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BACKGROUND The C677T polymorphism of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism has been associated with hypertension and coronary heart disease, but its relationship with carotid artery remains unknown. This study aimed to investigate the association between the C677T polymorphism of the MTHFR gene in patients with confirmed carotid artery atherosclerosis. MATERIAL AND METHODS This retrospective study included 210 patients with carotid artery atherosclerosis (the patient group) and 210 controls (the control group). Color Doppler ultrasound was used to identify carotid artery intimo-medial thickness and atherosclerotic plaques. Sanger sequencing using the polymerase chain reaction (PCR) was used to detect the MTHFR C677T gene polymorphism. Systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting plasma glucose (FPG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), glycosylated hemoglobin (HbA1c), and other laboratory indicators were measured. RESULTS SBP, DBP, FPG, TC, LDL-C, HbA1c, and intimo-medial thickness were significantly increased in the patient group compared with the control group, and HDL-C was significantly lower. The allele frequencies of the C667T locus of MTHFR gene were significantly different between the two groups (P

The cylindrical chaperonin GroEL and its cofactor GroES mediate ATP-dependent protein folding in Escherichia coli by transiently encapsulating non-native substrate in a nano-cage formed by the GroEL ring cavity and the lid-shaped GroES. Mechanistic studies of GroEL/ES with heterologous protein substrates suggested that the chaperonin is inefficient, typically requiring multiple ATP-dependent encapsulation cycles with only a few percent of protein folded per cycle. Here we analyzed the spontaneous and chaperonin-assisted folding of the essential enzyme 5,10-methylenetetrahydrofolate reductase (MetF) of E. coli, an obligate GroEL/ES substrate. We found that MetF, a homotetramer of 33-kDa subunits with (β/α)8 TIM-barrel fold, populates a kinetically trapped folding intermediate(s) (MetF-I) upon dilution from denaturant that fails to convert to the native state, even in the absence of aggregation. GroEL/ES recognizes MetF-I and catalyzes rapid folding, with ~50% of protein folded in a single round of encapsulation. Analysis by hydrogen/deuterium exchange at peptide resolution showed that the MetF subunit folds to completion in the GroEL/ES nano-cage and binds its cofactor flavin adenine dinucleotide. Rapid folding required the net negative charge character of the wall of the chaperonin cavity. These findings reveal a remarkable capacity of GroEL/ES to catalyze folding of an endogenous substrate protein that would have coevolved with the chaperonin system.

Background Studies and systematic reviews have reached inconsistent conclusions on the role of 5, 10-methylenetetrahydrofolate reductase (MTHFR) polymorphism C677T in acute lymphoblastic leukemia (ALL) risk. Material and methods The present meta-analysis comprising of 51 case-control studies, including 7892 cases and 14 280 controls was performed to reevaluate the association between MTHFR C677T polymorphism and ALL risk. Results Statistical differences were found in the dominant model (TT+CT vs. CC, odd ratio (OR)=0.89, 95% CI, 0.79-1.00, P=0.04) and the CT vs. CC (OR=0.89, 95% CI, 0.80-1.00, P=0.05), but not in the allele contrast model (T vs. C, OR=0.92, 95% CI, 0.84-1.01, P=0.08), additive model (TT vs. CC, OR=0.87, 95% CI, 0.73-1.05, P=0.15), or recessive model (TT vs. CT+CC, OR=0.94, 95% CI, 0.81-1.10, P=0.44) in overall populations. In the subgroup analyses stratified by age (children and adults) and ethnicity (Asian and Caucasian), no significant associations between MTHFR C677T polymorphism and ALL risk were observed. Conclusions The current study found no sufficient evidence of a protective role of MTHFR C677T polymorphism in ALL susceptibility.

Background Although many epidemiology studies have investigated the methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and their associations with lung cancer (LC), definite conclusions cannot be drawn. To clarify the effects of MTHFR polymorphisms on the risk of LC, we performed a meta-analysis in Chinese populations. Material/methods Related studies were identified from PubMed, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biology Medicine (CBM) until 16 February 2014. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the associations. Results A total of 11 studies with 2487 LC cases and 3228 controls were included in this meta-analysis. Overall, no significant association was found between MTHFR C677T polymorphism and LC risk when all studies in Chinese populations were pooled into this meta-analysis. In subgroup analyses stratified by geographical location and source of controls, significantly increased risk was found in North China (T vs. C: OR=1.28, 95% CI: 1.14-1.44; TT vs. CC: OR=1.67, 95% CI: 1.33-2.10; TT + CT vs. CC, OR=1.39, 95% CI=1.15-1.69; TT vs. CC + CT: OR=1.46, 95% CI: 1.03-2.06) and in population-based studies (TT vs. CC: OR=1.37, 95% CI: 1.14-1.65; TT vs. CC + CT: OR=1.25, 95% CI: 1.07-1.45). Conclusions This meta-analysis provides evidence that MTHFR C677T polymorphism may contribute to LC development in North China. Studies with larger sample sizes and wider spectrum of populations are warranted to verify this finding.

We show here that NdgR, a known transcriptional activator of isopropylmalate dehydratase in actinomycetes, may have other targets in the cell. An in-frame deletion mutant of ndgR showed unexpectedly poor growth in defined minimal medium even in the presence of leucine. To our surprise, it was supplementation of cysteine and methionine that corrected the growth. Based on this, we propose that NdgR induces cysteine-methionine biosynthesis. Direct involvement of NdgR in the very last steps of methionine synthesis with methionine synthase ( metH ) and 5,10-methylenetetrahydrofolate reductase ( metF ) was examined. From a pulldown assay, it was seen that NdgR was enriched from crude cell lysates with a strong affinity to metH and metF upstream sequences. Direct physical interaction of NdgR with these targets was further examined with a gel mobility shift assay. ndgR , leuC , metH , and metF were inducible in M145 cells upon nutrient downshift from rich to minimal medium but were not induced in the ndgR knockout mutant. Taking these observations together, NdgR-dependent metH-metF expression would account for the abnormal growth phenotype of the ndgR mutant although there may be additional NdgR-dependent genes in the Cys-Met metabolic pathways. As the first transcriptional factor reported for regulating Cys-Met metabolism in Streptomyces , NdgR links two disparate amino acid families, branched-chain amino acids (BCAAs) and sulfur amino acids, at the transcriptional level. Considering that Cys-Met metabolism is connected to mycothiol and one-carbon metabolism, NdgR may have broad physiological impacts.

