Methylenetetrahydrofolate Reductase

Plasma homocysteine concentrations are elevated in UK Indian Asians and may contribute to twice as many coronary heart disease (CHD) deaths in this group compared with European whites. The mechanisms underlying elevated homocysteine concentrations among Indian Asians are not well understood. In this study, we have investigated the extent to which the methylenetetrahydrofolate reductase (MTHFR) 677 C3T mutation accounts for elevated plasma homocysteine and increased CHD risk in Indian Asians compared with European whites. We investigated 454 male cases (with myocardial infarction or angiographically proven CHD: 224 Indian Asians, 230 European whites) and 805 healthy male controls (381 Indian Asians, 424 European whites). Fasting homocysteine concentrations, MTHFR 677 C3T genotype, and conventional CHD risk factors were measured. The prevalence of homozygous MTHFR 677T in Indian Asian controls was less than one third that in European white controls (3.1% versus 9.7%, PϽ0.001). In Indian Asians, the TT MTHFR genotype was not associated with homocysteine concentrations and was not present in any of the Asian controls with hyperhomocysteinemia (Ͼ15 mol/L). In contrast, among European whites, the TT MTHFR genotype was strongly related to elevated plasma homocysteine concentrations and was found in 27% of the European controls with hyperhomocysteinemia. Elevated homocysteine in Indian Asian compared with European white controls was accounted for by their reduced levels of B vitamins but not by the MTHFR 677T genotype. However, neither the TT MTHFR genotype nor B vitamin levels explained the elevated homocysteine concentrations in CHD cases compared with controls. TT MTHFR was not a risk factor for early-onset CHD in Indian Asians (odds ratio, 0.5; 95% confidence interval, 0.1 to 2.4; Pϭ0.39), unlike in European whites (odds ratio, 2.1; 95% confidence interval, 1.1 to 4.1; Pϭ0.02). We conclude that the MTHFR 677T mutation does not contribute to elevated plasma homocysteine concentrations or increased CHD risk in Indian Asians compared with European whites. Our results suggest that novel genetic defects and/or environmental factors influence homocysteine metabolism in Indian Asians residing in the United Kingdom.

Background-The role of circulating homocysteine as an atherosclerosis risk factor has recently been questioned. However, 5-methyl-tetrahydrofolate (5-MTHF), the circulating metabolite of folic acid participating in homocysteine metabolism, has direct effects on vascular function. We sought to distinguish the effects of plasma versus vascular tissue 5-MTHF and homocysteine on vascular redox and endothelial nitric oxide bioavailability in human vessels. Methods and Results-We used the methyl tetrahydrofolate reductase (MTHFR) gene polymorphism 677CϾT as a model of chronic exposure of the vascular wall to varying 5-MTHF levels in 218 patients undergoing coronary artery bypass graft surgery. Vascular superoxide, vascular 5-MTHF, and total homocysteine were determined in saphenous veins and internal mammary arteries obtained during surgery. Nitric oxide bioavailability was evaluated by organ bath studies on saphenous vein rings. MTHFR genotype was a determinant of vascular 5-MTHF (not vascular homocysteine). Both MTHFR genotype and vascular 5-MTHF were associated with vascular nitric oxide bioavailability and superoxide generated by uncoupled endothelial nitric oxide synthase. In contrast, vascular homocysteine was associated only with NADPH-stimulated superoxide. Conclusions-Genetic polymorphism 677 CϾT on MTHFR affects vascular 5-MTHF (but not homocysteine) and can be used as a model to distinguish the chronic effects of vascular 5-MTHF from homocysteine on vascular wall. Vascular 5-MTHF, rather than plasma or vascular homocysteine, is a key regulator of endothelial nitric oxide synthase coupling and nitric oxide bioavailability in human vessels, suggesting that plasma homocysteine is an indirect marker of 5-MTHF rather than a primary regulator of endothelial function. (Circulation. 2009;119:2507-2515.) Key Words: antioxidants Ⅲ atherosclerosis Ⅲ homocysteine Ⅲ nitric oxide synthase Ⅲ nitric oxide Ⅲ superoxide P lasma homocysteine is associated with cardiovascular risk 1,2 and surrogate markers such as oxidative stress 3 and endothelial dysfunction. 4 However, the potential causative role of homocysteine in vascular disease pathogenesis remains unclear. Although homocysteine may have direct effects on important biological processes such as thrombosis and production of reactive oxygen species, 1,2,7 interpretation of these effects is confounded by corresponding changes in folate status. Low plasma folate levels are strongly associated with elevated plasma homocysteine, 8 and intervention studies to reduce homocysteine typically use folate supplementation. 9,10 Recent evidence suggests that plasma folate may play important direct roles in the pathogenesis of atherosclerosis that are independent of homocysteine. 11 Indeed, 5-methyltetrahydrofolate (5-MTHF), the circulating form of folate, has a number of direct antiatherogenic effects by scavenging peroxynitrite radicals, 12 augmenting nitric oxide (NO) bioavailability, and decreasing vascular superoxide generation in the vascular wall. The potential beneficial effects of homocysteine lowering have been tested in recent clinical trials in patients with recent myocardial infarction, 9 stable coronary artery disease, 10 or stroke. Homocysteine lowering was achieved by combined folate and B vitamin supplementation but with no effect on major clinical outcomes, 9,10 perhaps except stroke. Thus, the primary value of homocysteine lowering, as distinct from folate supplementation,

