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.

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.

Associations of plasma homocysteine level and MTHFR gene C677T polymorphism with white matter lesions in Chinese Han population / 国际脑血管病杂志

Objeetive To investigate the associations of plasma homocysteine (Hcy) level and methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism with white matter lesion (WML) in a Chinese Han population.Methods A toal of 104 patients with WML and 74 controls were recruited.Hcy level and MTHFR gene C677T polymorphism were determined.The degree of severity of the WML was evaluated using a modified Scheltens scale.Results The plasma Hcy level (median and interquartile range,16.81 [11.33-18.92] μmol/L vs.11.40 [8.28-14.23] μmol/L;Z =5.415,P =0.001) and the proportion (85.6％ vs.54.1％;x2 =28.535,P ＜ 0.001) of patients with hyperhomocysteinemia (HHcy) in the WML group were significantly higher than those in the control group.However,there were no significant differences in the frequencies of C677T genotype (x2 =1.255,P =0.534) and allele (x2 =1.057,P =0.304).There are 89 patients with HHcy and 15 patient with normal Hcy in 104 patients with WML.The modified Scheltens scale score in the HHcy subgroup was higher that in the normal Hcy subgroup (8.06 ±5.61 vs.5.80 ±2.98;t =2.324,P=0.027).Multivariate logistic regression analysis showed that age (odds ratio[OR] 1.090,95％ confidence interval [CI] 1.049-1.133;P=0.001),hypertension (OR 1.719,95％ CI 1.645-2.307;P ＜ 0.001),and HHcy (OR 1.128,95％ CI 1.044-1.219;P =0.002) were the independent risk factors for white matter lesions.Conclusions HHcy is an independent risk factor for WML,whereas the MTHFR gene C677T polymorphism is not associated with WML.

Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in psoriasis in southern Turkey

Abstract: Background: Psoriasis is a multigenic and multifactorial dermatological disease linked to cardiovascular diseases. Increased levels of homocysteine in patients with psoriasis have been demonstrated in many studies. The most frequently investigated genetic defect that plays a role in homocysteine metabolism is single point substitution (C to T) located on the 677th nucleotide of the methylenetetrahydrofolate reductase gene (MTHFR). Objective: In this study, we aimed to investigate methylenetetrahydrofolate C677T polymorphism in psoriasis patients in Turkey. Methods: The study included 96 patients with psoriasis and 77 controls from southern Turkey. Methylenetetrahydrofolate C677T polymorphism was analysed using the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism methods. Results: In the psoriasis group, 34 CC (35.4%), 46 CT (47.9%) and 16 TT (16.7%) genotypes were found, respectively; while in the control group, the figures were 39 (50.6%), 35 (45.5%), 3 (3.9%). Homozygote and heterozygote T alleles of methylenetetrahydrofolate C677T polymorphism were significantly higher in the psoriasis than in the control group (p=0.013). Conclusion: We firstly found a correlation between methylenetetrahydrofolate C677T polymorphism and psoriasis among the southern Turkish population.

Correlation between methylenetetrahydrofolate reductase rs4846049 G/T polymorphism and ischemic stroke in a Chinese Han population / 国际脑血管病杂志

Objective To investigate the correlation between methylenetetrahydrofolate reductase (MTHFR) gene 3 '-untranslated region rs4846049 G/T polymorphism and risk of ischemic stroke in a Chinese Han population. Methods A total of 396 patients with ischemic stroke and 378 healthy subjects (control group ) were selected using a case-control study design. Large artery atherosclerosis and small artery occlusion in the case group were 268 and 128 cases, respectively. Polymerase chain reaction-restriction fragment length polymorphism and the direct sequencing method were used to detect MTHFR gene rs4846049 G/T polymorphism. Results As compared to the GG genotype, the TT genotype significantly increased the risk of ischemic stroke (odds ratio [OR] 2. 87, 95% confidence interval [CI] 1. 43-5. 76;P=0. 003). Compared with G allele, T allele significantly increased the risk of the disease (OR 1. 62, 95% OR 1. 28-2. 06; P< 0. 001 ). Subgroup analyses showed that the rs4846049 G/T polymorphism could significantly increase the onset risks of LAA and SAO subtype stroke (all P<0.05). Conclusions MTHFR gene rs4846049 G/T polymorphism may be associated with the increased susceptibility to ischemic stroke in the Chinese Han population. The T allele may be a genetic risk factor for ischemic stroke in the Chinese Han population.