Celiac disease (CD) is a polygenic chronic enteropathy conferring an increased risk for various nutrient deficiency states. Hyperhomocysteinemia is a frequent finding in CD and may be related to the development of venous thrombosis, cardiovascular disease, and stroke in untreated CD patients. Recently, a possible excess in the frequency of the MTHFR c.677C>T (rs1801133) gene variant in CD patients was reported. The purpose of this study was to determine if there exist differences in the distribution of polymorphic variants of genes involved in homocysteine/methyl group metabolism between CD patients and the general population. A set of 10 gene polymorphisms (MTHFR rs1801133, MTR rs1805087, MTHFD1 rs2236225, MTRR rs1801394, CBS 844ins68, BHMT1 rs7356530 and rs3733890, BHMT2 rs526264 and rs625879, and TCN2 rs1801198) was tested in 134 patients with CD and 160 matched healthy controls. The frequency of the MTR rs1805087 GG genotype in CD patients was lower than in controls (0.01 and 0.06, respectively), although statistical significance was not achieved (P = 0.06). For the other analyzed polymorphisms, there was no evidence of difference in both allelic and genotypic distribution between cases and controls. The exhaustive Multifactor Dimensionality Reduction analysis revealed no combination of interactive polymorphisms predicting the incidence of CD. In contrast to the well-documented clinical observations of increased risks of vascular disease in patients with longstanding untreated CD, in our group of patients no significant association with CD was found for all tested polymorphic variants of genes involved in homocysteine metabolism. These findings should be replicated in studies with a larger sample size. Electronic supplementary material The online version of this article (doi:10.1007/s11033-011-1077-7) contains supplementary material, which is available to authorized users.

Two single nucleotide polymorphisms (SNPs) of 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, A1298C and C677T, were widely considered to be related with various neoplasia disorders. We established a simple and effective capillary electrophoresis (CE) method for detection of two SNPs in MTHFR gene simultaneously. DNA samples were amplified by multiplex PCR with universal fluorescence-labeled primer and analyzed by single-strand conformation polymorphism (SSCP)-CE method. The CE method was performed using 1.5% hydroxyethyl cellulose in 1× TBE buffer containing 1M urea. The PCR products after SSCP procedure were electrokinetically injected at -10 kV, 30s. Separation voltage was -6 kV and the temperature was set at 20°C. The optimal SSCP-CE method was applied to detect two polymorphisms in MTHFR gene of acute lymphoblastic leukemia (ALL) and attention-deficit/hyperactivity disorder (ADHD) patients. Genotyping results were evaluated in terms of relationships between outcomes for ADHD patients after ALL chemotherapy and ALL disease. The SSCP-CE method and multiplex PCR with universal fluorescence primer were used as the fast technique for screening two SNPs in MTHFR gene, A1298C and C677T. The genotyping data were coincident with DNA sequencing. This SSCP-CE method was found feasible for detecting mutation of MTHFR gene in populations.

To investigate the impact of MTHFR C677T polymorphism on Bcl-2 gene promoter CpG island (CGI) methylation and Bcl-2 protein expression.MTHFR polymorphisms of 86 sporadic colorectal cancer (CRC) patients and 100 healthy volunteers were analyzed by PCR-based restriction fragment length polymorphism, and Bcl-2 promoter CGI methylation in 86 CRC tissues and 86 paired nonneoplastic adjacent tissues was determined by methylation-specific PCR. Bcl-2 oncoprotein expression in 70 CRC tissues and paired nonneoplastic adjacent tissues was detected by immunohistochemistry.The frequency of MTHFR 677 T allele and combined variant genotypes (677CT + TT) in CRC patients was significantly higher than that in healthy controls (p = 0.023 and p = 0.035, respectively), and there is a significant association between 677TT or 677(CT + TT) genotypes and CRC (OR = 2.534, p = 0.045 and OR = 1.888, p = 0.035, respectively). The frequency of methylated Bcl-2 promoter CGI in tumor tissues was significantly lower than that in nonneoplastic adjacent tissues (p = 0.014). The frequency of methylated Bcl-2 promoter CGI in CRC tissues of the individuals with CC genotype was significantly higher than that of those with CT/TT genotypes (p = 0.018), there was significant distribution difference of C and T alleles between individuals with methylated and unmethylated Bcl-2 promoter CGI in colorectal cancer tissues (p = 0.023). Bcl-2 promoter hypomethylation was significantly correlated with Bcl-2 oncoprotein expression in colorectal cancer tissues (r = 0.558, p0.001).Bcl-2 promoter is hypomethylated in colorectal cancer tissue, and there is a significant correlation between MTHFR 677 TT or CT/TT genotypes and CRC or Bcl-2 promoter CGI methylation/oncoprotein expression in CRC.

Altitude illness refers to a group of environmentally mediated pathophysiologies. Many people will suffer acute mountain sickness shortly after rapidly ascending to a moderately hypoxic environment, and an unfortunate few will develop potentially fatal conditions such as high altitude pulmonary edema or high altitude cerebral edema. Some individuals seem to be predisposed to developing altitude illness, suggesting an innate contribution to susceptibility. The implication that there are altitude-sensitive and altitude-tolerant individuals has stimulated much research into the contribution of a genetic background to the efficacy of altitude acclimatization. Although the effect of altitude attained and rate of ascent on the etiology of altitude illness is well known, there are only tantalizing, but rapidly accumulating, clues to the genes that may be involved. In 2006, we reviewed what was then known about the genetics of altitude illness. This article updates that review and attempts to tabulate all the available genetic data pertaining to these conditions. To date, 58 genes have been investigated for a role in altitude illness. Of these, 17 have shown some association with the susceptibility to, or the severity of, these conditions, although in many cases the effect size is small or variable. Caution is recommended when evaluating the genes for which no association was detected, because a number of the investigations reviewed in this article were insufficiently powered to detect small effects. No study has demonstrated a clear-cut altitude illness gene, but the accumulating data are consistent with a polygenic condition with a strong environmental component. The genes that have shown an association affect a variety of biological pathways, suggesting that either multiple systems are involved in altitude pathophysiology or that gene-gene interactions play a role. Although numerous studies have been performed to investigate specific genes, few have looked for evidence of heritability or familial transmission, or for epidemiological patterns that would be consistent with genetically influenced conditions. Future trends, such as genome-wide association studies and epigenetic analysis, should lead to enhanced understanding of the complex interactions within the genome and between the genome and hypoxic environments that contribute to an individual's capacity to acclimatize rapidly and effectively to altitude.