Total homocystein (tHcy) er etablert som risikofaktor for hjerte-og karsykdom. Vi har studert determinanter av plasma tHcy i et utvalg av den voksne norske befolkning basert på undersøkelse utført av Statens helseundersøkelser i samarbeid med Universitetet i Bergen i 1992-1993. Data ble innhentet ved klinisk undersøkelse, utfylling av tre spørreskjema og ved blodtester. I alt 18 043 personer i alderen 40-67 år møtte til undersøkelse og fikk målt plasma tHcy. Plasma folat, plasma kobalamin og 677C→T mutasjonen i genet for metylentetrahydrofolatreduktase (MTHFR) er bestemt i et underutvalg på 329 personer og på personer med svaert høye tHcy verdier (≥ 40 µmol/L). Resultatene fra Homocysteinundersøkelsen i Hordaland har vist at kjønn, alder, folatinntak, røykevaner og kaffeforbruk er de sterkeste determinanter for plasma tHcy nivå, mens kobalamininntak, fysisk aktivitet, blodtrykk og kolesterolnivå er mindre sterke determinanter. Bruk av multivitaminer eller B-vitaminer er forbundet med spesielt lave tHcy nivåer. Personer med tHcy ≥ 40 µmol/L er karakterisert ved høy forekomst (73%) av homozygositet for 677C→T mutasjonen i MTHFR genet og lavt folatnivå. Vi konkluderer derfor med at livsstil og etablerte risikofaktorer for hjerte-og karsykdom er vesentlige for nivået av plasma tHcy i den generelle voksne norske befolkning.

Chemotherapy-induced myelosuppression, including thrombocytopenia, is a recurrent problem during cancer treatments that may require dose alterations or cessations that could affect the anti-tumor effect of the treatment. To identify genetic markers associated with treatment-induced thrombocytopenia, we whole-exome sequenced 215 non-small cell lung cancer patients homogeneously treated with gemcitabine/carboplatin. The decrease in platelets (defined as nadir/baseline) was used to assess treatment-induced thrombocytopenia. Association between germline genetic variants and thrombocytopenia was analyzed at single-nucleotide variant (SNV) (based on the optimal false discovery rate, the severity of predicted consequence, and effect), gene, and pathway levels. These analyses identified 130 SNVs and 25 genes associated with thrombocytopenia (P-value<0.002). 23 SNVs were validated in an independent genome-wide association study (GWAS). The top associations include rs34491125 in JMJD1C (P-value=9.07×10 -5 ), the validated variants rs10491684 in DOCK8 (P-value=1.95×10 -4 ), rs6118 in SERPINA5 (P-value=5.83×10 -4 ) and rs5877 in SERPINC1 (P-value=1.07×10 -3 ), and the genes CAPZA2 (P-value=4.03×10 -4 ) and SERPINC1 (P-value=1.55×10 -3 ). The SNVs in the topscoring pathway "Factors involved in megakaryocyte development and platelet production" (P-value=3.34×10 -4 ) were used to construct weighted genetic risk scores (wGRS) and logistic regression models that predict thrombocytopenia. The wGRS predict which patients are at high or low toxicity risk levels, for CTCAE (OR=22.35, P-value=1.55×10 -8 ), and decrease (OR=66.82, P-value=5.92×10 -9 ). The logistic regression models predict CTCAE grades 3-4 (receiver operator characteristics (ROC) area under the curve (AUC) = 0.79), and large decrease (ROC AUC=0.86). We identified and validated genetic variations within hematopoiesis-related pathways that provide a solid foundation for future studies using genetic markers for predicting chemotherapy-induced thrombocytopenia and personalizing treatments. DNA extraction, exome enrichment, and sequencing DNA was extracted from whole blood using QIAamp DNA mini-kits (VWR International, Stockholm, Sweden) according to the manufacturer's protocol. Target enrichment and library preparation were performed using the Nextera Rapid Capture Exome kit (FC-140-1003, Illumina, San Diego, California, USA) according to the manufacturer's instructions and utilizing Agilent Bravo for automation. All samples were whole-exome sequenced on Illumina HiSeq 2500 v4 (generating 125 base-pair long paired-end reads) at

