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Methylenetetrahydrofolate Reductase (methylenetetrahydrofolate + reductase)
Terms modified by Methylenetetrahydrofolate Reductase Selected AbstractsBRIEF REPORT: Association between MTHFR 677C-T polymorphism and alcohol dependence according to Lesch and Babor typologyADDICTION BIOLOGY, Issue 4 2009Amine Benyamina ABSTRACT Prior studies have associated 677C-T Methylenetetrahydrofolate reductase (MTHFR) gene polymorphism with decreased enzymatic activity and modified homocysteine regulation. This study determines and compares MTHFR 677C-T distribution and examines its consequences on homocysteine metabolism and alcohol dependence in alcoholic patients classified according to the Babor and Lesch typologies. MTHFR TT genotype was more prevalent in AD patients with milder alcohol dependence (Babor type A) and with Lesch type 3, associated with depression. MTHFR TT was also associated with hyperhomocysteinemia. Determining MTHFR 677C-T genotype, folate and vitamin B12 levels could assist physicians in identifying type 3 patients and improve addictions management. [source] Methylenetetrahydrofolate reductase A1298C genotypes are associated with the risks of acute lymphoblastic leukaemia and chronic myelogenous leukaemia in the Korean populationINTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY, Issue 3 2006M. HUR Summary Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme involved in folate metabolism, DNA methylation and synthesis. We investigated the association between MTHFR polymorphisms and the risks of acute and chronic leukaemias. MTHFR C677T and A1298C were genotyped in 396 Korean individuals using multiplex polymerase chain reaction/restriction fragment-length polymorphism. They were acute lymphoblastic leukaemia (ALL, n = 89), acute myeloid leukaemia (AML, n = 55), biphenotypic acute leukaemia (n = 12), chronic myelogenous leukaemia (CML, n = 40), and normal controls (n = 200). C677T genotypes were not associated with the risk of each disease. A1298C variants, however, significantly decreased the risks of ALL and CML compared with 1298AA. Odds ratios and 95% confidence intervals of 1298AC and 1298AC + CC were 0.53 (0.31,0.93) and 0.54 (0.31,0.93) in ALL, and 0.34 (0.14,0.80) and 0.40 (0.18,0.89) in CML, respectively, compared with 1298AA. These findings demonstrate that the development of ALL and CML is more dependent on folate status, and more susceptible to DNA instability than that of AML. In addition, A1298C rather than C677T may be a more important genetic risk modifier in leukaemogenesis at least in the Korean population. [source] Homocysteine levels and sustained virological response to pegylated-interferon ,2b plus ribavirin therapy for chronic hepatitis C: a prospective studyLIVER INTERNATIONAL, Issue 2 2009Guglielmo Borgia Abstract Background: Chronic hepatitis C affects about 3% of the world's population. Pegylated interferon (IFN) , plus ribavirin is the gold standard treatment. Methylenetetrahydrofolate reductase(MTHFR) is a key enzyme in the metabolism of homocysteine. MTHFR gene polymorphisms and high levels of homocysteine are associated with a high degree of steatosis and fibrosis, conditions associated with a low sustained virological response (SVR) rate. Aims: To evaluate whether MTHFR polymorphisms and homocysteine levels are predictors of the outcome of treatment in 102 prospectively enrolled patients with chronic hepatitis C naive to treatment. Methods: Patients were treated with pegylated interferon ,-2b plus ribavirin. All patients underwent blood tests, assessment of homocysteine, vitamin B12, folate, hepatitis C virus (HCV)-RNA levels, screening for MTHFR gene polymorphisms and liver ultrasound examination. Results: Homocysteine levels were deranged (>16 ,mol/L) in 10.5% of MTHFR wild-type patients vs 40.3% of non-wild-type patients (P=0.015). Homocysteine levels were 14.4 ,mol/L in SVR patients and 15.5 ,mol/L in non-SVR patients (P=0.049). The SVR rate was 40.0% in MTHFR wild-type patients, 52.0% in heterozygote mutants and 39.3% in homozygote mutants (P=0.467). At logistic regression analysis, genotypes 2 and 3 (odds ratio: 12.328, 95% confidence interval: 3.390,44.837, P=0.0001), homocysteine <16 ,mol/L (odds ratio: 3.397, 95% confidence interval: 1.033,11.177, P=0.044) and aspartate aminotransferase (AST) levels <48 U/L (odds ratio: 3.262, 95% confidence interval: 1.125,9.458, P=0.029) were independent predictors of SVR. Conclusions: In patients with chronic hepatitis C, homocysteine levels are associated with the outcome of pegylated-IFN, plus ribavirin treatment, while polymorphisms of MTHFR are not. [source] Methylenetetrahydrofolate reductase and methionine synthase reductase gene polymorphisms and protection from microvascular complications in adolescents with type 1 diabetesPEDIATRIC DIABETES, Issue 4pt2 2008Esko J Wiltshire Abstract:, Folate status has been associated with endothelial dysfunction in adolescents with type 1 diabetes, and elevated total plasma homoocyst(e)ine (tHcy) is a risk for vascular disease in the non-diabetic population. Polymorphisms in genes involved in folate and homocysteine metabolism are implicated in vascular disease. We aimed to determine whether polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) genes are risk factors for early microvascular disease in a large group of adolescents with type 1 diabetes. Four hundred and eighty adolescents were screened annually for retinopathy and microalbuminuria for a median of 4 yr. Molecular analysis for the polymorphisms 677C,T, 1298A,C in MTHFR, and 66A,G in MTRR was performed. The MTRR 66GG genotype reduced the risk for elevated albumin excretion rate (AER) (OR 0.47, CI 0.25, 0.88, p = 0.018) and showed a trend to reduced risk for microalbuminuria (OR 0.27, CI 0.06,1.21, p = 0.09). Survival without elevated AER was increased with the MTRR 66GG genotype (12.4 vs. 9.7 yr, p = 0.04) and with the MTHFR 1298CC genotype (15.2 vs. 10.2 yr, p = 0.007). Conversely, survival without retinopathy was reduced with the MTHFR 677TT and MTRR 66GG combined genotype (6.2 vs. 10.2 yr, p = 0.015). The MTRR 66GG and MTHFR 1298 CC genotypes may confer protection against early nephropathy, possibly because they are associated