Correlations of methylenetetrahydrofolate reductase gene C677T polymorphism w ith ischemic stroke and hyperuricemia in Chinese Han population in Shandong, China / 国际脑血管病杂志

ObjectiveToinvestigatethecorrelationsofmethylenetetrahydrofolatereductase(MTHFR) gene C677T polymorphism w ith ischemic stroke and hyperuricemia in Chinese Han population in Shandong, China.Methods The patients w ith acute ischemic stroke and age-and sex-matched controls in Chinese Han population in Shandong, China w ere enrol ed. Polymerase chain reaction amplification and microarray hybridization w ere used to detect the MTHFR gene C677T polymorphism, and the serum uric acid concentration w as measured. Results A total of 145 patients w ith acute ischemic stroke and 145 age-and sex-matched controls in Chinese Han population in Shandong, China were enroled. The proportion of diabetes ( 26.90%vs. 6.89%; χ2 = 20.653, P< 0.001 ) and fasting blood glucose ( 5.56 ± 1.57 mmol/L vs.5.01 ±1.11 mmol/L;t= -3.390, P=0.001), homocysteine (median, interquartile range:18.2[16.30-22.55 μmol/L] vs.15.20[12.10-17.85 μmol/L]; Z= -6.323, P<0.001), and uric acid (43.0[361.60-490.45 μmol/L] vs.285.9[267.00-346.25 μmol/L]; Z= -10.360, P<0.001) levels in the ischemia stroke group w ere significantly higher than those in the control group. The distribution frequencies of TT genotype (42.07%vs.15.17%; χ2 =25.673, P<0.001) and T alele (58.28%vs. 34.48%; χ2 =33.008, P<0.001) in the ischemia stroke group w ere significantly higher than those in the control group. Multivariate logistic regression analysis showed that the uric acid (odds ratio [OR] 1.018, 95%confidence interval [ CI] 1.013-1.024; P<0.001), TT genotype ( vs.CT genotype OR 6.774, 95%CI 1.779-25.507; P=0.005), hypertension ( OR 1.919, 95%CI 1.013-3.636; P=0.045), and homocysteine (OR 1.153, 95%CI 1.059-1.258;P=0.001) w ere the independent risk factors for ischemic stroke. The ischemic stroke group w as combined w ith the control group, a total of 101 patients had hyperuricemia, and 189 had normal uric acid. The proportion in patients w ith diabetes ( 32.67%vs. 11.64%; χ2 = 23.749, P< 0.001), as wel as total cholesterol ( 5.67 ±1.56 mmol/L vs.5.10 ± 1.33 mmol/L; t= -3.255, P< 0.001 ) and homocysteine ( 19.50[17.10-24.70 μmol/L] vs. 15.40[12.60-18.05 μmol/L ]; Z= -7.236, P< 0.001 ) levels in the hyperuricemia group w ere significantly higher than those in the normal uric acid group. The distribution frequencies of the TT genotype (55.45%vs.13.76%;χ2 =56.409, P<0.001) and T alele (71.9%vs.32.54%;χ2 =79.561, P<0.001) w ere significantly higher than those in the normal uric acid group. Multivariate logistic regression analysis show ed that the TT genotype ( vs.CC genotype, OR 6.434, 95%CI 2.334-17.736; P<0.001 ), CT genotype ( vs.CC genotype, OR 2.234, 95%CI 1.019-4.898; P= 0.045 ), homocysteine ( OR1.081, 95%CI 1.010-1.157;P=0.024), and total cholesterin ( OR 1.363, 95%CI 1.123-1.653;P=0.002) w ere the independent risk factors for high hyperuricemia. Conclusions MTHFR gene C677T TT genotype and serum uric acid level are the independent risk factors for ischemic stroke in Chinese Han population in Shandong, China. MTHFR gene C677T TT genotype is also an independent risk factor for hyperuricemia in this population. Adjusting dietary habit may have a positive significance for the prevention of ischemic stroke in Chinese Han population in Shandong, China.