Objective: The objective of this research was focused on the development of new organoclay based composite that serves as both antibacterial and dye removing agent for the treatment of microbial and dyes contaminated water from the source.
Material and Methods: The cation exchange capacity (CEC) of the kaolinite was improved through acid treatment. Chlorhexidine- loaded zinc- kaolinite was prepared via adsorption of chlorhexidine acetate (0.5 mmol/L) on zinc-kaolinite. The composites were characterized using Field Emission Scanning Electron Microscopy (FESEM) and Energy Dispersive X-ray (EDX). The antibacterial assays of the composites were conducted against Staphylococcus aureus (S. aureus) and Salmonella typhi (S. typhi) using disc diffusion technique (DDT), minimum inhibitory concentration (MIC), and minimum bactericidal concentration (MBC).
Results: The CEC value of the acid treated kaolinite (Kaot2) was improved from 9.26 + 0.82 to 13.43+1.61 meq/100g, the morphology of the composite remains intact and indicate the presence of Zinc (Zn) after formulation. The target composite (Chx-Zn-Kaot2) shows its effectiveness against S. aureus and S. typhi showing the inhibition zones of 26 mm and 1.5 mm respectively. Similarly, MIC, with 120 mg/mL inhibit both organisms while MBC revealed that the target composite, 60 mg/mL kills S. aureus and 120 mg/mL kills S. typhi respectively.
Conclusion: The formulated target composite is a good candidate for the treatment of drinking water contaminated with such microorganisms and can be able to remove substantial content of dyes

Our study was designed to prospectively evaluate the role of the methylenetetrahydrofolate reductase (MTHFR) TT677 genotype, the prothrombin (PT) 620210A mutation, the factor V G1691A mutation in leukemic Turkish children treated according to modified BFM 95 study protocols with respect to the onset at thromboembolic events. Eighty-two consecutive leukemic children investigated had are established inherited prothrombotic risk factor: 29 children showed the MTHFR genotype (heterozygous, n = 22; homozygous, n = 7); 3 showed the heterozygous PT G20210A variant; 16 were carriers of the factor V mutation (heterozygous). In addition, combined prothrombotic defects were found in a further 11 patients the MTHFR mutation was combined with the F V mutation (n = 7), the PT G20210A variant (n = 2). In 7 (8.5%) of these 82 patients, venous thromboembolism occurred. In conclusion, the presence of inherited thrombophilia with Turkish children treated acute lymphoblastic leukemia may be useful for ...

Thrombosis of cerebral venous channel is a known complication of hypercoagulable states. Hyperhomocysteinaemia is a known hypercoagulable state. Obesity is a modern-day global epidemic. Disorders such as myocardial infarction (MI), stroke, and venous thromboembolism are on the rising trend and its increased morbidity and mortality is being associated with obesity. To date, however, the knowledge about the association between obesity and adult cerebral venous thrombosis (CVT) is sparse. We report a 44-year-old young morbidly obese metabolically unhealthy female who presented with headache, nausea, vomiting and giddiness. On evaluation, magnetic resonance venogram showed cerebral venous sinus thrombosis. On investigations, she had concomitant hyperhomocysteinaemia and metabolic syndrome. Cerebral venous sinus thrombosis causing stroke in young adults is uncommon with various conditions precipitating it.1,2,3 Severe headache (70 - 90 %), focal lateralized signs (25 % - 75 %), seizures ...

The aim of the project was to investigate homocysteinemia and Methylentetrahydrofolate reductase (MTHFR) gene (C677T) mutation with vascular diseases. The investigation comprised a total number of 378 subjects divided into two main groups: 194 healthy individuals and 184 patients: 91 with arterial occlusive disease (AOD) and 93 with thrombosis of deep vein (TDV). Concentration of total homocysteine (tHcy) in plasma was determined using the modified immunoenzyme method. Mutation of MTHFR C677T was examined with polymerase chain reaction with CVD StripAssay (ViennaLab Labordiagnostika GmbH) as a segment of 12 mutations of the cardiovascular system. Concentration of tHcy in patients with AOD was 16.3 ± 8.4 μmol/L in men, 14.1 ± 3.3 μmol/L in women and it was statistically significantly increased as compared to healthy subjects from the same gender (p<0.001). Concentration of tHcy in men with TDV was 14.0 ± 3.5 μmol/L, 13.4 ± 3.0 μmol/L in women and it was significantly increased in comparison to healthy subjects (p<0.001). Concentration of homocysteine in plasma of healthy subjects with different genotype of MTHFR C677T showed significantly higher values for TT when compared to CC genotype as well as to CT genotype. Comparison between healthy and sick individuals both separately, AOD and TDV, or as one entity, showed significantly higher values for the genotypes CC and CT, but not for the TT genotype. There was no correlation of MTHFR C677T gene mutations with AOD and TDV.

The main cause of reduced long-term graft survival is chronic allograft injury. Cardiovascular risk factors such as hyperhomocysteinemia seem to play an important role. As atherosclerotic lesions in chronic allograft injury may be due to hyperhomocysteinemia, we examined the hypothesis that the C677T variant of the methylenetetrahydrofolate reductase (MTHFR) gene, which is linked to elevated plasma homocysteine levels in patients with renal failure, determines renal allograft dysfunction. Endothelial dysfunction probably has a role in this process. The subjects included in this study were 32 renal allograft recipients (Group I) and 30 normal subjects as a control group (Group II). MTHFR genotype was determined by PCR, subsequently the patients were further classified into three subgroups according to the MTHFR genotypes: Group I (a): 6 allograft recipients with homozygous-TT type. Group I (b): 8 allograft recipients with heterozygous-CT type. Group I (c): 18 allograft recipients with wild-CC type. Estimation of total plasma homocysteine concentration, plasma folic acid, plasma and von Willebrand factor (vWF) were determined. Vascular responses of the brachi al artery were performed by high resolution ultrasound imaging. This study showed significantly higher levels of both homocysteine and von Willebrand factor (vWF) were found in renal allograft recipients as compared to the control group. A negative correlation was found between homocysteine levels and creatinine clearance suggesting hyperhomocysteinemia contributes to the renal allograft dysfunction. No significant difference was found as regards the plasma folic acid levels between the patients and controls. Allograft recipients with MTHFR homozygous-TT type showed significantly higher levels of homocysteine and vWF as compared to allograft recipients with heterozygous-CT type and those with wild-CC type. Also allograft recipients with homozygous-TT type showed lower levels of plasma folic acid and creatinine