Background— Carotid intima-media thickness (CIMT) is highly heritable and associated with stroke and myocardial infarction, making it a promising quantitative intermediate phenotype for genetic studies of vascular disease. There have been many CIMT candidate gene association studies, but no systematic review to identify consistent, reliable findings. Methods and Results— We comprehensively sought all published studies of association between CIMT and any genetic polymorphism. We obtained additional unpublished data and performed meta-analyses for the 5 most commonly studied genes (studied in at least 2 studies in a total of >5000 subjects). We used a 3-step meta-analysis method: meta-analysis of variance; genetic model selection; and random effects meta-analysis of the mean CIMT difference between genotypes. We performed subgroup analyses to investigate effects of ethnicity, vascular risk status, and study size. We accounted for potential reporting bias by assessing qualitatively the possible effects of including unavailable data. Polymorphisms in 3 of the 5 genes (apolipoprotein E, angiotensin I converting enzyme, and 5,10-methylenetetrahydrofolate reductase) had an apparent association with CIMT, but for all these, we found evidence of small study bias. Apolipoprotein E ε2/ε3/ε4 was the only polymorphism with a persistent, statistically significant but modest association when we restricted analysis to larger studies (>1000 subjects). Conclusions— Of the most extensively studied polymorphisms, apolipoprotein E ε2/ε3/ε4 is the only one so far with a convincing association with CIMT. Larger studies than have generally been performed so far may be needed to confirm the associations identified in future genome-wide association studies, and to investigate modification of effect according to characteristics such as ethnicity and vascular risk status.

Objective: The 5,10-methylenetetrahydrofolate reductase gene (MTHFR) has been linked to unipolar major depressive disorder (MDD) and magnetic resonance imaging (MRI) hyperintensities. The authors examined the relationship between the MTHFR C677T polymorphism (C677T) and a) geriatric depression, b) MRI hyperintense lesion volume, and c) neurocognitive test performance. Design: Cross-sectional. Setting: Duke University Medical Center. Participants: Depressed (N = 178) and comparison (N = 85) elderly subjects. Measurements: Subjects had blood drawn to assess MTHFR genotype, were imaged by MRI to determine their white matter hyperintense lesion (WML) and gray matter hyperintense lesion (GML) volume, and assessed using a comprehensive neurocognitive battery evaluating multiple domains of function. Linear regression models were fit to test the effect of genotype, a depression by genotype interaction, and an age by genotype interaction on both hyperintense lesion volume measures and neurocognitive task performance. Results: The MTHFR C677T genotype by age interaction term was significantly associated with MRI WML volume (p = 0.0175); however, this relationship was no longer statistically significant when WML volumes underwent a log transformation to produce a more normal distribution. The 677T allele was neither more frequent in depressed subjects nor associated with either gray matter hyperintensity volume or neurocognitive test performance. Conclusions: MTHFR genotype affects the relationship between age and WML volume where individuals who carry the 677T allele exhibit greater WML volume by age, although this relationship should be verified given the failure to replicate the finding using transformed WML volumes. Genotype was not related to GML volume, cognitive function, or presence of depression, although demographic differences could account for this negative finding.

Summary A 23-year-old man using Na-Valproic acid (VPA) was admitted to our clinic due to convulsion. The neurological examination revealed right hemiparesis. From the exitus notes, we learned that his two siblings had died from status epilepticus. Magnetic resonance imaging (MRI), MRI spectroscopy, and diffusion-weighted investigations (DWI) showed acute–subacute ischemic stroke in the left temporo-parieto-occipital region. The patient had an ischemic stroke. Heterozygote methylenetetrahydrofolate reductase (MTHFR) 677C/T polymorphism was determined on genetic examination. The homocysteine (Hcy) level was 18.2 mmol/l (5–15 mmol/l). So VPA treatment was stopped and oxcarbazepine treatment was started. MTHFR 677C/T polymorphism is associated with the risk of vascular diseases due to hyperhomocysteinemia. Heterozygote (MTHFR) 677C/T polymorphism has not been reported to be associated with epilepsy. In patients with heterozygote (MTHFR) 677C/T polymorphism and under long-term use of certain drugs the determination of Hcy plasma levels may be useful to prevent the development of atherothrombotic disease.

Objectives: In this study we analyzed the occurrence of ischemic brain stroke in Northern Poland in regard to risk factors. Design and methods: 131 ischemic stroke patients and 64 controls were studied. Analyzed risk factors included conventional risk factors, total plasma homocysteine level and polymorphisms of the main enzymes of homocysteine metabolism—methylenetetrahydrofolate reductase (polymorphisms C677T and A1298C) and cystathionine β synthase (polymorphism T833C). Results: We confirmed the occurrence of a number of conventional risk factors in ischemic stroke. We found that hyperhomocysteinemia is an independent risk factor (p = 0.0001). Plasma homocysteine correlated inversely with plasma vitamin B6. We also found a relationship between C677T polymorphism type and hyperhomocysteinemia (p = 0.0266). Conclusions: The occurrence of studied polymorphisms in the population of northern Poland was higher than reported previously for similar populations. However, none of the studied genetic factors were found to be significant risk factors in ischemic brain stroke.

Methionine auxotrophic mutants of Methylophilus methylotrophus AS1 expressing a mutant form of dapA (dapA24) encoding a dihydrodipicolinate synthase desensitized from feedback inhibition by L-lysine, and mutated lysE (lysE24) encoding the L-lysine exporter from Corynebacterium glutamicum 2256, produced higher amounts of L-lysine from methanol as sole carbon source than did other amino acid auxotrophic mutants. Especially, the M. methylotrophus 102 strain, carrying both dapA24 and lysE24, produced L-lysine in more than 1.5 times amounts higher than the parent. A single-base substitution was identified in this auxotroph in codon-329 of the open reading frame of metF, encoding 5,10-methylene-tetra-hydrofolate reductase. We constructed a metF disruptant mutant carrying both dapA24 and lysE24, and confirmed increases in L-lysine production. This is the first report to the effect that metF deficient increased L-lysine production in methylotroph.

Translation initiation from the ribosomal P-site is the specialty of the initiator tRNAs (tRNA(fMet)). Presence of the three consecutive G-C base pairs (G29-C41, G30-C40 and G31-C39) in their anticodon stems, a highly conserved feature of the initiator tRNAs across the three kingdoms of life, has been implicated in their preferential binding to the P-site. How this feature is exploited by ribosomes has remained unclear. Using a genetic screen, we have isolated an Escherichia coli strain, carrying a G122D mutation in folD, which allows initiation with the tRNA(fMet) containing mutations in one, two or all the three G-C base pairs. The strain shows a severe deficiency of methionine and S-adenosylmethionine, and lacks nucleoside methylations in rRNA. Targeted mutations in the methyltransferase genes have revealed a connection between the rRNA modifications and the fundamental process of the initiator tRNA selection by the ribosome.