Analysis of the relationship between MTHFR C677T polymorphism and unknown reason Embryo arrest by gene chip / 中国医师杂志

Objective To investigate the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism and unexplained embryo arrest relationship.Methods By the method of gene chip analysis of MTHFR gene C677T polymorphism;select August 2014 and September 2015 in Zhoukou City Center Hospital infertility clinic unexplained Embryo arrest was more than or equal to 2 349 times pregnant women as the case group,and 421 without abortion history of health by women as the control group.The genotype and allele frequency distribution of embryo arrest and C677T MTHFR were compared between the experimental and control groups.Results MTHFR C677T genotype C/C in experimental and control groups were distributed with significant difference [P ＜ 0.001,x2 =70.484,OR =0.267,95％ CI (0.195 ～ 0.366)].Genotype C/T in experimental and control groups was distributed without significant difference [P =0.714,x2 =0.156,OR =1.06,95％ CI (0.795 ～ 1.412)].T/T genotype in experimental and control groups was distributed with significant difference [P ＜ 0.001,x2 =98.812,OR =7.961,95％ CI (5.055 ～ 12.537)].C allele in experimental and control groups was distributed with significant difference [P ＜0.001,x2 =13.287,OR =0.291,95％ CI (0.236 ～0.361)].Allele t in experimental and control group was distributed with significant difference [P ＜0.001,x2 =13.287,OR =3.431,95％ CI (2.772 ～4.246)].Conclusions Embryo arrest was not associated with C677T gene mutations in MTHFR gene,and the high expression of T/T gene might be a risk factor for women of childbearing age.

Associação entre a homocisteína e os polimorfismos do gene da MTHFR em mulheres brasileiras obesas / Association between homocysteine and polymorphisms in MTHFR in Brazilian obese women

Fundamentos: Pesquisas nacionais brasileiras indicam aumento da obesidade e doenças cardiovasculares em mulheres. Objetivo: Determinar a frequência dos polimorfismos 677C>T e 1298A>C do gene da metilenotetra-hidrofolato redutase (MTHFR) em mulheres brasileiras obesas e avaliar sua associação com as concentrações séricas de homocisteína (Hcy),folato e cobalamina, no período após a fortificação das farinhas de trigo e milho com ácido fólico no Brasil. Métodos: Estudo transversal realizado no período de 2008 a 2009, com 133 mulheres obesas. Kits comerciais foramutilizados para realizar análises laboratoriais, incluindo mensuração de lipídeos e glicose por métodos enzimáticos; Hcy total e o folato plasmático, utilizando um imunoensaio competitivo; e cobalamina baseado em quimiluminescência. A genotipagem foi realizada por PCR, seguido por fragmento de restrição enzimática. Resultados: A média de idade dos participantes foi 39,0±4,4 anos e o índice de massa corporal, 32,5±2,1 kg/m². Distribuições dos genótipos encontradas: CC (47%), CT (44%) e TT (9%) para a posição 677 da MTHFR e AA (60%), AC (35%), e CC (5%) para a posição 1298. As concentrações de Hcy correlacionaram-se negativamente com a concentração de folato plasmático no grupo exibindo os genótipos 677CT, 1298AC ou 1298CC (r=0,554, p<0,01). Conclusão: Mulheres brasileiras obesas com genótipos 677TT estudadas apresentaram maiores concentrações de Hcy do que aquelas que apresentaram os genótipos 677CT e 677CC. Além disso, genótipos 1298CC mostraram associação com concentrações de Hcy maiores do que os genótipos 1298AC e 1298AA.

