Association of maternal MTHFD1 and MTHFD2 gene polymorphisms with congenital heart disease in offspring / 中国当代儿科杂志

OBJECTIVES@#To study the association of maternal methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) gene polymorphisms with congenital heart disease (CHD) in offspring.@*METHODS@#A hospital-based case-control study was conducted. The mothers of 683 children with CHD alone who attended Hunan Children's Hospital, from November 2017 to March 2020 were enrolled as the case group, and the mothers of 740 healthy children who attended the same hospital during the same period and did not have any deformity were enrolled as the control group. A questionnaire survey was performed to collect related exposure data, and then venous blood samples (5 mL) were collected from the mothers to detect MTHFD1 and MTHFD2 gene polymorphisms. A multivariate logistic regression analysis was used to evaluate the association of MTHFD1 and MTHFD2 gene polymorphisms with CHD. The four-gamete test in Haploview 4.2 software was used to construct haplotypes and evaluate the association between haplotypes and CHD. The generalized multifactor dimensionality reduction method and logistic regression analysis were used to examine gene-gene interaction and its association with CHD.@*RESULTS@#The multivariate logistic regression analysis showed that maternal MTHFD1 gene polymorphisms at rs11849530 (GA vs AA: OR=1.49; GG vs AA: OR=2.04) andat rs1256142 (GA vs GG: OR=2.34; AA vs GG: OR=3.25) significantly increased the risk of CHD in offspring (P<0.05), while maternal MTHFD1 gene polymorphisms at rs1950902 (AA vs GG: OR=0.57) and MTHFD2 gene polymorphisms at rs1095966 (CA vs CC: OR=0.68) significantly reduced the risk of CHD in offspring (P<0.05). The haplotypes of G-G-G (OR=1.86) and G-A-G (OR=1.35) in mothers significantly increased the risk of CHD in offspring (P<0.05). The gene-gene interaction analyses showed that the first-order interaction between MTHFD1 rs1950902 and MTHFD1 rs2236222 and the second-order interaction involving MTHFD1 rs1950902, MTHFD1 rs1256142, and MTHFD2 rs1095966 might be associated with risk of CHD (P<0.05).@*CONCLUSIONS@#Maternal MTHFD1 and MTHFD2 gene polymorphisms and their haplotypes, as well as the interaction between MTHFD1 rs1950902 and MTHFD1 rs2236222 and between MTHFD1 rs1950902, MTHFD1 rs1256142, and MTHFD2 rs1095966, are associated with the risk of CHD in offspring.

Association of a Polymorphism in the Gene Encoding Methylenetetrahydrofolate Dehydrogenase 1 (MTHFD1) 1958G> A with Orofacial Cleft

ABSTRACT Objective: To evaluate the possible association of a polymorphism in the gene encoding methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), 1958G>A, with the susceptibility to orofacial cleft in an Indonesian population. Material and Methods: A total of 200 stored secondary biological samples from 30 cases of orofacial cleft and 170 unaffected controls were analyzed to determine the polymorphism status at base 1958. The analysis was conducted using the PCR-restriction fragment length polymorphism technique after digestion with the Msp1 restriction enzyme. The samples were then subjected to agarose gel electrophoresis to investigate the presence or absence of the following fragments: genotype GG, 196, 86 and 40 base pairs (bp); genotype AA, 282 and 28 bp and genotype AG, 282, 196, 86, 40 and 28 bp. The test groups were compared using the Chi-square test. Results: The wild-type allele containing 1958G, as well as the genotype GG, were significantly more common in the control group than in the orofacial cleft group. Conclusion: The MTHFD1 1958G>A polymorphism was significantly associated with orofacial cleft susceptibility in the tested Indonesian population.

LncRNA Taurine-Upregulated Gene 1 Promotes Cell Proliferation by Inhibiting MicroRNA-9 in MCF-7 Cells / 한국유방암학회지

PURPOSE: This study was designed to investigate the role of taurine-upregulated gene 1 (TUG1) in MCF-7 breast cancer cells and the molecular mechanism involved in the regulation of microRNA-9 (miR-9). METHODS: The expression of TUG1 in breast cancer tissues and cells was evaluated using quantitative reverse transcription polymerase chain reaction. Cell viability was examined using a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay; cell cycle progression and apoptosis were analyzed using flow cytometry. A dual luciferase reporter assay was used to detect the relationship between TUG1 and miR-9. The expression of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) was measured by western blot. RESULTS: Higher expression of TUG1 was observed in breast cancer tissues and cell lines than in the corresponding controls. TUG1 knockdown reduced proliferation, suppressed cell cycle progression, and promoted apoptosis of MCF-7 cells. The dual luciferase reporter assay showed that TUG1 could negatively regulate the expression of miR-9. MiR-9 inhibition abrogated the effect of TUG1 knockdown on the proliferation, cell cycle progression, and apoptosis of MCF-7 cells. TUG1 positively regulated the expression of MTHFD2 in breast cancer cells. CONCLUSION: TUG1 knockdown was significantly associated with decreased cell proliferation and it promoted apoptosis of breast cancer cells through the regulation of miR-9.