Background Hyperhomocysteinemia, a condition that is strongly determined by dietary intake of B vitamins, has been suggested to be an independent risk factor for ischemic stroke (IS). To test this hypothesis, we performed a meta-analysis to investigate the associations between 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism, which plays a critical role in modulating plasma homocysteine concentrations, and IS risk. Materials and Methods We searched case–control studies on the association between MTHFR C677T genetic polymorphism and susceptibility to IS through PubMed, Embase, and Medline databases from January 2000 up to October 2014. The random-effects model was employed because moderate heterogeneity across studies was observed, as assessed by I 2 statistic. Publication bias was estimated using funnel plot and Egger's regression test. Results A total of 22 case–control studies were included in the current meta-analysis. Significant associations between MTHFR C677T genetic polymorphism and IS were found under the dominant model (pooled odds ratio [OR] = 1.40, 95% confidence interval [CI]: 1.24-1.57), the recessive model (pooled OR = 1.37, 95% CI: 1.16-1.61), and the allele model (pooled OR = 1.29, 95% CI: 1.18-1.42). Conclusions The meta-analysis suggests that MTHFR C677T genetic polymorphism is significantly associated with susceptibility to IS, which provides evidence supporting hyperhomocysteinemia as a risk factor for stroke.

Vascular disease and its risk factors have been associated with the age-related hearing loss. We examined the association of elevated plasma homocysteine and its determinants with hearing levels. Pure-tone air conduction thresholds in 728 individuals with sensorineural hearing loss were not associated with homocysteine, erythrocyte folate and Vitamin B6. Low concentrations of serum folate and Vitamin B12 were associated with better hearing. When folate status was below the median, 5,10-methylenetetrahydrofolate reductase (MTHFR) 677TT homozygotes had similar hearing levels to subjects with a C allele. However, when folate status was above the median, MTHFR 677TT homozygotes had on an average 5 dB (p = 0.037) and 2.6 dB (p = 0.021) lower PTA-high and PTA-low hearing thresholds, respectively, than the subjects with a 677C allele. The relationship between serum folate and hearing thresholds appeared to be dependent on MTHFR 677 genotype (CC, r = 0.13, p = 0.034; TT, r = -0.10, p = 0.291). This supports the hypothesis that a greater one-carbon moiety commitment to de novo synthesis of nucleotides and an increase in formyl-folate derivatives relative to methyl-folate derivatives is protective for hearing.

Background: Elevated plasma total homocysteine (tHcy) predisposes to vascular disease and results from interactions between genetic and nutritional factors. MTHFR C677T increases tHcy in association with low folate. CBS 844ins68 lowers tHcy and negates the raising effect of MTHFR C677T in healthy subjects, but it is unclear if this is the case in subjects at high risk of vascular disease. This study examines the effect on plasma tHcy of interactions between these polymorphisms in an at-risk group. Methods: Blood samples were collected from 376 subjects at increased risk of coronary artery disease. Plasma tHcy and vitamin B6 were measured by HPLC and red cell folate and serum vitamin B12 were measured by immuno-luminometric assay. MTHFR C677T and CBS 844ins68 status was established by standard PCR techniques. Results: MTHFR TT predisposed to hyperhomocysteinaemia; this was increased in the presence of low folate ( P12 ( P12 ( r= -0.26, P6 ( r= -0.25, P677T and CBS 844ins68. Discussion: In this population at high risk of coronary artery disease, plasma tHcy was determined by vitamin status. This was exacerbated by the MTHFR C677T mutation. CBS 844ins68 did not influence tHcy and did not negate the tHcy-raising effect of MTHFR C677T.

Methionine synthase reductase (MTRR) regenerates methylated cobalamin levels from the oxidised cob(II)alamin form and in so doing plays a crucial role in maintaining the active state of methionine synthase (MTR). MTR is an essential enzyme catalyzing the conversion of homocysteine to methionine. Single nucleotide polymorphisms (SNPs) within the MTRR gene may potentially compromise MTR activity leading to elevated homocysteine levels, a known risk factor for neural tube defects (NTDs). We studied the MTRR polymorphisms I22M (66A-->G), S175L (524C-->T), and K350R (1049A-->G) as potential NTD risk factors in a large homogeneous Irish NTD population. Degree of risk was assessed via case/control comparison, log-linear analysis, and transmission disequilibrium testing. No association was found between NTDs and I22M in mothers (p = 0.16, OR1.14 [0.95-1.38], n = 447) or cases (p = 0.13, OR1.15 [0.96-1.38], n = 470) compared to controls (n = 476). A dominant I22M paternal effect was found through case/control comparison and log-linear modelling (p = 0.019) (goodness-of-fit p=0.91, OR 1.46 [1.10-1.93], n = 423). No significant NTD association was found with S175L or K350R in cases or their parents and no interactions were observed between these polymorphisms and the D919G variant of MTR or the A222V variant of 5,10-methylenetetrahydrofolate reductase (MTHFR). We also compared the frequencies of I22M, S175L, and K350R in African-Americans versus American-Caucasians. The frequencies of I22M and K350R differed significantly between the two groups (p = 0.0005 and p = 0.0001, respectively). Our findings do not support an important role for these MTRR variants in NTDs.

Aim: We examined whether total homocysteine, B vitamins and the 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C→T polymorphism are related to common carotid intima-media thickness, a marker of atherosclerosis, and carotid distension, a marker of arterial stiffness. Methods: We used cross-sectional data from 819 individuals aged 50–70 years. B-mode ultrasound of the distal common carotid arteries was performed to determine maximum carotid intima-media thickness, mean carotid intima-media thickness and distension. Results: Carotid intima-media thickness and distension did not differ across homocysteine, serum folate, vitamin B 6 and vitamin B 12 quartiles or between MTHFR C677T genotype. Erythrocyte folate was independently associated with maximum carotid intima-media thickness (mean difference first versus third quartile, 0.03mm, 95% CI 0.004–0.06mm; first versus fourth quartile, 0.03mm, 95% CI −0.002 to 0.06mm). Further adjustment for homocysteine did not affect this association. Folate deficient subjects had greater maximum carotid intima-media thickness than those with high-normal folate concentrations (serum folate: mean difference 0.05mm, 95% CI 0.01–0.08mm; erythrocyte folate: mean difference 0.04mm, 95% CI −0.03 to 0.11mm). Conclusion: Low folate concentrations, independent of hyperhomocysteinemia, may promote atherogenesis. Our findings confirm the null association of homocysteine with carotid intima-media thickness observed in other population-based studies, suggesting that hyperhomocysteinemia does not perpetuate atherosclerosis or arterial stiffness.