Background: Brazilian national surveys have indicated a rise in obesity and cardiovascular disease in women.Objective: To determine the frequency of 677C>T and 1298A>C polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene in obese Brazilian women and to assess the potential association of these polymorphisms with serum concentrations of homocysteine (Hcy), folate and cobalamin after fortification of wheat and corn flour with folic acid in Brazil. Methods: A cross-sectional study was conducted from 2008 to 2009 with 133 obese women. Commercial kits were employed to perform laboratory analyses including measurement of lipids and glucose using enzymatic methods, total Hcy and serum folate using a competitive immunoassay and cobalamin based on chemiluminescence. Genotyping was performed by PCR, followed by restriction fragment lengthpolymorphism analysis. Results: The average age of participants was 39.0±4.4 years and mean body mass index was 32.5±2.1kg/m². The distributions of the genotypeswere CC (47%), CT (44%), and TT (9%) for the position MTHFR 677 and AA (60%), AC (35%), and CC (5%) for the position 1298. Hcy levels correlated negatively with serum folate in the group displaying the 677CT, 1298AC, or 1298CC genotypes (r=-0.554, p<0.01). Conclusion: Our findings suggest that obese Brazilian women with genotypes 677TT have higher Hcy concentrations than those carrying the genotypes 677CT and 677CC. Additionally, genotypes 1298CC are associated with higher Hcy concentrations than genotypes 1298AC and 1298AA.

Adultos jóvenes con deficiencia de metilentetrahidrofolato reductasa y aciduria etilenmalónica. Reporte de dos casos y revisión de tema / Female adults with ethylenmalonic aciduria and methylentretrahydropholate reductase deficiency: two cases report and review the literature / Adultos jovens com deficiência de metilentetrahidrofolato reductasa e aciduria etilenmalónica. Reporte de dois casos e revisão de tema

RESUMENLa combinación de la Aciduria etilmalónica y la homocistinuria son desórdenes del metabolismo heredados con un amplio espectro de manifestaciones clínicas que se pueden presentar desde la infancia hasta los adultos mayores. Sin embargo, con la detección temprana de estas enfermedades, en el periodo neonatal, se tendría la oportunidad de mejorar la calidad de vida de los pacientes afectados.

The impact of genomics in clinical medicine has been significant in recent years. Up to 2012, more than 3,000 genetic conditions have been implicated in clinical medicine. Today, with the new methodology of genome sequencing (next-generation sequencing (NGS) and comparative genomic sequencing (CGH), Mendelian conditions have been identified, as well as their role in genetic variations and polygenetic multifactorial disorders that affect the clinical prognosis and response to treatment.The integration of these diagnostic approaches in clinical practice requires an understanding of the basic principles of heredity, genome organization and molecular genetics. Generally, these conditions are single-gene disorders (also known as monogenic disorders), meaning that a single gene mutation is responsible for the disease.The genetic screening test analyzes hundreds of mutations for recessive genetic diseases. This test informs whether or not such mutations are present, which may lead to large-scale genotyping in children using multiple molecular probes.We report two cases of young adult women with symptoms and multiple medical consultations with disease recurrence and uncertain diagnosis, who underwent genetic testing and were determined to be carriers of heterozygous and homozygous mutant ethylmalonic aciduria and methylenetetrahydrofolate reductase deficiency, which could be responsible, in part, for their confusing symptoms.

A combinação da Aciduria etilmalónica e a homocistinuria são desordens do metabolismo herdados com um amplo espectro de manifestações clínicas que se podem apresentar desde a infância até os adultos maiores. No entanto, com a detecção precose destas doenças, no período neonatal, se teria a oportunidade de melhorar a qualidade de vida dos pacientes afetados.

