，quality evaluation with Newcastle Ottawa scale ，Meta-analysis was performed for adverse events of blood system induced by HDMTX in different genetic models with Rev Man 5.3 software. RESULTS ：Totally 25 cohort studies were included，23 studies of which were related to MTHFR C677T site （including 1 858 patients）and 16 studies related to MTHFR A1298C site （including 1 088 patients）. Results of Meta-analysis showed that MTHFR C677T mutation type significantly increased the risk of hematotoxicity [TT/CT vs. CC ：OR＝1.57，95％CI（1.12，2.20），P＝0.009；TT vs. CT/CC ：OR＝2.19，95％CI（1.49， 3.23），P＜0.001；T vs. C ：OR＝1.34，95％CI（1.03，1.74）， P＝0.03] and severe hematotoxicity [TT/CT vs. CC ：OR＝m 2.33，95％CI（1.43，3.81），P＜0.001]，including leukopenia [TT/CT vs. CC ：OR＝1.37，95％CI（1.02，1.82），P＝0.03]， severe leukopenia [TT/CT vs. CC ：OR＝1.63，95％CI（1.03， 010-82265810。E-mail：zhao_rongsheng@163.com 2.56），P＝0.04]，severe gra nulopenia [TT/CT vs. CC ：OR＝ ·2.26，95％CI（1.50，3.39），P＜0.001]. The mutation genotypes of MTHFR A1298C significantly decreased the risk of severe hematotoxicity [CC/AC vs. AA ：OR＝0.17，95％CI（0.04，0.76），P＝0.02]，including leukopenia [CC/AC vs. AA ：OR＝0.68， 95％CI（0.48，0.97），P＝0.03；CC vs. AC/AA ：OR＝0.28，95％CI（0.14，0.59），P＜0.001] and severe leukopenia [CC/AC vs. AA：OR＝0.43，95％CI（0.19，0.97），P＝0.04]. CONCLUSIONS ：Among patients with hematological neoplasms ，MTHFR C677T mutation may significantly increase the risk of hematotoxicity by HDMTX including the risk of leukopenia and granulopenia ；while MTHFR A1298C may reduce the risk of hematotoxicity by HDMTX ，including the risk of leukopenia.

Distributions of MTHFR C677T gene polymorphism among cerebral stroke patients in southern Anhui province / 中国临床药理学与治疗学

AIM: To investigate and analyze the distribution characteristic of 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism among cerebral stroke patients and to provide prevention and treatment for stroke patients in southern Anhui Province. METHODS: A total of 114 patients with cerebral stroke in the Second Affiliated Hospital of Wannan Medical College from January 2018 to October 2019 were included. The MTHFR C677T genotype was performed by fluorescence in situ hybridization analysis. The MTHFR C677T gene polymorphism distribution data of the cerebral stroke population in southern Anhui Province was compared with the reported gene distribution data of Han Chinese stroke population in other parts of China. RESULTS:The frequencies distribution of TT, CT and CC genotypes of MTHFR C677T were 28.90%, 50.00%, 21.10%. The frequencies of C and T alleles were 53.95% and 46.05%. There was no gender difference in the distribution of this gene. There were significant difference in CC genotype between Chongqing area, Heilongjiang area and Guangzhou area (P<0.05). There were significant difference in TT genotype between Chongqing area, northern Henan area and Heilongjiang area (P<0.05). CONCLUSION: The distribution of MTHFR C677T gene polymorphism in the Han population of southern Anhui Province is different from other areas. It can provide a scientific basis for the prevention and treatment of cerebral stroke in high-risk population in southern Anhui Province by genetic testing technology.

Intrauterine upper limb thrombosis: an unusual presentation

Intrauterine thrombosis with extremity ischemia presenting at birth in a newborn is a rare event. A 29 year old mother, 2nd gravida with one first trimester spontaneous abortion delivered a 33week gestation male preterm baby. On Examination, the entire left upper limb was ischemic and edematous with an absent flow on Doppler USG. Low molecular weight heparin (LMWH) was started after which gradually the limb turned pink with good volume pulsations. Thrombophilia mutation studies revealed the heterozygous state for the MTHFR (C677T) mutation only in the mother. Prompt diagnosis and early treatment has a favourable outcome in cases of intra-uterine thrombo-embolism.