Background Recently, a new mutation of the 5,10-methylenetetrahydrofolate reductase (MTHFR) encoding gene was first described (1793G > A). Only few reports have studied the prevalence of this polymorphism, especially in combination with other MTHFR mutations (677C > T, 1298A > C). Methods We cross-sectionally identified the novel MTHFR 1793G > A polymorphism in 730 kidney transplant recipients. MTHFR 677C > T and 1298A > C were also assessed and the frequency of each was described individually as well as in cross-tabulation with the other MTHFR genotypes. The expected number of patients for each MTHFR genotype combination was calculated and contrasted with the observed numbers. Fisher's exact test was used for statistical inference. Results The allelic frequency of MTHFR 1793G > A was 0·052. Seventy-two patients (9·9%) were heterozygous and two patients (0·3%) were homozygous. From the cross-tabulations, we identified 53 patients (expected: 33·6) with the MTHFR 1298AC/1793GA genotype and 17 patients (expected: 6·7) with the MTHFR 1298CC/1793GA genotype. Furthermore, we found two patients with double homozygosity for MTHFR 1793G > A and MTHFR 1298A > C (MTHFR 1793AA/1298CC genotype). The frequencies of these genotype combinations were substantially larger than could be expected (P A and MTHFR 1298A > C genotypes, possibly owing to a mutually stabilizing effect on MTHFR enzyme activity.

Nitrous oxide irreversibly oxidizes the cobalt atom of vitamin B12, inhibiting the cobalamin-dependent enzyme methionine synthase, which has a key role in many biochemical reactions that involve the nervous system. This case report concerns the neurologic deterioration and death of a child anesthetized twice, over a short period, with nitrous oxide before an inherited deficiency in 5,10-methylenetetrahydrofolate reductase (MTHFR), which is critical in similar metabolic pathways, was diagnosed.

Item does not contain fulltext BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) is one of the main regulatory enzymes of homocysteine metabolism. Elevated plasma total homocysteine (tHcy) is a major risk for cardiovascular disease. A common 677C-->T mutation in the MTHFR gene results in decreased enzymic activity, and contributes to increased plasma tHcy, in association with low plasma folate. A recently described 1298A-->C mutation in the MTHFR gene clearly reduces MTHFR activity (although to a lesser extent than the 677C-->T) but its effect on plasma tHcy levels is not yet clear. AIM: To investigate the frequency of these two MTHFR polymorphisms in a Portuguese population, and to correlate the MTHFR genotype with the biochemical phenotype at the level of homocysteine and folate concentrations. DESIGN: Prospective population survey. METHODS: We studied 117 healthy volunteers (71 females, 46 males). The 677C-->T and 1298A-->C mutations were screened by PCR-RFLP. Levels of plasma tHcy and folate, and red blood cell folate, were determined. RESULTS: The allele frequencies of the 677C-->T and 1298A-->C mutations were 0.33 and 0.28, respectively. Homozygotes for the 677C-->T mutation had significantly elevated plasma tHcy and RBC folate levels and significantly lowered plasma folate concentrations than subjects without the mutation. The 1298A-->C mutation showed a significant effect on plasma tHcy, but not on plasma folate or RBC folate levels. DISCUSSION: The observed 677T allele frequency is not consistent with the idea of a north-south gradient as previously suggested. The 1298A-->C mutation is common in Portugal. Both MTHFR mutations showed effects on plasma tHcy levels.

Thrombophilias are inherited or acquired conditions that predispose individuals to thromboembolism. New inherited thrombophilias are recognized each year. Some, but not all, studies have found an association between inherited thrombophilias and adverse pregnancy outcomes, including fetal loss. The controversy regarding the clinical implications of thrombophilias in pregnancy is clouded by differences in study populations, the number of thrombophilias tested, interactions between thrombophilias, and the retrospective nature of most studies, just to name a few factors. The lack of adequately designed studies also extends to clinical management. Clear evidence to determine when to test, whom to test, which thrombophilias to test for, when to treat, and what to treat with is not available. Further studies to investigate these questions are urgently needed.

The folate cycle and disease in humans. The prevalence of hyperhomocysteinemia in renal disease patients, its treatment by folate administration, and its aggravation by the 677 C→T mutation of methylene-tetrahydrofolate (methylene-THF) reductase has established the folate cycle as an important factor in the pathogenesis and management of renal disease. Proper function of the folate cycle depends on normal function of involved enzymes adequate of the vitamin and its correct disposition within the body. Vital processes in folate disposition include conversion of dietary folylpolyglutamates to monoglutamates, intestinal absorption, receptor and carrier-mediated transport across cell membranes, and cellular export. Folate coenzymes are responsible for the one-carbon unit transfer in intermediary metabolism and are required for several reactions in key metabolic processes, for example of purine, pyrimidine and methionine synthesis, and glycine and serine metabolism. Methionine synthase and its recently discovered reducing protein as well as methylene tetrahydrofolate reductase are key folate enzymes in homocysteine metabolism. Deficiencies of these enzymes are important causes of severe disease in the rare remethylation defects causing homocystinuria. Knowledge of their catalytic and molecular properties is important in understanding possible causes of moderate hyperhomocysteinemia, as for example, the well-known 677 C→T transition of methylene tetrahydrofolate reductase.

Effect of MTHFR genotypes and hyperhomocysteinemia on patient and graft survival in kidney transplant recipients. Background The total homocysteine (tHcy) plasma level, which is partly determined by the MTHFR 677C→T genotype, may be associated with vascular disease. We prospectively examined the influence of MTHFR genotypes (677C→T, 1298A→C) and tHcy plasma concentration on all cause mortality and graft outcomes of renal transplant recipients. Methods Baseline tHcy plasma levels of 189 patients (three groups with either the MTHFR 677CC, CT or TT genotype, including 63 patients in each group, were matched for age, gender, body mass index and creatinine clearance at baseline), were obtained between September 1996 and May 1997. Follow-up data (time until return to dialysis therapy, time and cause of death) were collected from April to June 1999. Kaplan-Meier survival estimations were calculated and plotted, the groups (three MTHFR 677C→T genotype groups, or three MTHFR 1298A→C genotype groups, or two groups with tHcy plasma levels above/below 15 μmol/L) were compared by log-rank test. Age, gender, body mass index (BMI), time since transplantation, serum creatinine, creatinine clearance, combined MTHFR 677C→T/1298A→C genotypes, tHcy, folate and vitamin B 12 plasma levels were evaluated with regard to graft and patient survival in a multivariate Cox-proportional hazard regression model. Results During the follow-up period of 2.26 ± 0.66 years, 9 patients died (5 in the TT, 2 in the CT and 2 in the CC genotype group; P = 0.34) and 22 returned to dialysis treatment (7 in the TT, 9 in the CT and 6 in the CC genotype group; P = 0.65). There was also no influnce of MTHFR 1298A→C genotypes (AA genotype, 114 patients; AC genotype, 64 patients; CC genotype, 11 patients) on patient or graft survival ( P = 0.7087 and P = 0.1633, respectively). Two of 93 patients with a tHcy plasma level ≤15 μmol/L died, in contrast to 7 of 96 patients in the low tHcy > 15 μmol/L group, P = 0.0778. Two patients in the low tHcy group had to return to dialysis, in contrast to 20 patients in the high tHcy group ( P = 0.0001). In the multivariate model there was no significant predictor of patient survival, and the serum creatinine was the only predictor of graft survival ( P Conclusions In summary, our study shows that neither MTHFR 677C→T/1298A→C genotypes nor hyperhomocysteinemia are independently associated with patient or graft survival following kidney transplantation.