Association Study between Folate Pathway Gene Single Nucleotide Polymorphisms and Gastric Cancer in Koreans

Gastric cancer is ranked as the most common cancer in Koreans. A recent molecular biological study about the folate pathway gene revealed the correlation with a couple of cancer types. In the folate pathway, several genes are involved, including methylenetetrahydrofolate reductase (MTHFR), methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR), and methyltetrahydrofolate-homocysteine methyltransferase (MTR). The MTHFR gene has been reported several times for the correlation with gastric cancer risk. However, the association of the MTRR or MTR gene has not been reported to date. In this study, we investigated the association between the single nucleotide polymorphisms (SNPs) of the MTHFR, MTRR, and MTR genes and the risk of gastric cancer in Koreans. To identify the genetic association with gastric cancer, we selected 17 SNPs sites in folate pathway-associated genes of MTHFR, MTR, and MTRR and tested in 1,261 gastric cancer patients and 375 healthy controls. By genotype analysis, estimating odds ratios and 95% confidence intervals (CI), rs1801394 in the MTRR gene showed increased risk for gastric cacner, with statistical significance both in the codominant model (odds ratio [OR], 1.39; 95% CI, 1.04 to 1.85) and dominant model (OR, 1.34; 95% CI, 1.02 to 1.75). Especially, in the obese group (body mass index > or = 25 kg/m2), the codominant (OR, 9.08; 95% CI, 1.01 to 94.59) and recessive model (OR, 3.72; 95% CI, 0.92 to 16.59) showed dramatically increased risk (p < 0.05). In conclusion, rs1801394 in the MTRR gene is associated with gastric cancer risk, and its functional significance need to be validated.

Single nucleotide polymorphisms of folate metabolism pathway genes in central chinese families with neural tube defects / 中华围产医学杂志

Objective To investigate the contribution of single nucleotide polymorphisms (SNP)variation in folate metabolism pathway genes and its interaction with environmental risk factors to the etiology of NTD. Methods In 275 families from central China, a total of 278 aborted fetal tissues or blood samples were collected from NTD individuals, 478 maternal and/or paternal blood samples were also obtained as controls. Folate supplementation, maternal diabetes mellitus and medication before pregnancy and during the first trimester of pregnancy were investigated. SNP analyses of all samples were performed by CEQ 8800. Case-parent control study and transmission/disequilibrium tests (TDT) were performed according to environmental cofactors stratification to evaluated 28 SNP in 12 folate pathway genes associated with human NTD. Results Only gene MTHFR rs1801133 was significantly associated with NTD, and synergistic effects of environmental risk factors (no folate supplementation and maternal diabetes) were shown on the occurrence of NTD. Linkage disequilibrium between BHMT rs3733890 and NTD existed in case of no folate supplementation,whereas the genotype alone did not contribute to the etiology of NTD. Other SNP were not significantly associated with NTD. Conclusions MTHFR rs1801133 is a risk factor of NTD, but BHMT rs3733890 is not an independent risk factor. Further investigations in folate and methionine cycle genes are requird in larger scale to enclose the interactions between gene and gene, or gene and environmental factors.