The neurofibromatosis of type 1 (Von Recklinghausen disease) -NF1-belongs to the genetic disorder group known as phakomatosis. Its inheritance pattern is dominant autosomal with variable penetrance. It is produced by the mutation of the gene NF1 of the chromosome 17q (tumour supresor gene which encodes a protein -neurofibromine-which modules the transduction of signals through the guanosin triphosphatase path -GTPase-). It's characterized by the presence of benign tumors from the peripheral nerves which are nominated neurophybromas (they are compounded by the proliferation of Schwann cells and phybroblasts), pigmented skin lesions ("café au lait spots"), freckles on unexposed areas like the armpits, iris hamartomal (Lisch's nodules) and seudoarthrosis of the tibia . It has been described that the patients with NF1 can present neurovascular abnormalities which tend to brain ischemia [3], although this uncommon association is not well characterized.

Purpose: Fluorouracil (5-FU) is widely used in the treatment of colorectal cancer. Methylenetetrahydrofolate reductase (MTHFR) could play an important role in the action of 5-FU, an inhibitor of thymidylate synthetase, by converting 5,10-methylenetetrahydrofolate, a substrate of thymidylate synthetase, to 5-methyltetrahydrofolate. A polymorphism in MTHFR (677 C-->T; A222V) reduces enzyme activity and presumably increases the level of 5,10-methylenetetrahydrofolate. This increase would be expected to correlate with an improved response to 5-FU. The aim of the present study was to investigate the association between the MTHFR polymorphism and response to 5-FU and other fluoropyrimidines in patients with metastatic colorectal cancer. Experimental design: Forty-three patients with metastatic colorectal adenocarcinoma were analyzed. All patients were treated with p.o. or i.v. fluoropyrimidine-based chemotherapy. A comprehensive chart examination was performed to determine tumor response rates. Genomic DNA was extracted from blood, and MTHFR genotypes were determined. Results: At least one copy of the mutant valine allele was present in 26 patients (21 heterozygotes and 5 homozygotes). The remaining 17 patients carried only the alanine allele. Exploration of the relationship between MTHFR alleles and response rates revealed a statistically significant difference in the frequency of the valine allele among responders versus nonresponders (P = 0.0351). This observation was associated with an odds ratio of 2.86 (95% confidence interval 1.06-7.73) for a response in individuals with a valine allele. Conclusions: Our results show a link between the MTHFR polymorphism and tumor response to fluoropyrimidine-based chemotherapy and suggest that MTHFR genotyping may be of predictive benefit in selecting treatment regimens.

Periconceptional folate supplementation reduces the risk of neural-tube defects. We studied the frequency of the 677C-TF mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene in 55 patients with spina bifida and parents of such patients (70 mothers, 60 fathers). 5% of 207 controls were homozygous for the 677CMT mutation compared with 16% of mothers, 10% of fathers, and 13% of patients. The mutation was associated with decreased MTHFR activity, low plasma folate, and high plasma homocysteine and red-cell folate concentrations. The 677C->T mutation should be regarded as a genetic risk factor for spina bifida.

Maternal periconceptional use of vitamin supplements containing folic acid substantially reduces the risk of neural tube defects (NTDs) in the offspring. The mechanism underlying this reduction in risk is unknown. Several recent studies have reported an association between homozygosity for a variant form (the C677T genotype) of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene and risk for NTDs in individuals. 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. Using data from two California case-control interview studies (1987-1991 birth cohorts), the authors investigated whether an interaction for spina bifida risk existed between infant MTHFR C677T genotype and maternal use of supplements containing folic acid. The authors genotyped the allelic variants of MTHFR in 214 livebom case infants with spina bifida and 503 control infants for whom information on maternal periconceptional vitamin use was available. The percentage of all case infants with the C677T MTHFR mutation, for both homozygous (TT) and heterozygous (TC) genotypes, was slightly higher than that of controls. The C677T genotype was substantially more frequent among both case and control Hispanic infants than among non-Hispanic infants. Among all infants whose mothers did not periconceptionally use vitamins containing folic acid, the risk of spina bifida, as measured by the odds ratio, was 1.6 (95% confidence interval (Cl) 0.8-3.1) for all infants with the TT genotype and 2.0 (95% Cl 0.5-7.4) for non-Hispanic white infants with the TT genotype, as compared with infants with the CC genotype. This result indicates a modestly increased risk associated with the C677T genotype. A lower risk estimate (odds ratio = 1.2, 95% Cl 0.4-4.0) was observed among infants whose mothers periconceptionally used vitamin supplements containing folic acid. This population-based California study found a modestly increased risk of spina bifida among infants who were homozygous for the C677T genotype, but only minimal evidence of an interaction between the C677T genotype and maternal folic acid intake in the occurrence of spina bifida. If this mutant MTHFR genotype plays a role in the association between maternal vitamin use and NTD risk, it may be a small role, or it may be conditional on maternal genotype.