Carcinogênese de cabeça e pescoço: impacto do polimorfismo MTHFD1 G1958A / Head and neck carconogenesis: impact of MTHFD1 G1958A polymorphism

OBJETIVO: Investigar o polimorfismo MTHFD1 G1958A envolvido no metabolismo do folato no risco para o câncer de cabeça e pescoço e verificar a associação entre esse polimorfismo com fatores de risco e características clínico-histopatológicas. MÉTODOS: Estudo retrospectivo que avaliou o polimorfismo MTHFD1 G1958A em 694 indivíduos (240 pacientes e 454 controles), por meio da técnica de análise de polimorfismo de comprimento de fragmento de restrição. Para análise estatística foram utilizados os testes de regressão logística múltipla e qui-quadrado. RESULTADOS: Tabagismo e idade superior a 42 anos foram preditores da doença (p < 0,05). Os genótipos MTHFD1 1958GA ou AA foram associados ao tabagismo (p = 0,04) e etilismo (p = 0,03) e estão presentes em maior proporção em tumores com estádios mais avançados (p = 0,04) e em pacientes com menor sobrevida (p = 0,03). CONCLUSÃO: A presença do polimorfismo MTHFD1 G1958A associada aos hábitos tabagista e etilista aumenta o risco para desenvolvimento de câncer de cabeça e pescoço.

OBJECTIVE: To investigate the MTHFD1 G1958A polymorphism involved in the folate metabolism as a risk for head and neck cancer, and to find the association of the polymorphism with the risk factors and clinical and histopathological characteristics. METHODS: Retrospective study investigating MTHFD1 G1958A polymorphism in 694 subjects (240 patients in the Case Group and 454 in the Control Group) by Restriction Fragment Length Polymorphism (RFLP) Analysis. Multiple logistic regression and chi-square tests were used in the statistical analysis. RESULTS: Multivariable analysis showed that smoking and age over 42 years were disease predictors (p < 0.05). MTHFD1 1958GA or AA genotypes were associated with smoking (p = 0.04) and alcoholism (p = 0.03) and were more often found in more advanced stage tumors (p = 0.04) and in patients with a shorter survival (p = 0.03). CONCLUSION: The presence of MTHFD1 G1948A polymorphism associated with smoking and alcoholism raises the head and neck cancer risk.

Association of coronary artery disease with polymorphisms of angiotensin-converting enzyme and methylenetetrahydrofolate reductase gene.

OBJECTIVE: Angiotensin-converting enzyme plays an important role in maintaining blood pressure, while methylenetetrahydrofolate reductase is involved in homocysteine metabolism. As hypertension and elevated homocysteine levels are among the various risk factors for coronary artery disease, the two polypeptides might need to be considered while determining the risk. Our study aimed to assess the association between common polymorphisms in these genes and susceptibility to coronary artery disease. METHODS: We studied 268 north Indian individuals with coronary artery disease and 90 age-matched controls. The distribution of the genotypes and allele frequencies of both genes were analyzed using polymerase chain reaction amplification and restriction fragment length polymorphism analysis. RESULTS: The frequency of the D allele was significantly higher among the patients (62%) than the controls (44%) (p=0.001, odds ratio=2.06). The same goes for the DD genotype (37% vs 21%) (p=0.004). The combined frequency of the D allele carriers was significantly higher among patients of coronary heart disease, with a difference of 20% (85% vs 65%) (p=0.003, odds ratio=3.1; CI: 1.3-7.29). However, the frequency of the T and C alleles, as well as that of the CC, CT and TT genotypes of the methylenetetrahydrofolate reductase gene, did not differ significantly between the two groups. CONCLUSION: We conclude that coronary artery disease in north Indian patients is strongly associated with the carrier state of the angiotensin-converting enzyme D allele, but not with the C677T transition in the methylenetetrahydrofolate reductase gene.