Association of methylenetetrahydrofolate reductase gene rs1801133 polymorphism with lung cancer risk / 第二军医大学学报

[Abstract] Objective To explore the association between methylenetetrahydrofolate reductase (MTHFR) rs1801133 polymorphism and lung cancer risk. Methods This case-control study included 974 lung cancer patients and 1 005 healthy controls living in Shanghai and Taizhou, Jiangsu Province. After collecting the peripheral blood samples of the participants, the whole blood genomic DNA was extracted for MTHFR gene rs1801133 genotyping. The effect of rs1801133 on lung cancer susceptibility was analyzed through unconditional logistic regression analysis. Results Compared with CC genotype, MTHFR rs1801133 CT and TT genotypes significantly decreased lung cancer risk (odds ratio [OR]＝0.801, 95% confidence interval [CI]: 0.651-0.985, P＝0.035; OR＝0.754, 95% CI: 0.582-0.975, P＝0.032), but this association became insignificant after adjusting age, gender, smoking status, and family cancer history (OR＝0.841, 95% CI: 0.677-1.045, P＝0.118; OR＝0.799, 95% CI: 0.609-1.047, P＝0.104). However, in dominant model, CT＋TT genotypes exhibited a significantly reduced lung cancer risk in males (OR＝0.764, 95% CI: 0.597-0.977, P＝0.032) and those with a family cancer history (OR＝0.600, 95% CI: 0.385-0.925, P＝0.022), and a significantly reduced risk for having squamous cell carcinoma (OR＝0.727, 95% CI: 0.542-0.976, P＝0.033). Conclusion The MTHFR gene rs1801133 CT mutation might reduce the risk of lung cancer in males and those with a family history of cancer, especially those with squamous cell carcinoma.

Correlation between methylenetetrahydrofolate reductase gene polymorphism and Methotrexate toxicity in pediatric acute lymphoblastic leukemia in southern Fujian / 中华实用儿科临床杂志

Objective@#To explore the association between methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C gene polymorphisms and toxicity of Methotrexate(MTX) chemotherapy in pediatric acute lymphoblastic leukemia (ALL).@*Methods@#From January 2015 to June 2018, 128 pediatric patients with ALL in southern Fujian who were admitted at the First Affiliated Hospital of Xiamen University were selected.Their peripheral blood 2 mL was collected and genomic DNA was extracted.The MTHFR genotype was detected by polymerase chain reaction(PCR) direct sequencing method, and the clinical significance of HD-MTX on ALL children with toxic and side effects was evaluated according to the National Cancer Institute-Common Toxicity Criteria.@*Results@#Among 128 children, 54 cases(42.2%) presented rash, 48 cases (37.5%)with mucosal lesions, 51 cases (39.8%) with liver function damage, 23 cases (18.0%) with renal function damage, 52 cases (40.6%) with gastrointestinal reactions, 38 cases (29.7%)with leukopenia, 34 cases (26.6%) with thrombocytopenia and 63 cases (49.2%) with hemoglobin reduction.There was no significant difference in the incidence of MTX adverse reactions (rash, mucosa lesions, liver and renal function damage, gastrointestinal reaction, leukopenia, hemoglobin decrease and thrombocytopenia) between the MTHFR C677T and A1298C polymorphisms (all P>0.05). The different clinical risk (MTX dose) of the children was not statistically signi-ficant in the MTHFR C677T and A1298C genotypes and allele frequencies (χ2=2.573, 2.264, 1.615, 0.267; all P>0.05). There was no significant difference among the abnormal incidence of MTX at 24 h, 48 h and 72 h (all P>0.05).@*Conclusions@#MTHFR C677T and A1298C polymorphisms do not seem to be good markers of MTX-related toxicity and/or outcome in pediatric ALL in southern Fujian, and its clinical application still needs further discussion.

Correlation betWeen methylenetetrahydrofolate reductase gene polymorphism and Methotrexate toxicity in pediatric acute lymphoblastic leukemia in southern Fujian / 中华实用儿科临床杂志