The activity of the enzyme methylenetetrahydrofolate reductase (MTHFR) determines homocysteine (Hcy) levels, and polymorphisms in its gene affect the activity of the enzyme. Changes in the enzyme&#39;s activity may lead to a higher susceptibility to develop arterial and venous thromboembolic disease. The aim was to analyze the relationship between the C677T and A1298C polymorphisms of MTHFR, Hcy levels, and prothrombotic biomarkers in pulmonary embolism (PE) and acute myocardial ischemia (AMI). Clinical files of patients with thromboembolic diseases having complete data and whose doctor had requested an assay to determine the polymorphisms of the MTHFR gene, Hcy levels, and prothrombotic biomarkers were studied to search for the correlation between mutations of the MTHFR gene and Hcy levels in the different diseases. We included 334 files: 158 were from women and 176 from men (51 [19 SD] years). Sixty-three percent have had thrombosis, 8% AMI, and 31% PE. Patients with thrombosis ha...

BackgroundNeurocognitive impairment occurs in 20–40% of childhood acute lymphoblastic leukemia (ALL) survivors, possibly mediated by folate depletion and homocysteine elevation following methotrexate treatment. We evaluated the relationship between folate pathway polymorphisms and neurocognitive impairment after childhood ALL chemotherapy.ProcedureSeventy‐two childhood ALL survivors treated with chemotherapy alone underwent a neurocognitive battery consisting of: Trail Making Tests A (TMTA) and B (TMTB), Grooved Pegboard Test Dominant‐Hand and Nondominant‐Hand, Digit Span subtest, and Verbal Fluency Test. We performed genotyping for: 10‐methylenetetrahydrofolate reductase (MTHFR 677C&gt;T and MTHFR 1298A&gt;C), serine hydroxymethyltransferase (SHMT 1420C&gt;T), methionine synthase (MS 2756 A&gt;G), methionine synthase reductase (MTRR 66A&gt;G), and thymidylate synthase (TSER). Student&#39;s two sample t‐test and analysis of covariance were used to compare test scores by genotype.Res...

Background: Obesity is a systemic and chronic disease with genetic susceptibility, characterized by an increase in storage and irregular distribution of body fat. Aim: The aim of this study is to evaluate the association of polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and peroxisome proliferator-activated receptor (PPAR) genes with obesity among adult females in Al-Madina, Saudi Arabia. Method: The participants in this study were 114 healthy females aged 18-60 years. Body mass index (BMI) and body composition parameters were assessed. Triglycerides, total cholesterol, HDL, and LDL were measured. Real-time PCR was used to detect the selected genetic polymorphisms of PPAR-γ rs1801282 and MTHFR rs1801131. Results: Weight, BMI, fat-percentage, FFM, truncal fat mass, and LDL were significantly higher in the overweight and obese group than in the normal BMI group. PPAR-γ genotype and allele polymorphism frequencies in the overweight and obesity group showed no statistically significant differences compared to those of the normal weight group. However, a significant difference was found between the frequency of both T and G alleles of MTHFR in the normal BMI and overweight and obese group (p = 0.03) and a significant correlation with the fat-percentage in both groups (p = 0.01). A significant correlation between the MTHFR genotypes and the fat-percentage in both groups was also found (p = 0.04). Conclusion: In this population of Saudi females, we found that MTHFR GG genotype and G allele are significantly correlated with the deposition of fat in the body; women with this allele and genotype should be advised to control their weight and fat intake, as this is also associated with LDL levels that may affect their cardiovascular system. PPAR-γ did not seem to play a role in obesity of the recruited subjects.

We assessed the effect of a recently described mutation in the MTHFR gene (1298 A → C) on the risk of deep venous thrombosis (DVT) by determining its prevalence in 190 patients with verified DVT and in age‐, race‐ and gender‐matched controls. MTHFR 1298 A → C was found in 42.1% of patients and in 41.1% of controls. The OR for venous thrombosis was 1.07 (95% CI 0.70–1.65) for heterozygotes and 0.83 (95% CI 0.33–2.08) for homozygotes. The OR for the factor V Leiden (FVL) mutation was 3.40 (95% CI 1.22–9.48), for FII 20210 G → A was 5.22 (95% CI 1.12–24.2) and for MTHFR 677 C → T, 1.24 (95% CI 0.82–1.87). No significant increased risk for venous thrombosis was found when MTHFR 1298 A → C was coinherited with FVL (OR 2.85, 95% CI 0.88–9.23), FII 20210 G → A (OR 7.19, 95% CI 0.87–59.4) or MTHFR 677 C → T (OR 1.44, 95% CI 0.71–2.92). These data do not support a critical role of MTHFR 1298 A → C in the predisposition to DVT.