C677T polymorphism of the 5,10-Methylenetetra-hydrofolate reductase [MTHFR] gene as a risk factor for neural tube defects among Egyptian families

Methylenetetrahydrofolate reductase [MTHFR] deficiency leads to impairment in folate metabolism and is implicated as a risk factor for neural tube defects [NTDs]. C677T MTHFR polymorphism is associated with NTDs, in some populations. Although the prevalence of this mutation has been reported from various ethnic populations, no data concerning Egyptian are available. C677T polymorphism was analyzed by PCR-RFLP. The frequencies of the C677T MTHFR polymorphism was determined in 35 case mothers, 19 case fathers and 9 children with NTDs compared with healthy 30 matched controls. In addition, allele and genotype frequencies were classified into different groups according to offspring NTD phenotype, consanguinity of the parents and number of affected offspring with NTD and or abortion. The prevalence of the polymorphic, homozygous [T/T] and heterozygous [C/T] C677T MTHFR genotypes were 6.3% and 38.1%, respectively, giving an allele frequency of 0.25. We observed increased frequency of heterozygotes of MTHFR in NTDs mothers versus the control although, C677T allele frequency was 0.28 in controls. Consanguinity rate was 45.7% among our families but it seems unlikely that it had an additional effect on the heterozygosity of the mutant genotype in this sample. In conclusion, neither homozygosity nor heterozygosity for the C677T polymorphism in the MTHFR gene constitute a genetic risk factor in the total NTDs but could be a risk of spina bifida aperta in this sample of Egyptian families. It is noteworthy to mention that this is the first report from Egypt evaluating the relationship between MTHFR677C>T and NTD

molecular study of methylenetetrahyrofolate reductase gene in mothers of standard down syndrome patients

The observation that a lot of children with Down syndrome are born to mothers with young age made it important to identify the mechanisms involved in this young age group. It was found that DNA hypomethylation is associated with chromosomal instability and abnormal chromosome segregation. This knowledge led to the clarification of the role of enzymes involving in the methylation reaction like Methylene Tetrahydrofolate Reductase enzyme [MTHFR]. The C-T common polymorphism at nucleotide 677 [C677T], which results into an alanine to valine substitution in the MTHFR protein, caused higher thermolability and reduced enzyme activity in lymphocyte extracts. In order to verify this association, we studied the presence of the C677T polymorphism of the MTHFR gene in 50 mothers of Down syndrome children and 50 control mothers. A non-significant higher incidence of the mutant T allele in Down syndrome children mothers [6%] than in control [2%] was detected. These results do not support the presence of an increased risk of Down syndrome mothers carriers of the T allele in Egyptian population

Relationship between polymorphism of methylenetetrahydrofolate dehydrogenase and congenital heart defect / 生物医学与环境科学（英文）

<p><b>OBJECTIVE</b>To investigate the relationship between G1958A gene polymorphism of methylenetetrahydrofolate dehydrogenase (MTHFD) and occurrence of congenital heart disease (CHD) in North China.</p><p><b>METHODS</b>One hundred and ninety-two CHD patients and their parents were included in this study as case group in Liaoning Province by birth defect registration cards, and 124 healthy subjects (age and gender matched) and their parents were simultaneously selected from the same geographic area as control. Their gene polymorphism of MTHFD G1958A locus was examined with PCR-RFLP, and serum folic acid and homocysteine (Hcy) levels were tested with radio-immunoassay and fluorescence polarization immunoassay (FPIA).</p><p><b>RESULTS</b>There existed gene polymorphism at MTHFD G1958A locus in healthy subjects living in North China. The percentages of GG, GA, and AA genotype were 57.98%, 35.57%, and 6.45% respectively, and the A allele frequency was 24.23%, which was significantly different from Western population. No difference was observed when comparing genotype distribution and allele frequency between the case and control groups, so was the result from the comparison between genders. The A allele frequency of arterial septal defect patients' mothers (10.87%) was significantly lower than that of controls (28.15%) (P=0.014), with OR=0.31 (95% CI: 0.09-0.84), and no difference in the other subgroups. The percentage of at least one parent carrying A allele in arterial septal defect subgroup (43.48%) was significantly lower than that in controls (69.64%) (P=0.017), with OR=0.34 (95% CI: 0.12-0.92). The analysis of genetic transmission indicated that there was no transmission disequillibrium in CHD nuclear families. Their serum folic acid level was significantly higher than that of controls (P=0.000), and Hcy level of the former was higher than that of the latter with no statistical significance (P>0.05). Serum Hcy and folic acid levels of mothers with gene mutation were lower than those of mothers with no mutation.</p><p><b>CONCLUSION</b>No significant difference of genotype distribution and allele frequency existed between CHD patients and healthy population. MTHFD G1958A mutation in parents (particularly in mother) can decrease the risk of arterial septal defect in offspring. The possible mechanism of protection might be mutation, which can increase MTHFD enzyme activity, folic acid metabolism and homocysteine remethylation, and decrease Hcy level.</p>

Frequência dos polimorfismos dos genes do TNF alfa e da MTHFR em um grupo de pacientes leucêmicos da cidade de Salvador - BA / Frequency of TNT-Alpha and MTHFR gene polymorphisms in a group of leukemia patients in Salvador, Brazil