with lower tHcy. The MTHFR 677 TT was only related to earlier onset retinopathy in combination with MTRR 66GG. [source] Methylenetetrahydrofolate reductase polymorphisms, serum methylenetetrahydrofolate reductase levels, and risk of childhood acute lymphoblastic leukemia in a Chinese populationCANCER SCIENCE, Issue 3 2010Na Tong (Cancer Sci 2010; 101: 782,786) Methylenetetrahydrofolate reductase (MTHFR), involved in DNA methylation and nucleotide synthesis, is thought to be associated with a decreased risk of adult and childhood acute lymphoblastic leukemia (ALL). Accumulating evidence has indicated that two common genetic variants, C677T and A1298C, are associated with cancer risk. We hypothesized that these two variants were associated with childhood ALL susceptibility and influence serum MTHFR levels. We genotyped these two polymorphisms and detected MTHFR levels in a case,control study of 361 cases and 508 controls. Compared with the 677CC and 677CC/CT genotypes, the 677TT genotype was associated with a statistically significantly decreased risk of childhood ALL (odds ratio = 0.53, 95% confidence interval = 0.32,0.88, and odds ratio = 0.55, 95% confidence interval = 0.35,0.88, respectively). In addition, a pronounced reduced risk of ALL was observed among low-risk ALL and B-phenotype ALL. Moreover, the mean serum MTHFR level was 8.01 ng/mL (±4.38) in cases and 9.27 ng/mL (±4.80) in controls (P < 0.001). MTHFR levels in subjects with 677TT genotype was significantly higher than those with 677CC genotype (P = 0.010) or 677CT genotype (P = 0.043) in controls. In conclusion, our results provide evidence that the MTHFR polymorphisms might contribute to reduced childhood ALL risk in this population. [source] Methylenetetrahydrofolate reductase gene C677T mutation is related to the defects in the internal elastic lamina of the artery wallEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 12 2002P. Hämelahti Abstract Background The C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene leads to C/C, C/T and T/T genotypes, which affect the plasma homocysteine concentration in humans. In mini-pigs, high serum homocysteine levels are associated with defects in the internal elastic lamina (IEL) of the artery wall, which are apparently related to the migration of smooth muscle cells into the intima during atherogenesis. We studied the association between the MTHFR genotypes and the number of gaps in the IEL in the wall of the five major abdominal arteries. Materials and methods The autopsy study included 123 subjects (90 males and 33 females) aged 18,93. For the light microscopy, a 0·5 cm circular segment of the coeliac, the superior mesenteric, the inferior mesenteric and the renal arteries were cut and embedded in paraffin blocks. The circumference of the IEL, the thickness of the intima and the number of the gaps per millimetre in the IEL were measured by MOP 3 image analysis. Results The T-allele carriers (C/T and T/T) of the MTHFR gene had significantly less gaps in the IEL than the subjects with the C/C genotype in the superior mesenteric and in the left renal arteries (2·02 ± 2·25 vs. 2·53 ± 1·89, P < 0·04 and 0·56 ± 1·09 vs. 1·82 ± 2·66, P < 0·02, respectively). The trend was similar for the coeliac and the right renal arteries. Conclusions Our result suggests that MTHFR polymorphism may be involved in the fragmentation of the IEL. [source] Mutated 5,10-methylenetetrahydrofolate reductase, hyperhomocysteinemia and risk for cardiovascular disease.EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 1 2001Nature, nurture or nonsense? No abstract is available for this article. [source] Livedoid vasculopathy and hypercoagulability in a patient with primary Sjögren's syndromeINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 4 2007Raquel Cardoso MD Background, A 31-year-old woman presented with a 5-year history of painful ulcerations, palpable purpura, porcelain-white atrophic scars of the malleolar region and dorsal aspect of the feet, livedo reticularis on the limbs, arthralgia, xerophthalmia, and xerostomia. Methods, Skin biopsy revealed vessel wall hyalinization and thrombosis of the microvasculature with a very scarce dermal inflammatory infiltrate. Biopsy of the oral mucosa showed mononuclear infiltration of an intralobular duct of a salivary gland. Results, Laboratory studies, including autoantibodies and inflammation markers, were normal, except for a positive rheumatoid factor. Coagulation screening revealed C677T methylenetetrahydrofolate reductase (MTHFR) mutation, with a normal serum homocysteine. The patient was treated with oral methylprednisolone (32 mg/day with progressive reduction) and enoxaparin (20 mg/day subcutaneously), with complete ulcer healing within 4 months. Conclusion, Livedoid vasculitis or vasculopathy has not been referred to previously in association with Sjögren's syndrome, but may be associated with other autoimmune disorders and anomalies of coagulation, namely factor V Leiden mutation, protein C deficiency, and MTHFR mutation, associated or not with hyperhomocysteinemia, a condition that seems to confer an increased risk of recurrent arterial and venous thrombosis. We stress the importance of anticoagulant therapy for ulcer healing and for the prevention of other thrombotic events. [source] An investigation of associations between alcohol use disorder and polymorphisms on ALDH2, BDNF, 5-HTTLPR, and MTHFR genes in older Korean menINTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, Issue 5 2010Sangmoon Shin Abstract Background This study aimed to investigate the association of alcohol use disorder (AUD) with four candidate genes in older Korean men: aldehyde dehydrogenase 2 (ALDH2, 1/2), brain-derived neurotrophic factor (BDNF, val66met), serotonin transporter gene linked polymorphic region (5- HTTLPR, s/l), and methylenetetrahydrofolate reductase (MTHFR, c.677C,>,T). Methods A community sample of 300 men aged 65 or over were categorized into 68 subjects with AUD and 232 controls according to clinical examinations and DSM-IV criteria. Genotype distributions and allele frequencies were compared. Results Men with AUD had significantly higher ALDH2*1 and BDNF met allele frequencies compared to controls (p -values,<,0.05). No significant