Fasting total homocysteine (tHcy) and the methylenetetrahydrofolate reductase (MTHFR) C677T mutation were evaluated in 91 patients with venous thromboembolism and without acquired thrombophilia, and in 91 age-matched and sex-matched controls. Hyperhomocysteinemia was detected in 11 patients (12.1%) and in two controls (2.2%), yielding an odds ratio (OR) for venous thrombosis of 6.1 [95% con®dence interval (CI), 1.3±28.4]. After excluding 21 patients and four controls with other known genetic risk factors for venous thrombosis, the OR was not substantially changed (7.0; 95% CI, 1.5±33.1). The prevalence of the MTHFR 677TT genotype was not signi®cantly different in patients (9.9%) and in controls (5.5%), with an OR for venous thrombosis of 1.8 (95% CI, 0.6±5.8). Subjects with the MTHFR 677TT genotype showed higher levels of tHcy compared with the 677CC genotype in patients (P 0.010) and in controls (P 0.030). In conclusion, we found that fasting hyperhomocysteinemia is a risk factor for venous thrombosis in patients without known acquired thrombophilia and other genetic risk factors for venous thrombosis. Although tHcy levels are signi®cantly higher in those homozygous for the MTHFR C677T mutation, this genotype does not increase the thrombotic risk in our study population. Blood Coagul Fibrinolysis 13:271±275 # 2002 Lippincott Williams & Wilkins.

Background: Migraine is a common disorder that often coexists with depression. While a functional polymorphism in methyleneterahydrofolate reductase gene (MTHFR C677T) has been implicated in depression; the evidence to support an association of MTHFR with migraine has been inconclusive. We aim to investigate the effect of this variant on propensity for migraine and to perform a systematic review and meta-analysis of studies of MTHFR and migraine to date. Methods: Individuals with migraine (n = 447) were selected from the Depression Case Control (DeCC) study to investigate the association between migraine and MTHFR C677T single nucleotide polymorphism (SNP) rs1801133 using an additive model compared to non-migraineurs adjusting for depression status. A meta-analysis was performed and included 15 studies of MTHFR and migraine. Results: MTHFR C677T polymorphism was associated with migraine with aura (MA) (OR 1.31, 95% CI 1.01-1.70, p = 0.039) that remained significant after adjusting for age, sex and depression status. A meta-analysis of 15 casecontrol studies showed that T allele homozygosity is significantly associated with MA (OR = 1.42; 95% CI, 1.10-1.82) and total migraine (OR = 1.37; 95% CI, 1.07-1.76), but not migraine without aura (OR = 1.16; 95% CI, 0.36-3.76). In studies of non-Caucasian population, the TT genotype was associated with total migraine (OR= 3.46; 95% CI,, whereas in studies of Caucasians this variant was associated with MA only (OR = 1.28; 95% CI, 1.002-1.63). Conclusions: MTHFR C677T is associated with MA in individuals selected for depression study. A meta-analysis of 15 studies supports this association and demonstrated effects across ethnic groups.

Objective. To identify pharmacy faculty members' perceptions of psychological contract breaches that can be used to guide improvements in faculty recruitment, retention, and development. Methods. A list of psychological contract breaches was developed using a Delphi procedure involving a panel of experts assembled through purposive sampling. The Delphi consisted of 4 rounds, the first of which elicited examples of psychological contract breaches in an open-ended format. The ensuing 3 rounds consisting of a survey and anonymous feedback on aggregated group responses. Results. Usable responses were obtained from 11 of 12 faculty members who completed the Delphi procedure. The final list of psychological contract breaches included 27 items, after modifications based on participant feedback in subsequent rounds. Conclusion. The psychological contract breach items generated in this study provide guidance for colleges and schools of pharmacy regarding important aspects of faculty recruitment, retention, and development.

Aims: To determine the frequency of C677T and A1298C polymorphisms of the MTHFR gene and correlate them with homocysteine serum levels in patients with Turner syndrome (TS) and controls. Methods: This case-control study included 78 women with TS and a control group of 372 healthy individuals without personal or family history of cardiovascular disease and cancer. C677T (rs1801133) and A1298C (rs1801131) polymorphisms were detected by polymerase chain reaction-restriction fragment-length polymorphism and the TaqMan system, respectively. Homocysteine serum levels were determined by high-performance liquid chromatography. The results were analyzed statistically, and p < 0.05 was considered to represent a significant difference. Results: The homocysteine levels change was 13.9 + 3.3 nM in patients with TS and 8.8 + 3.2 nM in the control group. No significant difference between groups was found ( p = 0.348). Single-marker analysis revealed no association between MTHFR C677T polymorphism and TS when genotype ( p = 0.063) or allelic ( p = 0.277) distribution was considered. Regarding MTHFR A1298C polymorphism, a statistical difference was found between the TS group and the control group, for both genotype ( p < 0.0001) and allele ( p < 0.0001) distribution. Haplotype analysis of 2 MTHFR polymorphisms identified 2 haplotypes-CC and TC-associated with TS ( p < 0.001 and p = 0.0165, respectively). However, homocysteine levels were not higher in patients with haplotype risk. Conclusion: The results suggest that the C677T and A1298C polymorphisms of the MTHFR gene are not related to homocysteine levels in Brazilian patients with TS, despite the differential distribution of the mutated allele C (A1298C) in these patients. Further studies are needed to investigate the possible genetic interaction with homocysteine levels in TS.