As leucemias são neoplasias hematológicas decorrentes do desequilíbrio entre as taxas de proliferação, maturação e apoptose das células hematopoéticas, comumente associadas com polimorfismos gênicos. Polimorfismos nos genes do TNFalfa e da enzima MTHFR têm sido associados como fatores de susceptibilidade para diversas patologias, inclusive neoplasias hematológicas. O presente estudo investigou a freqüência do polimorfismo -308 da região promotora no gene do TNFalfa, cuja variante genotípica AA está associada a níveis de transcrição elevados da citocina, e dos polimorfismos C677t e A1298C no gene da MTHFR, que estão associados com atividade enzimática reduzida. Para investigação dos polimorfismos foi utilizada a técnica de PCR-RFLP. Foram estudados 94 pacientes leucêmicos, sendo 66 portadores de LMC e 28 de LMA-M3, além de 100 indivíduos da população de Salvador. Dos 66 pacientes com LMC. Cinco (7,6 por cento) foram homozigotos para a variante genotípica menos comum (AA) do polimorfismo -308 do TNF. Essa freqüência foi de 3,7 por cento entre os 28 portadores de LMA-M3 e de 3,0 por cento entre os indivíduos do grupo populacional. Dentre os portadores de 66 LMC, dois (3,0 por cento) foram homozigotos para a variante TT do polimorfismo C677T da MTHFR, sendo que foi encontrada freqüência de 7,1 por cento entre os portadores de LMA-M3 e de 6,0 por cento para o grupo populacional. Para o polimorfismo A1298C da MTHFR, as freqüências encontradas para a variante CC foram de 4,5 por cento entre os 66 portadores de LMC, 3,6 entre os 28 portadores de LMA-M3 e 5,0 por cento entre os indivíduos do grupo populacional. Diante dos resultados obtidos, concluímos que os polimorfismos -308 (TNF alfa), bem como C677T e A1298(MTHFR) parecem não interferir diretamente com os mecanismos de patogênese da LMC e LMA-M3.

Defectos de cierre del tubo neural: mecanismos y prevención / Neural tube closure defects: pathogenic mechanisms and prevention

Esta revisión crítica abarca los datos recientemente publicados sobre causas, mecanismos de desarrollo y tácticas de prevención para los defectos de cierre del tubo neural (DCTN). La enzima 5,10-metilenetetrahidrofolato reductasa (MTHFR), codificada por el gen con mutación C677T o A1298C, resulta ser termolábil. Como causa de DCTN, se discute la acción teratogénica de la hipertermia, ya que la variante termolábil de la MTHFR disminuye su capacidad con el aumento de la temperatura. La MTHFR termolábil podría influir en el proceso de selección natural, explicando la ausencia o baja frecuencia de personas homocigotas por la mutación C677T dentro de poblaciones nativas de áreas con altas temperaturas ambientales. La exposición de la sangre de los capilares de la capa papiliforme de la dermis a la radiación ultravioleta, puede propiciar la fotólisis del ácido fólico. Se proponen las medidas que podrían ayudar a disminuir la ocurrencia de DCTN en México.

Hiperhomocist(e)inemia / Hyperhomocyst(e)inemia

A través de numerosos datos derivados de observaciones epidemiológicas y experimentales, se ha establecido que existe una correlación positiva entre la hiperhomocist(e)inemia (HH(e)) y las enfermedades vasculares. Los datos clínicos confirman que la homocisteína (Hcy) es un factor de riesgo independiente de afecciones arteriales oclusivas (coronaria, cerebrovascular y periféricovascular) así como también trombosis venosa periférica. Este aminoácido contiene un sulfhidrilo y se forma por la desmetilación de la metionina. Es normalmente catalizado a cistationina por la enzima cistationina ß-sintetasa (CBS), dependiente de fosfato de piridoxal. Homocisteína también es remetilada a metionina por las enzimas 5-metiltetrahidrofolato-Hcy metiltransferasa (metionina sintetasa), dependiente de vitamina B12 y betaína-Hcy metiltransferasa. Estados nutricionales tales como deficiencias en vitamina B12, vitamina B6 o folato y defectos genéticos de las enzimas CBS o 5,10-metilentetrahidrofolato reductasa, pueden contribuir al aumento de los niveles plasmáticos de Hcy. La patogénesis del daño vascular inducido por Hcy puede ser multifactorial: daño directo sobre el endotelio, aumento de la peroxidación de lipoproteínas de baja densidad, incremento de tromboxano A2 plaquetario o menor activación de la proteína C. En el presente trabajo, se describen los más recientes estudios acerca de la patogénesis de la HH(e) y las implicancias para una óptima terapia