An open reading frame of 885 nucleotides was identified as the Leptospira interrogans metF gene. The deduced amino acid sequence (294 amino acids) showed similarities with Escherichia coli methylene tetrahydrofolate reductase (MetF or MTHFR) (33% identity) and with the N-terminal part of human MTHFR (33% identity). The L. interrogans metF gene complements an E. coli metF mutant to prototrophy, suggesting the functionality of the folate branch converging to form methionine. In addition, the L. interrogans MetF was found to be thermolabile. The metF gene belonged to the CII secondary chromosome, in contrast to the previously isolated metY and metX genes, which have been localized to the CI chromosome of Leptospira sp.

We hypothesized that elevated plasma homocysteine concentrations (hyperhomocysteinemia) exist in patients receiving antiepileptic drugs (AED), and a long-term administration of AED may result in an increased risk of occlusive vascular disease in these patients. A total of 62 patients who received AED monotherapy (phenytoin, lamotrigine, carbamazepine or valproate) participated in this study. Blood concentrations of homocysteine, folate, vitamin B-12 and pyridoxal-5′-phosphate (PLP, a coenzyme form of vitamin B-6) were measured, and thermolabile genotypes of 5,10-methylenetetrahydrofolate reductase (MTHFR) were also determined. Of 62 patients, only seven (11.4%) had hyperhomocysteinemia. Of 20 patients who received phenytoin, three (15.0%) had hyperhomocysteinemia, whereas 85% of these had plasma folate concentrations below the normal range. However, erythrocyte folate concentrations were abnormally low in only 25% of the patients who received phenytoin. Valproate administration increased serum vitamin B-12 concentrations. Over 55% of the entire patients had PLP concentrations below the normal range, although the reason is unknown. Only three patients had the homozygous thermolabile genotype of MTHFR; therefore, meaningful statistical analysis was not possible in this study. However, one patient with homozygous genotype who received phenytoin therapy had hyperhomocysteinemia with poor folate nutritional status, and the other two had normal homocysteine concentrations with normal folate status. Our data suggest that hyperhomocysteinemia is not a serious clinical concern in epileptic patients when folate nutriture is adequate.

Objectives: To implement cost effective and clinically relevant thrombophilic genotyping and homocysteine analysis in our coagulation laboratory. Methods: We describe genotyping assays for three of the genetic defects associated with hereditary thrombosis: factor V Leiden A1691G, methylenetetrahydrofolate reductase C677T, and prothrombin gene G20210A. A second confirmatory assay for factor V Leiden using allele specific oligonucleotide polymerase chain reaction is also presented. We suggest an algorithm for the rational integration of the traditional assays routinely used to investigate venous thrombosis with genotyping and plasma homocysteine measurements. Results: These polymerase chain reaction based assays were designed to be performed under identical reaction conditions, permitting simultaneous setup, amplification, digestion, and analysis. Conclusions: The three genotyping assays presented are robust and relatively easy to perform. Use of an algorithm will ensure efficient resource utilization and minimize unnecessary testing.

This paper examines whether there is a relationship between a common mutation in the methylenetetrahydrofolate reductase gene, MTHFR*val, and the risk of colorectal cancer, with or without lymph node metastases. MTHFR genotypes were ascertained from peripheral leukocyte samples obtained from 200 colorectal patients, including TMN stages I-VI, and from 460 healthy, unrelated adults without colorectal cancer, who served as controls. The frequency of homozygosity for the MTHFR*val/*val genotype among the colorectal cancer patients was lower (14.0%) than among controls (16.1%). The latter finding results in an estimated MTHFR*val allele frequency of 0.41. The MTHFR*val allele (677CT) reduces colorectal risk slightly [odds ratio (OR), 0.87]. However, there was a significantly higher incidence of metastatic lymph nodes per case in MTHFR*val/*val patients, when compared with MTHFR*ala/*ala controls (6.9 +/- 1.55 vs. 3.7 +/- 0.57, p = 0.003). These results suggest that the MTHFR genotype might be of prognostic significance in colorectal carcinoma.

Observational studies have provided leads regarding a number of micronutrients which may account for the apparent protective effects of high intakes of vegetables and fruit against many types of cancer. In general, these leads have not been confirmed by randomised controlled trials. This apparent conflict raises issues about the timing and duration of a critical period or periods during which micronutrient intake may influence the development of cancer, the dose, possible interaction between high doses of micronutrients and exposures conferring a high risk of cancer and gene-micronutrient interactions. When gene-environmental interaction exists, failure to take both of these sets of factors into account leads to bias in the estimation of disease risk. As a result of recent advances, it is now possible to take measures of genetic susceptibility into account. Therefore, in future studies, the opportunity should be taken to obtain DNA samples to determine genotypes for polymorphisms potentially affecting micronutrient metabolism.

Whether the 677C-T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene acts as a risk factor for homocysteine-related vascular disease remains a matter of debate. Testing for the 677C-T nucleotide substitution and assay of plasma homocysteine were carried out simultaneously in 69 controls and 113 vascular disease patients from the Paris area. The variant gene frequency as well as the variant homozygous genotype frequency were very similar in controls and patients. Conversely, plasma homocysteine levels were substantially higher in patients than in controls. A slight interaction between the 677C-T MTHFR polymorphism and homocysteinaemia was observed in the patient group only, while a negative correlation between fasting homocysteine and plasma folate levels was found in all individuals homozygous for the 677C-T MTHFR genotype, irrespective of vascular disease. These data suggest that the 677C-T MTHFR polymorphism is not a major determinant of the vascular disease but contributes to increased plasma homocysteine concentration in conjunction with low plasma folate levels.

OBJECTIVE: To estimate the risk for spina bifida associated with the common mutation C677T of the MTHFR gene in a country with a relatively low prevalence of NTDs. DESIGN: Case-control study. SUBJECTS: Cases: 203 living patients affected with spina bifida (173 myelomeningocele and 30 lipomeningocele); controls: 583 subjects (306 young adults and 277 unselected newborns) from northern and central-southern Italy. SETTING: Cases: three spina bifida centres; young adult controls: DNA banks; newborn controls: regional neonatal screening centres. MAIN OUTCOME MEASURES: Prevalence of the C677T genotypes in cases and controls by place of birth; odds ratios for spina bifida and estimated attributable fraction. RESULTS: The prevalence of T/T, T/C, and C/C genotype was 16.6%, 53.7%, and 29.7% in controls and 25.6%, 43.8%, and 30.6% in cases, respectively. We found no differences between type of defect or place of birth. The odds ratio for spina bifida associated with the T/T genotype v C/C plus T/C was 1.73 (95% CI 1.15, 2.59) and the corresponding attributable fraction was 10.8%. No increased risk was found for heterozygous patients (OR=0.79, 95% CI 0.53-1.18). CONCLUSION: This study, as well as the meta-analysis we updated, shows that homozygosity for the MTHFR C677T mutation is a moderate risk factor in Europe, and even in Italy where there is a relatively low prevalence of spina bifida. The estimated attributable fraction associated with this risk factor explains only a small proportion of cases preventable by periconceptional folic acid supplementation. Thus, other genes involved in folate-homocysteine metabolism, their interaction, and the interaction between genetic and environmental factors should be investigated further.