BACKGROUND: Dysfunctions in the folate metabolism can result in DNA hypomethylation and abnormal chromosome segregation. Two common polymorphisms of this enzyme (C677T and A1298C) reduce its activity, but when associated with aneuploidy studies the results are conflicting. The objective of the present study is to analyze the MTHFR gene polymorphisms in women with Turner Syndrome and in a control group, correlating the findings to the chromosomal aneuploidy. METHODS: The study comprised 140 patients with Turner Syndrome, of which 36 with chromosome mosaicism and 104 non-mosaics, and a control group of 209 fertile and healthy women without a history of any offspring with aneuploidy. Polymorphisms C677T and A1298C were studied by RFLP-PCR and the results were statistically analyzed. RESULTS: The frequency of genotypes MTHFR 677CC, 677CT and 677TT in the patients with Turner Syndrome and chromosome mosaicism was, respectively, 58.3%, 38.9% and 2.8%. Among the patients with non-mosaic Tu...

Coronary artery diseases (CAD) are influenced by multiple genes of modest effect as the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism, related to MTHFR activity and total plasma homocysteine (tHcy) concentration. This study was designed to evaluate tHcy, oxidized low-density lipoprotein (LDL) (ox-LDL), high-sensibility C-reactive protein (Hs CRP) levels, and homocysteine thiolactonase (HTase) activities as new risk factors for CAD and to investigate an association between MTHFR polymorphism tHcy concentrations and coronary syndrome severity. Our results showed significantly higher levels of tHcy and ox-LDL in patients associated with lower HTase activities. These levels increased proportionally to disease severity. Total plasma Hcy levels were negatively correlated to HTase activities in patients where the TT genotype was significantly more frequent. In a multivariate analysis, tHcy level was the only independent factor affecting the coronary syndrome severity....

Background:Vitamin D deficiency is highly prevalent in patients with systemic lupus erythematosus (SLE). Vitamin D acts through the vitamin D receptor (VDR) that is present in most cells, and it can regulate the transcription of over 200 genes. The expression of vitamin D receptors by a variety of cells belonging to the innate and adaptive immune systems has created interest with regards to the role of vitamin D in the pathogenesis of SLE. Several polymorphisms of the VDR gene have been described, namely Bsml, Apal, Taql and Fokl. A number of VDR gene polymorphism genotypes have been associated with increased risk of SLE mostly in Asians and Africans.1Objectives:The aim of this study was to establish whether an association was present between VDR gene polymorphisms and SLE susceptibility in a cohort of SLE patients living in Malta. A further aim was to assess the relationship between these VDR gene polymorphisms and SLE disease characteristics.Methods:59 SLE patients living in Malta...

Background: The strong observational association between total homocysteine (tHcy) concentrations and risk of coronary artery disease (CAD) and the null associations in the homocysteinelowering trials have prompted the need to identify genetic variants associated with homocysteine concentrations and risk of CAD. Objective: We tested whether common genetic polymorphisms associated with variation in tHcy are also associated with CAD. Design: We conducted a meta-analysis of genome-wide association studies (GWAS) on tHcy concentrations in 44,147 individuals of European descent. Polymorphisms associated with tHcy (P , 10 28 ) were tested for association with CAD in 31,400 cases and 92,927 controls. Results: Common variants at 13 loci, explaining 5.9% of the variation in tHcy, were associated with tHcy concentrations, including 6 novel loci in or near MMACHC (2.1 3 10 29 ), SLC17A3 (1.0 3 10 28 ), GTPB10 (1.7 3 10 28 ), CUBN (7.5 3 10 210 ), HNF1A (1.2 3 10 212 ), and FUT2 (6.6 3 10 29 ), and variants previously reported at or near the MTHFR, MTR, CPS1, MUT, NOX4, DPEP1, and CBS genes. Individuals within the highest 10% of the genotype risk score (GRS) had 3-mmol/L higher mean tHcy concentrations than did those within the lowest 10% of the GRS (P = 1 3 10 236 ). The GRS was not associated with risk of CAD (OR: 1.01; 95% CI: 0.98, 1.04; P = 0.49). Conclusions: We identified several novel loci that influence plasma tHcy concentrations. Overall, common genetic variants that influence plasma tHcy concentrations are not associated with risk of CAD in white populations, which further refutes the causal relevance of moderately elevated tHcy concentrations and tHcy-related pathways for CAD.