Thrombophilic mutations and risk of retinal vein occlusion

PURPOSE: The association of retinal vein occlusion and hereditary thrombophilia abnormalities is not established, with controversial results in the literature. This study investigates the association between retinal vein occlusion and three thrombophilic mutations: factor V 1691A (factor V Leiden), prothrombin 20210A (PT 20210A) and homozygous methylenetetrahydrofolate reductase 677T (MTHFR 677TT). METHODS: 55 consecutive retinal vein occlusion patients and 55 controls matched by age, gender and race, were tested for the presence of the following mutations: factor V Leiden, PT 20210A and MTHFR 677TT. The frequencies of the three mutations in cases and controls were compared. RESULTS: Factor V Leiden was found in 3.6 percent of patients and in 0 percent of controls; PT 20210A was found in 1.8 percent of patients and 3.6 percent of controls, (matched-pair odds ratio, 0.5; 95 percent confidence interval, 0.04 to 5.51); MTHFR 677TT was found in 9 percent of patients and 9 percent of controls (matched-pair odds ratio, 1; 95 percent confidence interval, 0.92 to 3.45). Arterial hypertension was more frequent in patients than controls (matched-pair odds ratio, 3.4; 95 percent confidence interval, 1.25 to 9.21). CONCLUSIONS: This study suggests that thrombophilic mutations are not risk factors for RVO. Routine investigation of hereditary thrombophilia in these patients is not justified.

OBJETIVOS: A associação entre oclusão venosa retiniana e trombofilias hereditárias não está estabelecida, com resultados controversos na literatura. O presente estudo investiga a associação entre a oclusão venosa retiniana e três mutações trombofílicas: fator V 1691A (fator V Leiden), protrombina 20210A (PT 20210A) e mutação C677T do gene da metileno-tetra-hidro-folato redutase (MTHFR 677TT). MÉTODOS: Cinquenta e cinco pacientes portadores de oclusão venosa retiniana e 55 controles pareados por idade, sexo e raça foram testados para a presença das seguintes mutações: fator V Leiden, PT 20210A e MTHFR 677TT. As freqüências das três mutações em casos e controles foram comparadas. RESULTADOS: Fator V Leiden foi encontrado em 3,6 por cento dos pacientes e em 0 por cento dos controles; PT 20210A foi encontrada em 1.8 por cento dos pacientes e em 3,6 por cento dos controles, (odds ratio, 0,5; 95 por cento IC, 0,04 to 5,51); MTHFR 677TT foi encontrada em 9 por cento dos pacientes e em 9 por cento dos controles (odds ratio, 1; 95 por cento IC, 0,92 to 3,45). Hipertensão arterial foi encontrada mais freqüentemente em pacientes do que em controles (odds ratio, 3,4; 95 por cento IC, 1,25 to 9,21). CONCLUSÕES: O presente estudo sugere que mutações trombofílicas não são fatores de risco para oclusão venosa retiniana. A investigação rotineira para trombofilias hereditárias neste grupo de pacientes não é indicada.

Methylenetetrahydrofolate reductase gene polymorphism and its association with coronary artery disease

CONTEXT AND OBJECTIVE: Obstructive coronary artery disease (CAD) is characterized by the deposition of atherosclerotic plaque on the coronary artery wall. Its manifestations depend on interactions between environmental and genetic risk factors. The aim of this work was to analyze the frequency of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in patients with CAD and its association with plasma homocysteine levels. Risk factors for CAD were also evaluated. DESIGN AND SETTING: Retrospective with blind quantitative analysis, at Hospital de Base, Faculdade de Medicina de São José do Rio Preto. METHODS: One hundred and twenty-seven individuals were studied. All completed a questionnaire to analyze risk factors for CAD. MTHFR polymorphism was investigated by restriction fragment length analysis and correlated with the number of affected arteries and degree of arterial obstruction determined by coronary cineangiography, and with plasma homocysteine levels measured by liquid chromatography/sequential mass spectrometry. RESULTS: Smoking (p = 0.02) and high-density lipoprotein cholesterol (p = 0.01) were associated with CAD. The C allele was the most prevalent in patients (0.61) and controls (0.66). There was no correlation between MTHFR/C677T polymorphism and plasma homocysteine levels. However, in patients with the TT genotype there was a correlation with the prevalence of coronary obstruction greater than 95 percent (p = 0.02) and the presence of two affected arteries (p = 0.04). CONCLUSIONS: The TT genotype is associated with coronary artery obstruction greater than 95 percent and the presence of two affected arteries. This confirms the relationship between genetic variants in specific patient subgroups and cardiovascular diseases.