differences in genotype or allele frequencies were found for 5- HTTLPR or MTHFR (p -values,>,0.3). Conclusions AUD was associated with ALDH2*1 and BDNF met alleles in older Korean men. The first is consistent with previous research and likely to be explained by a protective effect of unpleasant symptoms following alcohol consumption associated with ALDH2*2. The second finding is novel and might be accounted for by BDNF -mediated serotonin or dopamine pathways. However, given the relatively small sample size, the results should be regarded as preliminary and requiring independent replication. Copyright © 2009 John Wiley & Sons, Ltd. [source] Methylenetetrahydrofolate reductase gene and risk of Alzheimer's disease in KoreansINTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, Issue 5 2008Jae-Min Kim Abstract Background The association between methylenetetrahydrofolate reductase (MTHFR) c.677C,>,T (A222V) polymorphism and Alzheimer's disease (AD) is controversial. The objectives of the study were to investigate the association between MTHFR c.677C,>,T polymorphism and AD in Korean elders and to the extent to which it is modified by the major components of one-carbon metabolism and apolipoprotein E (APOE) genotype. Methods Seven hundred and thirty-two community residents aged 65 or over were clinically assessed for AD. Genotyping was performed for MTHFR c.677C,>,T and APOE; serum levels of folate, vitamin B12, and homocysteine were assayed. Age, gender and education were included as covariates. Results A trend of association between TT genotype of MTHFR c.677C,>,T and AD was found [adjusted OR (95% CI): 1.73 (0.80,3.74)]. The association was significant in the presence of below-median vitamin B12 level [3.66 (1.14,11.71)] and in APOE e4 non-carriers [2.97 (1.00,8.55)] with significant interaction terms, and bordered on significance in the presence of above-median homocysteine level [2.73 (0.94,7.90)]. Conclusions These findings suggest gene-environment and gene-gene interactions on the risk of AD in Koreans. Copyright © 2007 John Wiley & Sons, Ltd. [source] Homocysteine, the MTHFR 677 C,T polymorphism and family history of premature cardiovascular diseaseJOURNAL OF HUMAN NUTRITION & DIETETICS, Issue 3 2009A. Carey Background:, Cardiovascular disease (CVD) is the main cause of premature death in the UK and accounts for 36% of all premature male deaths and 27% of female deaths every year (British Heart Foundation, 2006). Although many risk factors for CVD are known, family history has been identified as being of particular importance in premature CVD (Lloyd-Jones et al., 2004). Recently, it was suggested that an elevated homocysteine (tHcy) may be associated with premature CVD (Homocystiene Studies Collaboration, 2002). The main genetic determinant of tHcy is the common 677 C,T polymorphism, in the enzyme methylenetetrahydrofolate reductase (MTHFR), which is prevalent in approximately 10% of the UK population. Relatively few studies have examined the association between tHcy and premature CVD and hardly any have considered the role of this polymorphism. The aim of this study therefore was to examine the relationships between the MTHFR 677 C,T polymorphism, tHcy and a family history of CVD in patients with established premature CVD. Methods:, An analysis was conducted on medical, lifestyle and family history data collected from patients and age-sex matched controls, recruited through the GENOVIT study in 2003. This case,control study involved n = 404 premature CVD patients and a similar number of age-sex matched controls, all of whom were screened for the TT genotype. A subset of patients (n = 196) and controls (n = 167) provided a blood sample, from which the tHcy concentration was established. Independent sample t -tests were used to determine differences between patients and controls and differences among genotype groups were examined using a one-way analysis of variance, followed by a Tukey's post hoc test. Results:, Plasma tHcy was significantly elevated in patients with a family history of CVD (compared to those without) (P = 0.013). A nonsignificant trend towards higher tHcy (compared to those without) was observed in patients with the TT genotype (P = 0.419). Furthermore, specifically in those with the TT genotype, those with a family history of CVD (compared to those without) showed significantly higher tHcy concentrations (P < 0.005). Those with the TT genotype who smoked had significantly higher tHcy (P < 0.05) than the CC and CT genotypes. Discussion:, The findings presented provide evidence to support an association between the MTHFR 677C,T polymorphism, elevated homocysteine and family history of premature CVD. Given that dietary levels of riboflavin have been shown to lower homocysteine specifically in individuals with the TT genotype (McNulty et al., 2006), these results have implications for the dietary management of premature CVD in those individuals with a genetic predisposition for elevated tHcy. In conclusion, further research in larger cohort numbers, regarding the correlation between family history, tHcy and the MTHFR polymorphism, would be beneficial for establishing their cause and effect relationship. References British Heart Foundation (2006) All Deaths and Deaths Under 75 by Cause and Sex, 2005, England, Wales, Scotland, N Ireland and United Kingdom. Available at http://www.bhf.org.uk/research_health_professionals/resources/heart_statistics.aspx. Homocystine Studies Collaboration (2002) Homocysteine and the risk of ishaemic heart disease and stroke. JAMA288, 2015,2022. Llyod-Jones, D.M., Nam, B.H., D'Agostino, R.B., Levy, D., Murabito, J.M., Wang, T.J., Wilson, P.W. & O'Donnell, C.J. (2004) Parental cardiovascular disease as a risk factor for cardiovascular disease in middle-aged adults, a prospective study of parents and offspring. JAMA291, 2204,2211. McNulty, H., Dowey le, R.C., Strain, J.J., Dunne, A., Ward, M., Molloy, A.M., McAnena. L.B., Hughes, J.P., Hannon-Fletcher, M. & Scott, J.M. Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C->T polymorphism. Circulation113, 74,80. [source] Double inherited thrombophilias and adverse pregnancy outcomes: Fashion or science?JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH (ELECTRONIC), Issue 5 2010Giovanni Larciprete Abstract Aim:, To determine to what extent double inherited thrombophilias are associated with adverse obstetric complications correlated with fetoplacental insufficiency, such as preeclampsia, hemolytic anemia elevated liver enzymes and low platelet count (HELLP) syndrome, gestational hypertension, fetal growth restriction (FGR), intrauterine death (ID), abruptio placentae and disseminated intravascular coagulopathy. Methods:, Pregnant women coming to delivery were retrospectively divided into two groups: group A (controls) and group B (cases). Patients belonging to group B had one of the following: severe preeclampsia, HELLP syndrome, gestational hypertension, FGR, intrauterine death, abruptio placentae of disseminated intravascular coagulopathy. We detected methylenetetrahydrofolate reductase (MTHFR) A1298C, MTHFR C677T, factor V Leiden, PAI-1, mutant prothrombin G20210A, plasma homocysteine, antithrombin III, protein S and activated protein C resistance. Normal pregnant women or pregnant women with double defects were enrolled in this study. Results:, The combination of MTHFR C677T mutation with PAI-1 (5G/5G) mutation was significantly linked with the occurrence of ID. HELLP syndrome was significantly related to the simultaneous presence of factor VIII and X mutations. The combination of MTHFR C677T with factor VIII mutation and the combination of factor II and V mutations were significantly related to the occurrence of abruptio placentae. We found an association between double isoforms MTHFR mutation and FGR. Conclusion:, It seems that some thrombophilias and a combination of thrombophilic factors carry a greater risk than others for a given adverse outcome. Further studies are needed to check the link between thrombophilic gene mutations and adverse pregnancy outcomes, such as recurrent miscarriages and deep venous thrombosis. [source] MTHFR C677T Polymorphism and Risk of HCC in Patients With Liver Cirrhosis: Role of Male Gender and Alcohol ConsumptionALCOHOLISM, Issue 1 2009Carlo Fabris Background:, A single nucleotide polymorphism (SNP) C677T in the methylenetetrahydrofolate reductase (MTHFR) gene has been identified. The TT or CT genotypes show a marked reduction of the enzyme activity; this causes higher homocysteine levels and alterations of folate metabolism. Folate metabolism is essential for DNA synthesis and methylation, crucial steps in carcinogenesis. In this paper, we investigated whether the MTHFR C677T SNP could influence the occurrence of hepatocellular carcinoma (HCC) in a cohort of patients transplanted for end stage liver disease of different etiologies. Methods:, Two hundred and twelve consecutive patients who underwent liver transplantation for end stage liver disease due to hepatitis B or C, alcoholic liver disease, and other causes were studied. Two hundred and thirty-six blood donors served as controls. Focal hepatic lesions were searched in the sectioned explanted livers. The presence of the MTHFR C677T SNP was determined via polymerase chain reaction amplification. Results:, Among the 65 patients with HCC, 22 had the CC genotype, 30 the CT, and 13 the TT genotype. Only in patients with alcoholic liver disease was a significant association detected between the TT genotype and the presence of liver cancer (6/17 vs. 5/46, p < 0.05). At stepwise logistic regression analysis the independent selected predictors of HCC were found: age at transplantation >55 years (p < 0.001) and the association among male gender, alcoholic liver disease, and MTHFR TT genotype (p = 0.002). Conclusions:, The present study suggests that male TT carriers with alcoholic cirrhosis bear an increased risk of developing HCC. [source] Hyperhomocysteinemia and low B vitamin levels are independently associated with venous thromboembolism: results from the EDITH study: a hospital-based case,control studyJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 4 2006E. OGER Summary.,Background:,Moderate hyperhomocysteinemia and B vitamins deficiency are thought to be risk factors for venous thromboembolism (VTE). The causality and independence of those associations are still questioned. Methods:,We measured fasting serum total homocysteine, folates, and vitamin B12 levels as well as 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T genotypes in 467 patients hospitalized with a first well-documented deep vein thrombosis and/or pulmonary embolism not related to a major acquired risk factor and 467 controls matched for gender and age. Results:,Mild hyperhomocysteinemia, low serum folates, and vitamin B12 were associated with VTE independently of each other. In multivariate analysis, odds ratios (OR) (95% CI) for VTE associated with mild hyperhomocysteinemia (>15 ,mol L,1), low serum folates (,,4.9 nmol L,1), and vitamin B12 (, 253 pmol L,1) were 1.48 (1.05,2.08), 3.14 (1.35,7.32) and 1.42 (1.03,1.98), respectively. An MTHFRC677T genotype was not significantly associated with VTE; OR (95% CI): 1.13 (0.70,1.81) Conclusions:,The current data provides further knowledge in the complex relationship between hyperhomocysteinemia, low vitamin levels, and VTE. [source] Preeclampsia and its interaction with common variants in thrombophilia genesJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 9 2004M. P. M. De Maat Summary., Recently, it has been proposed that abnormalities in coagulation and fibrinolysis contribute to the development of preeclampsia by increasing the thrombotic tendency. This hypothesis was tested in women who have had preeclampsia (cases) compared with matched controls. Polymorphisms in the thrombophilia genes {plasminogen activator inhibitor type 1 [PAI-1 ,675(4G/5G)], thrombin activatable fibrinolysis inhibitor (TAFI ,438G/A and 1040C/T), methylenetetrahydrofolate reductase (MTHFR 677C/T), factor V (FV Leiden R/Q506), prothrombin (FII 20210G/A) and factor XIIIA (FXIIIA V/L34)} were determined in 157 women with preeclampsia and 157 women with uncomplicated pregnancy. The associated risk of preeclampsia was analyzed using logistic regression methods. The frequency distributions of the genotypes of these six polymorphisms in thrombophilia genes were similar in the case and control groups. We found no differences in the prevalence of genetic risk factors of thrombosis in women with preeclampsia compared with controls, which makes it unlikely that these polymorphisms are risk factors for preeclampsia. [source] Methylenetetrahydrofolate Reductase Polymorphisms, Folate, and Cancer Risk: A Paradigm of Gene-Nutrient Interactions in CarcinogenesisNUTRITION REVIEWS, Issue 7 2000F.R.C.P.