We present a case of combined central retinal vein and cilioretinal artery occlusion which, due to the absence of the temporal branch retinal artery, was initially misdiagnosed as a combined central retinal vein occlusion and temporal branch retinal artery occlusion. Given that - in contrast to cases of combined central artery and central retinal vein occlusion - the prognosis for cilioretinal artery occlusion with central retinal vein occlusion is quite good, this case illustrates the importance of suspecting an unusual condition in the presence of a combined occlusion.

Major determinants of hyperhomocysteinemia in peritoneal dialysis patients. The mechanisms leading to elevated total homocysteine concentrations in peritoneal dialysis patients are only partially understood. We show that a common polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene (C677T transition) results in increased total homocysteine levels in peritoneal dialysis patients compared to age- and sex-matched healthy individuals. The allelic frequency of the C677T transition in the MTHFR gene in peritoneal dialysis patients (0.29) was comparable to the frequency in healthy individuals (0.34). Separate comparison of the total homocysteine plasma levels between non-carriers of the MTHFR polymorphism (C/C), heterozygous (C/T) and homozygous (T/T) subjects was performed by analysis of covariance in the patient and the control group. In the patient group the mean total homocysteine level was 61.7 ± 40.1 μmol/liter in individuals with the (T/T) genotype, which was significantly higher than the total homocysteine concentration of 23.1 ± 15.8 μmol/liter in (C/T) patients and 22.2 ± 11.1 μmol/liter for non-carriers ( P = 0.0001). Vitamin B 12 ( P = 0.0001), folate ( P = 0.0005), serum creatinine ( P = 0.016), albumin ( P = 0.0157) and dialysis center ( P = 0.0173) significantly influenced total homocysteine plasma levels in peritoneal dialysis patients, whereas this was not the case for age, gender, weekly Kt/V, weekly creatinine clearance, residual renal function, duration of dialysis, mode of peritoneal dialysis and vitamin intake. Folate levels in peritoneal dialysis patients were significantly affected by the MTHFR genotype ( P = 0.016). Elevated total homocysteine levels in diabetic patients with cardiovascular disease were associated with increased cardiovascular morbidity. In summary, the present study provides evidence that homozygosity for the C677T transition in the MTHFR gene, low vitamin B 12 and low folate levels result in elevated total homocysteine levels in peritoneal dialysis patients.

Moderate hyperhomocysteinaemia (MHH) is a risk factor for arteriosclerosis and thrombosis. About 10%-20% of the normal population have homocysteine levels contributing to an increased risk for arterial and venous disease. Main regulating enzymes of homocysteine metabolism are cystathionine beta-synthase (CBS) and methylenetetrahydrofolate reductase (MTHFR). Heterozygosity for CBS deficiency is most likely not an important cause for MHH in vascular disease. A recently discovered cause of MHH is reduced MTHFR activity due to a homozygous C677T mutation in the coding region of MTHFR. This mutation has been related to an increased risk for cardiovascular disease, although a number of studies are not confirmative. The elevated homocysteine levels due to this mutation can be normalized by administration of vitamins involved in homocysteine metabolism, in particular folate.

Low folate intake is an important determinant of elevated blood levels of homocysteine. Because elevated homocysteine has been shown to be a possible graded risk factor for CHD, sufficient folate intake may be important in the prevention of CHD. The magnitude of the association between folate and CHD is consistent with its effects on homocysteine.

The role of homozygosity for the C677T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene as an independent risk factor for primary and recurrent stroke has been questioned, although recent data appear to be supportive. However, the association of homozygous C677T MTHFR mutation with silent brain infarctions in infancy has not been reported. The authors describe an 11-month-old male who had suffered a silent brain infarction followed by a symptomatic arterial stroke. The evaluation revealed mildly elevated homocysteine levels secondary to homozygous C677T alleles for MTHFR and iron deficiency anemia. An extensive evaluation for other causes of infarction was negative. We suggest that the mother's homozygous MTHFR status played a role in the early onset of stroke and that iron deficiency anemia may have contributed to the recurrence. The patient was treated with anticoagulation therapy, folic acid, and iron supplementation and has not had a recurrent event during 3 years of follow-up. This case provides further evidence that homozygous MTHFR mutation is a predisposing factor for early and recurrent pediatric stroke, including silent infarcts, especially in the presence of other risk factors.

Total plasma homocysteine (tHcy) was significantly higher in 28 children with spina bifida (median 6.05 mumol/l) as compared with 76 controls (median 4.94 mumol/l). This difference was confined to a subgroup of patients (16/28) with one or two C677T-mutated alleles in the methylenetetrahydrofolate reductase gene. Since we found no significant difference between patients and controls in serum folate, erythrocyte folate, serum cobalamin or serum methylmalonic acid, which were within the normal range for both patients and controls, the elevated tHcy could not be attributed to vitamin deficiencies. Our findings point to an additional genetic defect involving folate-dependent enzymes in a subgroup of patients with neural-tube defects.

Periconceptional folate intake reduces both the occurrence and recurrence risk of neural tube defects. Plasma homocysteine levels can be elevated in mothers of a child with a neural tube defect, suggesting a dysfunctional folate metabolism. Very recently we showed that a common 677C--T mutation in the 5,10-methylene tetrahydrofolate reductase gene, causing thermolability of the enzyme, is a risk factor for spina bifida offspring. Restriction enzyme analysis of the genomic 5,10-methylene tetrahydrofolate reductase polymerase chain reaction fragment revealed a significantly higher prevalence of a +/+ genotype among spina bifida patients and their mothers. The risk for spina bifida offspring is the strongest if both the mother and her child have the mutation in the homozygous state. Enzymatic analysis showed that homozygosity for the 677C--T mutation causes a decreased 5,10-methylene tetrahydrofolate reductase activity, resulting in elevated plasma homocysteine and red blood cell folate levels and lowered plasma folate and cysteine values. This extended study demonstrates that a nucleotide substitution in the coding region of 5,10-methylene tetrahydrofolate reductase, resulting in reduced activity and an impaired homocysteine and folate metabolism, is a genetic risk factor for spina bifida.