CONTEXTO E OBJETIVO: A doença arterial coronariana (DAC) caracteriza-se pelo depósito de placa aterosclerótica na parede arterial coronária. Sua manifestação é dependente da interação entre fatores de risco ambientais e genéticos. O objetivo deste trabalho é analisar a freqüência do polimorfismo MTHFR/C677T em pacientes com doença arterial coronária e sua associação com o nível de Hcy plasmática. Fatores de risco para DAC também foram avaliados. TIPO DE ESTUDO: Retrospectivo com análise cega quantitativa, no Hospital de Base, Faculdade de Medicina de São José do Rio Preto. MÉTODOS: Foram estudados 127 indivíduos. Todos responderam a um questionário para análise dos fatores de risco para DAC. O polimorfismo MTHFR/C677T, investigado por análise de comprimento de fragmentos de restrição, foi correlacionado com número de artérias afetadas e grau de obstrução arterial, determinadas pela cinangiocoronariografia, e com o nível de Hcy plasmática. RESULTADOS: Tabagismo (p = 0,02) and HDLc (p = 0,01) foram associados com DAC. O alelo C foi o mais prevalente em pacientes (0,61) e controles (0,66; p = 0,49). O polimorfismo MTHFR/C677T não apresentou associação com níveis de Hcy plasmática. Entretanto, nos pacientes com genótipo TT observou-se a prevalência de obstrução coronariana acima de 95 por cento (p = 0,02) e a presença de duas artérias lesadas (p = 0,04). CONCLUSÕES: Associou-se o genótipo TT com o grau de obstrução arterial coronária acima de 95 por cento e a presença de duas artérias lesadas; confirma-se, assim, a relação de variantes genéticas em subgrupos específicos de pacientes com doenças cardiovasculares.

The C677 Mutation in Methylene Tetrahydrofolate Reductase Gene: Correlation with Uric Acid and Cardiovascular Risk Factors in Elderly Korean men

The C677T mutation in the methylene tetrahydrofolate reductase (MTHFR) gene results in elevated homocysteine levels and, presumably, in increased cardiovascular risk. Moreover, elevated homocysteine levels are reportedly associated with high serum uric acid levels. We evaluated the MTHFR genotype and a panel of biochemical, hematological variables, and lifestyle characteristics in 327 elderly Korean men (age range 40-81 yr; mean, 51.87). This study shows that mutation of the MTHFR gene may be a risk for hyperuricemia. The mean uric acid levels for the C/C, C/T and T/T genotypes were 5.54, 5.91 and 6.33 mg/dL, respectively (p=0.000). The T/T genotype was significantly more frequent in subjects with high uric acid levels (p=0.003). Thus, this mutation of the MTHFR gene is implied by the study results to be a risk factor of hyperuricemia in elderly Korean men. However, the relationship between the MTHFR mutation and uric acid metabolism remains unclear. Therefore, further studies are necessary to explain the associated between the MTHFR mutation and elevated uric acid levels, and to examine potential relationships between it and conventional cardiovascular risk factors.

Relationship between three thrombophilic gene mutations and unexplained recurrent early spontaneous abortion / 中华妇产科杂志

Objective To explore the relationship of methylenetetrahydrofolate reductase (MTHFR)gene C677T,factor V(FV)gene G1691A and prothrombin(PT)gene G20210A polymorphisms to unexplained recurrent early spontaneous abortion(URESA).Methods One hundred and twelve patients with URESA and 100 women with at least 1 normal pregnancy and without any miscarriage were analyzed for MTHFR,FV and PT gene polymorphisms by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP).Results MTHFR gene T/T genotype and T allele frequencies were increased in URESA patients[38.4%(43/112)and 59.8%(134/224)]versus controls[18.0%(18/100)and 43%(43/100),P