(C), Young-In Kim M.D. Recent epidemiologic studies suggest that common polymorphisms of methylenetetrahydrofolate reductase (MTHFR) with allele frequencies up to 35% in the general North American population may modulate cancer risk. In some cancers, folate and other nutrients involved in the MTHFR metabolic pathway appear to interact with MTHFR polymorphisms to further modify cancer risk. In carcinogenesis, MTHFR polymorphisms thus provide a paradigm of gene-nutrient interactions, an emerging and important topic in the field ofnutritisn and cancer. Furthermore, MTHFR polymorphisms and MTHFR-nutrient interactions provide an opportunity to identify an ideal target group of individuals, at high risk of developing cancer, for rational, effective, and safe chemoprevention using these nutrients. [source] Methylenetetrahydrofolate reductase and methionine synthase reductase gene polymorphisms and protection from microvascular complications in adolescents with type 1 diabetesPEDIATRIC DIABETES, Issue 4pt2 2008Esko J Wiltshire Abstract:, Folate status has been associated with endothelial dysfunction in adolescents with type 1 diabetes, and elevated total plasma homoocyst(e)ine (tHcy) is a risk for vascular disease in the non-diabetic population. Polymorphisms in genes involved in folate and homocysteine metabolism are implicated in vascular disease. We aimed to determine whether polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) genes are risk factors for early microvascular disease in a large group of adolescents with type 1 diabetes. Four hundred and eighty adolescents were screened annually for retinopathy and microalbuminuria for a median of 4 yr. Molecular analysis for the polymorphisms 677C,T, 1298A,C in MTHFR, and 66A,G in MTRR was performed. The MTRR 66GG genotype reduced the risk for elevated albumin excretion rate (AER) (OR 0.47, CI 0.25, 0.88, p = 0.018) and showed a trend to reduced risk for microalbuminuria (OR 0.27, CI 0.06,1.21, p = 0.09). Survival without elevated AER was increased with the MTRR 66GG genotype (12.4 vs. 9.7 yr, p = 0.04) and with the MTHFR 1298CC genotype (15.2 vs. 10.2 yr, p = 0.007). Conversely, survival without retinopathy was reduced with the MTHFR 677TT and MTRR 66GG combined genotype (6.2 vs. 10.2 yr, p = 0.015). The MTRR 66GG and MTHFR 1298 CC genotypes may confer protection against early nephropathy, possibly because they are associated with lower tHcy. The MTHFR 677 TT was only related to earlier onset retinopathy in combination with MTRR 66GG. [source] Methylenetetrahydrofolate reductase polymorphism in Kawasaki diseasePEDIATRICS INTERNATIONAL, Issue 3 2000Hirokazu Tsukahara Abstract Background: A genetic aberration in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene (677 C to T substitution) has been shown to result in reduced enzyme activity. The hypothesis tested in the present study was that a higher proportion of Kawasaki disease (KD) patients with coronary artery lesions (CAL) would have the T677 allele compared with patients without CAL and healthy subjects. Methods: Genotypes for MTHFR were determined in 75 KD patients (male : female ratio 52:23) and 238 healthy subjects (male : female ratio, 110:128) by the polymerase chain reaction and restriction fragment length polymorphism method. Results: The results indicated that female KD patients had a significantly higher frequency of the TT genotype compared with female control subjects. In the female population, the frequency of the TT genotype in patients with initial coronary aneurysm was significantly lower than in patients without this manifestation. Analysis of the data for the male population showed that the frequency of the TT genotype in KD patients developing coronary stenosis, occlusion or myocardial infarction was higher than that in those without these manifestations, although the difference was statistically insignificant. Conclusions: The TT genotype may protect female KD patients against initial aneurysm formation and predispose male KD patients to severe coronary complications. Further large-scale studies may be required to confirm the contribution of homocysteine in the coronary sequelae of KD. [source] Genetic factors associated with skin cancer in renal transplant patientsPHOTODERMATOLOGY, PHOTOIMMUNOLOGY & PHOTOMEDICINE, Issue 2-3 2007Mary Elizabeth Laing Background: Non-melanoma skin cancer represents a significant cause of morbidity and mortality among renal transplant recipients. Established risk factors that increase susceptibility to skin cancer after transplantation include skin type, sun exposure and level of immunosuppression. Methods: A comprehensive literature review was carried out to discuss relevant genetic polymorphism for the development of skin cancer in organ transplant recipients. These include genetic polymorphisms in glutathione S -transferase, interleukin-10, retinoblastoma and p53 genes. We also discuss genetic polymorphisms in the folate pathway, melanocortin 1 receptor and vitamin D receptor recently discovered in our group. Results: No single factor is causative in cutaneous carcinogenesis in transplant recipients. Interactions of some of the above mechanisms with known environmental factors lead to increased risk. Conclusion: Polymorphisms in methylenetetrahydrofolate reductase are potentially correctable with folic acid supplementation; however, further evaluation is required in adequately powered prospective clinical trials. Avoidance of known oncogenic environmental factors and genetic risk evaluation may improve outcomes in transplant patients. [source] Polymorphisms in genes related to folate and cobalamin metabolism and the associations with complex birth defectsPRENATAL DIAGNOSIS, Issue 6 2008R. Brouns Abstract Objective To investigate the associations between biomarkers and genetic variants involved in homocysteine metabolism and the risk of complex birth defects. Methods Total homocysteine (tHcy), folate, cobalamin, apo-transcobalamin (apo-TC) and apo-haptocorrin (apo-HC) were measured in the amniotic fluid of 82 women who were pregnant with a child having a complex birth defect, such as neural tube defect, cleft lip and/or palate, heart defect or omphalocele, and in 110 women pregnant with a non-malformed child. The determined genotypes of the child comprised of 5, 10-methylenetetrahydrofolate reductase (MTHFR 677C > T, 1298A > C), methionine synthase (MTR 2756A > G), methionine synthase reductase (MTRR 66A > G) and transcobalamin (TCN2 776C > G). Univariate and multivariate logistic regression analyses were performed. Results Significantly lower cobalamin and higher apo-TC, apo-HC, tHcy and folate concentrations were determined in amniotic fluids of cases compared with controls (p,0.001). Logistic regression analysis revealed that after adjustment for maternal age, children carrying the MTHFR 677T allele showed a four-fold increased risk of having a complex birth defect, OR (95% CI) = 4.0 (1.1,15.4). Other genotypes did not show significant associations. Conclusion The MTHFR 677C > T polymorphism in conjunction with reduced folate- and/or cobalamin status may increase the risk of complex birth defects. Copyright © 2008 John Wiley & Sons, Ltd. [source] C677T polymorphism of methylenetetrahydrofolate reductase gene affects plasma homocysteine level and is a genetic factor of late-onset Alzheimer's diseasePSYCHOGERIATRICS, Issue 1 2004Tomoyuki KIDA Abstract Background:, Elevated plasma homocysteine levels are known as a risk for atherosclerotic vascular disease and venous thrombosis and have been shown as a risk for late-onset Alzheimer's disease (LOAD). Method:, To examine the effect of genetic factors predisposing to elevated plasma homocysteine levels on the occurrence of LOAD, we determined the genotype of a C677T polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene and a variable number tandem repeat (VNTR) spanning exon 13,intron 13 boundary of cystathionine ,-synthase (CBS) gene in patients with LOAD and community-based control subjects. Results:, Logistic regression indicated that the MTHFR-T allele was a risk for LOAD (P < 0.05), independently from apolipoprotein E-,4 (APOE-,4) allele. Kaplan,Meier tests showed that in APOE-,4 non-carriers, individuals with the MTHFR-TT genotype have occurences of LOAD earlier than those with the MTHFR-CC genotype (P < 0.05). Multiple regression analysis indicates that MTHFR-T allele increases plasma homocysteine levels (P = 0.0002), while the number of X chromosomes decreases (P = 0.01). Plasma homocysteine level was not correlated with age, plasma albumin reflecting nutritional condition, and the dose of APOE-,4 allele. The CBS-20 VNTR allele showed the same trend to increase plasma homocysteine level as the MTHFR-T allele, but a risk effect for LOAD was not evident. Conclusion:, A genetic propensity for elevated plasma homocysteine levels, explained by the MTHFR-T allele encoding defective enzymatic function, is involved in the development of LOAD, particularly in APOE-,4 non-carriers, and that homocysteine metabolism could be a preventive target to LOAD in the elderly. [source] Which Thrombophilic Gene Mutations are Risk Factors for Recurrent Pregnancy Loss?AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 4 2006Cyle S. Goodman Problem, Thrombophilia has been associated with poor obstetrical outcomes. To determine the association of specific inherited thrombophilias and recurrent pregnancy loss, 10 thrombophilic genes were investigated. Method of study, A total of 550 women with a history of recurrent pregnancy loss had buccal swabs taken for DNA analyses of the following gene mutations: factor V G1691A, factor V H1299R (R2), factor V Y1702C, factor II prothrombin G20210A, factor XIII V34L, , -fibrinogen -455G>A, PAI-1 4G/5G, HPA1 a/b(L33P), methylenetetrahydrofolate reductase (MTHFR) C677T, MTHFR A1298C. The frequencies of these mutations were compared with controls published in the literature. Results, When examined individually, PAI-1 4G/5G (P = 0.009), factor XIII V34L (P < 0.0001), and homozygous MTHFR C667T (P < 0.0001) correlated significantly with recurrent pregnancy loss compared with controls. The frequency of the factor V Y1702C mutation was extremely low in patients and controls; thus, this gene was removed from further calculations. The remaining six mutated genes, when analyzed cumulatively, also corresponded with recurrent pregnancy loss (P < 0.0001). Conclusion, A panel of thrombogenic gene mutations consisting of factor V G1691A, factor V H1299R (R2), factor II prothrombin G20210A, factor XIII V34L, , -fibrinogen -455G>A, PAI-1 4G/5G, HPA1 a/b(L33P), MTHFR C677T, and MTHFR A1298C can identify individuals at risk for recurrent pregnancy loss. [source] Association of the C677T polymorphism in the methylenetetrahydrofolate reductase gene with sudden sensorineural hearing loss,,§THE LARYNGOSCOPE, Issue 4 2010Yasue Uchida MD Abstract Objectives/Hypothesis: To investigate the recently reported association of the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene with sudden sensorineural hearing loss (SSNHL), we analyzed data from a community-based Japanese population. Study Design: Nested case-control study. Methods: Among 2,174 adults (1,096 males and 1,078 females) aged 40 to 79 years old who participated in the National Institute for Longevity Sciences,Longitudinal Study of Aging, we compared 33 cases of prevalent SSNHL, defined as a self-reported otolaryngologist diagnosis, with the other cases. Multiple logistic regression was used to obtain odds ratios (ORs) for SSNHL in subjects with the MTHFR C677T polymorphism, with adjustment for other possibly influential factors under additive, dominant, and recessive genetic models. Results: The per-allele ORs for SSNHL risk were 1.687 (95% confidence interval [CI], 1.023,2.780) in model 1, with adjustment for age and sex, and 1.654 (CI, 1.003,2.728) in model 2, with adjustment for smoking status, body mass index, histories of heart disease, hypertension, and diabetes, in addition to the factors in model 1. In model 3, a significant association between SSNHL and the C677T polymorphism was observed under all genetic models independent of factors including