Objective To explore the association between methylenetetrahydrofolate reductase( MTHFR) C677T and A1298C gene polymorphisms and toxicity of Methotrexate(MTX)chemotherapy in pediatric acute lympho-blastic leukemia(ALL). Methods From January 2015 to June 2018,128 pediatric patients with ALL in southern Fu-jian who were admitted at the First Affiliated Hospital of Xiamen University were selected. Their peripheral blood 2 mL was collected and genomic DNA was extracted. The MTHFR genotype was detected by polymerase chain reaction(PCR) direct sequencing method,and the clinical significance of HD-MTX on ALL children with toxic and side effects was evaluated according to the National Cancer Institute-Common Toxicity Criteria. Results Among 128 children,54 cases (42. 2% )presented rash,48 cases(37. 5% )with mucosal lesions,51 cases(39. 8% )with liver function damage,23 ca-ses(18. 0% )with renal function damage,52 cases(40. 6% )with gastrointestinal reactions,38 cases(29. 7% )with leu-kopenia,34 cases(26. 6% )with thrombocytopenia and 63 cases(49. 2% )with hemoglobin reduction. There was no significant difference in the incidence of MTX adverse reactions(rash,mucosa lesions,liver and renal function damage, gastrointestinal reaction,leukopenia,hemoglobin decrease and thrombocytopenia ) between the MTHFR C677T and A1298C polymorphisms(all P>0. 05). The different clinical risk(MTX dose)of the children was not statistically signi-ficant in the MTHFR C677T and A1298C genotypes and allele frequencies( χ2 =2. 573,2. 264,1. 615,0. 267;all P>0. 05). There was no significant difference among the abnormal incidence of MTX at 24 h,48 h and 72 h(all P>0. 05). Conclusions MTHFR C677T and A1298C polymorphisms do not seem to be good markers of MTX-related toxicity and/or outcome in pediatric ALL in southern Fujian,and its clinical application still needs further discussion.

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.

Research Progress of Folate Metabolic Gene Polymorphism / 医药导报

Through summarizing and analyzing a large number of documents and reports of large academic conferences in China, the current situation and the prospect of individualized drug delivery model were analyzed based on folate metabolic gene in pharmaceutical care. Folate metabolic genemethylenetetrahydrofolate reductase (MTHFR) C677T and methionine synthase reductase (MTRR) A66G were related with development of multiple diseases. Its polymorphism guidesindividualized drug administrationto increase the efficacy of drugs or decrease adverse effects.

The relationship between of ACE I/D and the MTHFR C677T polymorphisms in the pathophysiology of type 2 diabetes mellitus in a population of Brazilian obese patients

ABSTRACT Objectives This study aimed to evaluate the frequencies of the angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) and methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphisms in obese patients with and without type 2 diabetes mellitus (T2DM). Subjects and methods These polymorphisms were analyzed by polymerase chain reaction in 125 patients with obesity, 47 (T2DM) and 78 (Control Group). Results No significant difference was found on comparing the T2DM and Control Groups in respect to the genotypic frequencies of the polymorphisms - (II: 13.3% vs. 12.0%; ID: 37.8% vs. 37.3; DD: 48.9% vs. 50.7%; CC: 36.2% vs. 39.0%; CT: 46.8% vs. 49.3%; TT: 17.0% vs. 11.7%), and alleles (I: 32.2% vs. 30.7%; D: 67.8% vs. 69.3%; C: 59.6% vs. 63.6%; T: 40.4% vs. 36.4%) and their synergisms in the pathophysiology of T2DM. On analyzing the T2DM Group, there were no significant differences in the presence of complications. In this population of Brazilian obese patients, no correlation was found between the ACE and MTHFR polymorphisms in the development of T2DM. Conclusion Analyzing only the group with diabetes, there was also no relationship between these polymorphisms and comorbidities.

Polymorphism of MTHFR C677T gene and MTHFR A1298C gene among physical examinees in Taizhou City / 预防医学

Objective To explore the distribution of methylenetetrahydrofolate reductase (MTHFR) C677T gene and MTHFR A1298C gene polymorphism among 1644 physical examinees in Taizhou region. Methods Fluorescence quantitative PCR method was used to detect MTHFR C677T and MTHFR A1298C genotype in 1644 physical examinees from Taizhou Central Hospital from September 2016 to September 2017. According to the characteristics of gender, the distribution features of MTHFR C677T and MTHFR A1298C genotype were described, and then were compared with data about the physical examinees in other cities in China. Results Among the 1644 physical examinees, MTHFR 677CC, 677CT and 677TT genotype frequency were 40.09％, 44.53％and 15.39％ respectively and MTHFR 677 allele frequency was 37.65％. MTHFR 1298AA, 1298AC and 1298CC genotype frequency were 65.69％, 30.47％ and 3.83％ respectively and MTHFR 1298 allele frequency was 19.07％. Statistical significance was found in genotype distribution of MTHFR C677T between males and females (P=0.036), and no statistical significance was found in genotype distribution of MTHFR A1298C between males and females (P=0.278) . As compared with the physical examinees in Henan, Wulumuqi and Beijing regions, there were statistically significance differences in the distribution of MTHFR C677T genotype and allele frequencies in Taizhou region (P <0.05) . Conclusion The distribution of MTHFR C677T gene polymorphism among physical examinees in Taizhou region is affected by gender, and the results shows certain regional specificity.