Statistical studies have demonstrated that various agents may reduce the risk of cancer’s development. One of them is activity of flavin-dependent enzymes such as flavin-containing monooxygenase (FMO)GS-OX1, FAD-dependent 5,10-methylenetetrahydrofolate reductase and flavin-dependent monoamine oxidase. In the last decade, many papers concerning their structure, reaction mechanism and role in the cancer prevention were published. In our work, we provide a more in-depth analysis of flavin-dependent enzymes and their contribution to the cancer prevention. We present the actual knowledge about the glucosinolate synthesized by flavin-containing monooxygenase (FMO)GS-OX1 and its role in cancer prevention, discuss the influence of mutations in FAD-dependent 5,10-methylenetetrahydrofolate reductase on the cancer risk, and describe FAD as an important cofactor for the demethylation of histons. We also present our views on the role of riboflavin supplements in the prevention against cancer.

Objective It has been reported that aberrant DNA methylation can be associated with HPV infection and cervical tumorigenesis. The aim of this study was to evaluate the possibility that polymorphic variants of genes that may affect DNA methylation status are associated with the risk of cervical cancer in the Polish population. Design and method Employing PCR-RFLPs and HRM analyses, we examined the prevalence of BHMT Arg239Gln (rs3733890), MTR Asp919Gly (rs1805087), MTHFR Ala222Val (rs1801133), MTHFD1 Arg653Gln (rs2236225) and MTRR Ile22Met (rs1801394) genotypes and alleles in patients with advanced cervical cancer (n = 124) and controls (n = 168). Results The odds ratio (OR) for BHMT Gln/Gln genotype was 0.433 (95% CI = 0.1780–1.054; p = 0.0602). The OR for patients having the BHMT Arg/Gln or Gln/Gln genotypes was 0.579 (95% CI = 0.3622–0.924; p = 0.0216). We also observed a significantly higher frequency of the BHMT 239Gln allele in controls than in patients, p = 0.0165. The genotype and allele frequencies of the MTR Asp919Gly, MTHFR Ala222Val, MTHFD1 Arg653Gln and MTRR Ile22Met gene variants did not display statistical differences between patients with cervical cancer and controls. We also did not find a significant association between the distribution of any genotypes or alleles and cancer characteristics. Conclusion Our results might suggest the protective role of the BHMT 239Gln variant in cervical cancer incidence.

Elevated fasting plasma homocysteine (Hcy) level is a vascular disease risk factor. Plasma Hcy is affected by 5,10-methylenetetrahydofolate reductase (MTHFR) genotype and dietary folate intake. This cross-sectional study in 434 Japanese adults examined the associations among objectively measured physical activity (PA), plasma Hcy adjusting for dietary folate intake, and MTHFR C677T genotype. Daily PA was measured by triaxial accelerometry and all subjects completed a questionnaire about their dietary habits. Plasma Hcy and MTHFR C677T genotype were determined. Plasma Hcy in subjects with the TT genotype was significantly higher than in those with CC or CT genotype (p < 0.001). Plasma Hcy was significantly different between ≥200 (7.6 ± 0.2 nmol/mL) and

Recurrent miscarriages (RM) are significant social and clinical problem. One of suggested reason of RM is hyperhomocysteinemia. Polymorphic genes involved in homocysteine and folate metabolism, including 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, are considered as an important risk factors for homocysteine accumulation and modulator of RM susceptibility. Therefore the aim of this study was to evaluate the frequency of MTHFR polymorphisms (677CT, 1298AC, and 1793GA) in women with recurrent miscarriages.We have analyzed 104 Polish women with a history of 3 or more unexplained recurrent miscarriages in the first pregnancy trimester (6-13 gestation week). The control group consisted of 169 women without obstetrical complication, any history of miscarriage and with at least one live birth in anamnesis. The investigated polymorphisms were determined by PCR/RFLP methods.For MTHFR 1793GA polymorphism we have observed significant overrepresentation of heterozygotic GA genotypes in RM group (15.38% vs. 4.14% in the controls, OR=4.21, p=0.003). For 677CT and 1298AC we have shown lack of significant association with RM. Nevertheless, such significant association was observed if more than one mutated MTHFR variant was present in one patient.Our research indicate the possible role of MTHFR 1793GA polymorphism in pathogenesis of RM. The noticed tendency to more frequent occurrence of haplotypes of MTHFR gene including two or three mutated alleles showed the possibility of summarized amplification of these variants effect influencing RM susceptibility.

Udgivelsesdato: 2010-Jun-24 Plasma homocysteine associates positively with cardiovascular disease. C-to-T substitution at base 677 of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene associates with increased plasma homocysteine. The association of adiponectin with cardiovascular disease is unclear. This study of survivors of a 30-year cohort of the Jewish Israeli population, 310 men and 273 women (mean age, 70.5 +/- 7.0 years for both), investigated the relationship between adiponectin and homocysteine, and between adiponectin and the MTHFR C677T genotype. Serum adiponectin associated positively with total homocysteine in both men (r = 0.27, P < .001) and women (r = 0.22, P < .001). In women, the TT MTHFR genotype associated with lower median adiponectin levels, 8.98 mg/L, compared with 9.88 and 10.57 mg/L for TC and CC, respectively (P = .05; CC vs TT, P = .01). In men, the trend was opposite, but not statistically significant: 7.90, 7.03, and 6.88 mg/L for TT, TC, and CC genotypes, respectively (P = .5). This study demonstrated a positive association between homocysteine and adiponectin in both elderly men and women and a statistically significant association between adiponectin and MTHFR C677T genotypes in women only.

We investigated associations among intake of folate, vitamin B2, vitamin B6, vitamin B12, and polymorphisms of 5,10-methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) genes and breast cancer risk in a Japanese population. A hospital based, case-control study was conducted in Nagano Prefecture, Japan, in 388 pairs of patients with histologically confirmed invasive breast cancer and age- and area-matched controls selected from medical checkup examinees. Energy-adjusted intakes of folate and other B vitamins were derived from a validated food frequency questionnaire. Genotyping was completed for MTHFR (C677T and A1298T) and MTR (A2756G). Odds ratios and 95% confidence intervals were calculated by the conditional logistical regression model. Median dietary folate intake (microg/day) in the control group was 438.2 (interquartile range: 354.9-542.9). Neither dietary intake of folate, vitamin B2, vitamin B6, or vitamin B12 nor polymorphisms of MTHFR or MTR genes were significantly associated with breast cancer risk. Further, no significant interaction was found among nutrients, polymorphisms, and breast cancer risk. Associations of nutrients with breast cancer risk did not differ by hormone receptors status. We conclude that dietary intake of folate and related B vitamins and genotypes of MTHFR or MTR have no overall association with breast cancer risk in Japanese women.