folic acid and homocysteine, although there were only 25 cases and 1,677 controls due to the addition of moderating factors. Conclusions: Our results suggest that the T allele of MTHFR C677T could be associated with susceptibility to SSNHL, and even imply that this mutation could be a risk factor that is independent of blood folic acid and homocysteine. Laryngoscope, 2010 [source] Thrombophilic Gene Mutations and Recurrent Spontaneous Abortion: Prothrombin Mutation Increases the Risk in the First TrimesterAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 2 2001Rudolf Pihusch PROBLEM: Thrombophilic predisposition may be one of the underlying causes of recurrent spontaneous abortions (RSA). We studied the prevalence of five thrombophilic gene mutations in patients with RSA. METHOD OF STUDY: 102 patients with two or more consecutive abortions and 128 women without miscarriage were analyzed for factor V Leiden mutation (FVL), prothrombin G20210A mutation (PTM), C677T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, glycoprotein IIIa (GPIIIa) C1565T polymorphism, and ,-fibrinogen G-455A polymorphism by polymerase chain reaction (PCR) techniques. RESULTS: No differences in the prevalence of FVL, MTHFR T/T, GPIIIa and ,-fibrinogen polymorphism were detected. Heterozygous PTM occurred more often in patients with RSA. This effect was significant in a subgroup with abortions exclusively in the first trimester (6.7% vs. 0.8%, P=0.027, OR 8.5). CONCLUSIONS: In contrast to the other mutations and polymorphisms, heterozygous PTM is more common in patients with abortions in the first trimester. This might reflect an influence of PTM on pathogenesis of early pregnancy loss. [source] Testing for Genetic Association With Constrained Models Using TriadsANNALS OF HUMAN GENETICS, Issue 2 2009J. F. Troendle Summary It has been shown that it is preferable to use a robust model that incorporated constraints on the genotype relative risk rather than rely on a model that assumes the disease operates in a recessive or dominant fashion. Previous methods are applicable to case-control studies, but not to family based studies of case children along with their parents (triads). We show here how to implement analogous constraints while analyzing triad data. The likelihood, conditional on the parents genotype, is maximized over the appropriately constrained parameter space. The asymptotic distribution for the maximized likelihood ratio statistic is found and used to estimate the null distribution of the test statistics. The properties of several methods of testing for association are compared by simulation. The constrained method provides higher power across a wide range of genetic models with little cost when compared to methods that restrict to a dominant, recessive, or multiplicative model, or make no modeling restriction. The methods are applied to two SNPs on the methylenetetrahydrofolate reductase (MTHFR) gene with neural tube defect (NTD) triads. [source] Genetic and lifestyle variables associated with homocysteine concentrations and the distribution of folate derivatives in healthy premenopausal womenBIRTH DEFECTS RESEARCH, Issue 8 2010Carolyn M. Summers Abstract BACKGROUND Low folate and high homocysteine (Hcy) concentrations are associated with pregnancy-related pathologies such as spina bifida. Polymorphisms in folate/Hcy metabolic enzymes may contribute to this potentially pathogenic biochemical phenotype. METHODS The study comprised 26 Caucasian and 23 African-American premenopausal women. Subjects gave fasting blood samples for biochemical phenotyping and genotyping. Total Hcy (tHcy) and both plasma and red blood cell (RBC) folate derivatives (i.e. tetrahydrofolate [THF], 5-methylTHF [5-MTHF], and 5,10-methenylTHF [5,10-MTHF]) were measured using stable isotope dilution liquid chromatography, multiple reaction monitoring, and mass spectrometry. Eleven polymorphisms from nine folate/Hcy pathway genes were genotyped. Tests of association between genetic, lifestyle, and biochemical variables were applied. RESULTS In African American women, tHcy concentrations were associated (p < 0.05) with total RBC folate, RBC 5-MTHF, B12, and polymorphisms in methionine synthase (MTR) and thymidylate synthase (TYMS). In Caucasian women, tHcy concentrations were not associated with total folate levels, but were associated (p < 0.05) with RBC THF, ratios of RBC 5-MTHF:THF, and polymorphisms in 5,10-methylenetetrahydrofolate reductase (MTHFR) and MTR. In African Americans, folate derivative levels were associated with smoking, B12, and polymorphisms in MTR, TYMS, methionine synthase reductase (MTRR), and reduced folate carrier1 (RFC1). In Caucasians, folate derivative levels were associated with vitamin use, B12, and polymorphisms in MTHFR, TYMS, and RFC1. CONCLUSIONS Polymorphisms in the folate/Hcy pathway are associated with tHcy and folate derivative levels. In African American and Caucasian women, different factors are associated with folate/Hcy phenotypes and may contribute to race-specific differences in the risks of a range of pregnancy-related pathologies. Birth Defects Research (Part A), 2010. © 2010 Wiley-Liss, Inc. [source] Metabolic effects and the methylenetetrahydrofolate reductase (MTHFR) polymorphism associated with neural tube defects in southern Brazil,BIRTH DEFECTS RESEARCH, Issue 7 2004Têmis Maria Félix Abstract BACKGROUND The importance of metabolic factors in neural tube defects (NTDs) has been the focus of many investigations. Several authors have suggested that abnormalities in homocysteine metabolism, such as hyperhomocysteinemia, folate deficiency, and low vitamin B12, may be responsible for these malformations and that both nutritional factors and genetic abnormalities are associated with them. METHODS We conducted a case-control study to investigate the influence of biochemical and genetic factors in NTDs in infants in southern Brazil. Levels of folate, vitamin B12, total homocysteine (t-Hcy) and the 677C>T and 1298A>C polymorphisms of the MTHFR gene were analyzed in 41 NTD child,mother pairs and 44 normal child,mother control pairs. RESULTS Subjects in the case group had a higher mean blood folate level than those in the control group. The level of vitamin B12 was lower in mothers in the NTD group than in control mothers (p = 0.004). The level of t-Hcy was not different in the two groups, but t-Hcy and vitamin B12 were correlated (p = 0.002). There was no difference in the genotype distribution for 677C>T and 1298A>C polymorphisms of MTHFR in the case and control pairs. The level of t-Hcy was correlated with 677TT. CONCLUSIONS Despite the small sample in this study, we suggest that low vitamin B12 and, consequently, hyperhomocysteinemia are important risk factors for NTDs in our population. Birth Defects Research (Part A), 2004. © 2004 Wiley-Liss, Inc. [source] Evaluation of infant methylenetetrahydrofolate reductase genotype, maternal vitamin use, and risk of high versus low level spina bifida defects,BIRTH DEFECTS RESEARCH, Issue 3 2003Kelly A. Volcik BACKGROUND Several studies have suggested that homozygosity for the C677T 5,10-methylenetetrahydrofolate reductase (MTHFR) variant is a potential risk factor for neural tube defects (NTDs), as individuals homozygous for the C677T allele have slightly elevated homocysteine concentrations under conditions of low folic acid intake. It has been hypothesized that maternal folic acid supplementation prevents NTDs by partially correcting reduced MTHFR activity associated with the variant form of the enzyme. METHODS Genomic DNA was extracted from newborn screening blood spots obtained from 145 infants with spina bifida (SB) and 260 nonmalformed control infants. The MTHFR C677T genotype was determined by restriction enzyme digestion of PCR amplification products with Hinf1. We investigated whether infant MTHFR genotype influenced the risk for the anatomic level of the SB lesion (high vs. low); we also explored whether maternal vitamin use influenced this risk. RESULTS Compared to controls, the frequency of SB infants with the homozygous 677 TT genotype was greatest in those infants with high level SB defects (26%; odds ratio [OR] = 2.9; 95% confidence interval [CI] = 0.9,10.1) than for those with low level SB defects (22%; OR = 1.8; 95% CI = 0.9,3.2). Furthermore, homozygous 677TT infants whose mothers did not use vitamins containing folic acid had a modestly increased risk of SB (OR = 1.8; 95% CI = 0.8,3.9), with this risk increasing more than three-fold (OR = 5.5; 95% CI = 0.8,28.1) for those infants with high level SB defects whose mothers did not use vitamins. CONCLUSIONS Based upon our observations, it is suggested that the association between the infant MTHFR homozygous variant genotype and spina bifida risk may be conditional upon both lesion level and maternal vitamin use. Birth Defects Research (Part A) 67:154,157, 2003. © 2003 Wiley-Liss, Inc. [source] Cellular folate vitamer distribution during and after correction of vitamin B12 deficiency: a case for the methylfolate trapBRITISH JOURNAL OF HAEMATOLOGY, Issue 5 2006Y. M. Smulders Summary Haematological sequellae of vitamin B12 deficiency are attributed to disturbed DNA synthesis, but vitamin B12 itself plays no role in DNA biosynthesis. A proposed explanation for this is the methylfolate trap hypothesis. This hypothesis states that B12 deficiency impairs overall folate metabolism because 5-methyltetrahydrofolate (5MTHF) becomes metabolically trapped. This trap results from the fact that 5MTHF can neither be metabolised via the methionine synthase pathway, nor can it be reconverted to its precursor, methylenetetrahydrofolate. Other manifestations of the methylfolate trap include cellular folate loss because of shorter 5MTHF polyglutamate chains and global hypomethylation. The methylfolate trap has never been demonstrated in humans. We describe a patient with B12 deficiency who was homozygous for the common methylenetetrahydrofolate reductase (MTHFR) C677T mutation. We analysed red blood cell (RBC) folate vitamers and global DNA methylation by liquid chromatography (LC) in combination with tandem mass spectrometry, and 5MTHF polyglutamate length by LC-electrochemical detection. Compared to post-B12 supplementation values, homocysteine was higher (52·9 ,mol/l vs. 16·8 ,mol/l), RBC folate was lower (268·92 nmol/l vs. 501·2 nmol/l), the 5MTHF fraction of RBC folate was much higher (94·5% vs. 67·4%), polyglutamate chain length was shorter (more tetra- and pentaglutamates), and global DNA methylation was 22% lower. This is the first time that virtually all features of the methylfolate trap hypothesis have been demonstrated in a human with vitamin B12 deficiency. [source] Abdominal venous thrombosis in neonates and infants: role of prothrombotic risk factors , a multicentre case,control studyBRITISH JOURNAL OF HAEMATOLOGY, Issue 2 2000Christine Heller The factor V (FV) G1691A mutation, the prothrombin (PT) G20210A variant, the methylenetetrahydrofolate reductase (MTHFR) T677T genotype, together with fasting homocysteine (HCY) concentration, lipoprotein (Lp)(a), anti-thrombin (AT), protein C (PC), protein S (PS) and anti-cardiolipin antibodies were investigated in 65 consecutively recruited infants (neonate to <,12 months) with renal venous thrombosis (RVT; n = 31), portal vein thrombosis (PVT; n = 24) or hepatic vein thrombosis (HVT n = 10), and 100 age- and sex-matched healthy controls. FV G1691A was found in 14 babies (heterozygous: RVT n = 9, PVT n = 4; homozygous HVT n = 1) and five controls, the MTHFR TT677 genotype together with increased HCY in four infants with thrombosis (RVT n = 2; PVT n = 1; HVT n = 1) compared with one control, and the PT G20210A variant was present in one control only. PC type I deficiency was diagnosed in three patients (RVT n = 2; PVT n = 1) and AT deficiency in two patients (RVT n = 1; PVT n = 1). Three neonates with spontaneous thrombosis showed FV G1691A combined with Lp(a) and the FV G1691A was combined with the PT G20210A genotype in two infants. Additional triggering factors were reported in 27 patients (41·5%). The overall odds ratios (ORs) and 95% confidence intervals (CIs) with respect to the different thrombosis locations were: RVT (OR/CI: 10·9/3·85,31·1; P < 0·0001), PVT (5·47/1·7,17·6; P < 0·0007) and HVT (3·3/0·58,18·7; P = 0·18). The data presented here suggest that genetic prothrombotic risk factors also play an important role in abdominal venous thrombosis during infancy. [source] | ||||||||||||||||||||||||||||