Thromboembolism (TE) is a complex disease caused by various acquired and inherited factors. The common mutations; factor V Leiden G1691A (FVL G1691A), prothrombin G20210A (PTG20210A), and methylene tetrahydrofolate reductase C677T (MTHFR C677T) are important inherited causes in both venous and arterial thrombosis. The association between ABO blood groups and thrombophilia has been noted by researchers. We aimed to determine the frequency and association of ABO blood groups as a risk factor along with 3 thrombophilia mutations and another 3 thrombophilia markers in a group of patients with unstimulated thrombosis. In a prospective case-control study, we focused on 100 samples, 50 patients with documented thrombosis as well as 50 healthy age-matched controls. Multiplex polymerase chain reaction and reverse hybridization to oligonucleotide particular probes were employed to detect FVL G1691A, PT G20210A, and MTHFR C677T mutations. Analysis of other thrombophilia markers including prote...

Severe hyperhomocysteinemia due to cystathionine ␤-synthase (CBS) deficiency is a strong risk factor for premature cardiovascular disease. Among untreated patients, Ϸ50% have suffered a thromboembolic event by 30 years of age. We report on 3 sisters with severe hyperhomocysteinemia due to homozygosity for the CBS 833T3 C mutation. These patients, who displayed no other known thrombophilic predisposition, had suffered single or multiple venous thrombosis before CBS deficiency was diagnosed relatively late in life. In this family, homozygosity for the 833T3 C mutation was associated with a mild phenotype with respect to other sequelae of CBS deficiency. Consequently, our results indicate that most cases with this genotype may remain undiagnosed. Investigated family members heterozygous for the 833T3 C mutation displayed normal total homocysteine in plasma (tHcy) levels, even when they were homozygous for the methylenetetrahydrofolate reductase 677C3 T polymorphism. The prevalence of homozygosity for the 833T3 C mutation has previously been estimated at no less than 1:20 500 in our population. Because a reduction of the severely elevated levels of tHcy in CBS deficiency reduces cardiovascular risk and because homozygosity for the 833T3 C mutation is more prevalent than previously thought, our results emphasize the importance of measuring tHcy routinely in thrombophilia screening.

Pathogenesis in spontaneous abortion is complex and involves the interaction of multiple genetic and environmental factors. C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene have implications in the fetal viability. This paper aims to establish the association between these polymorphisms and the risk of miscarriage. In this study we determined the allelic and genotypic frequencies of the MTHFR gene polymorphisms in a sample of 250 women from Romania, 100 with 1-3 miscarriages and 150 without history of miscarriages. The genomic DNA was extracted from the peripheral blood collected on EDTA and the kit used was the peqGOLD blood DNA mini kit (ATP Biotech) . The methods used to study polymorphisms were PCR and RFLP. The results of this study showed that women with spontaneous abortion have a higher proportion of the 677TT genotype compared with the control group and the distribution of allelic and genotypic frequencies for polymorphism A1298C, does not present significant differences between the study group and control. The study also found that the frequency of the combined 677TT/1298 AA genotypes is higher in the study group compared with control being associated with the risk of miscarriage. In conclusion, the study revealed significant differences between the results obtained from the two groups.

Aims: Patients with diabetes that are African-Americans or Asians have a higher chance of developing diabetic nephropathy than Caucasian. Our objective was to evaluate the association between self-reported color-race, genomic ancestry, and the presence of chronic kidney disease (CKD), assessed by glomerular filtration rate and albuminuria in patients with type 1 diabetes. Methods: This is a multicenter, observational, cross-sectional study with 1564 patients, conducted between August 2011 and August 2014 in 14 public clinics from 10 Brazilian cities. The ethnic aspects of the patients were evaluated using self-reported color-race and genomic ancestry (divided in European, African, and Amerindian). We divided the patients into groups: normal renal function and CKD. Results: More patients self-declared themselves as black and brown in the group with CKD. The multivariate logistic analysis revealed that self-reported color-race was not associated with CKD and that a higher African ancestry was also not associated with CKD (p=0.06). Patients with an African ancestry of 50% or higher had an association with CKD that did not persist after the multivariate analysis. Conclusion: In our patients, from an admixed, multi-ethnic population, we did not find an association between self-reported color-race, genomic ancestry and CKD. It is important to note that despite the fact that we did not find a significant p-value in the multivariate analysis concerning African ancestry and CKD, we found a narrow confidence interval (0.961-3.98) with an OR of 1.956. Further studies should be conducted to confirm the lack of association between African ancestry and CKD, especially from populations with higher African or Amerindian ancestries to better understand the association between self-reported color-race and genomic ancestry with CKD.

Introduction: Nonarteritic anterior ischemic optic neuropathy (NAION), painless loss of central and/or peripheral vision, is a multifactorial disease caused by insufficient blood flow through the posterior ciliary arteries to the optic nerve head. Mutations in the methylenetetrahydrofolate reductase (MTHFR) gene, triggering hyperhomocysteinemia as a consequence of a decreased activity of the codified enzyme, have been considered to be among the risk factors of NAION. Objective: The main aim was to study the association of the most common

Venous thromboembolism (VTE) is an important cause of morbidity and mortality stemming from cardiovascular disease. It is a multifactorial disease caused by a combination of acquired risk factors, of which advanced age is the most significant, and genetic factors, including the variants FV G1691A, FII G20210A, and MTHFR C677T. We estimated the prevalence of these genomic variants in an elderly population of northeastern Brazil. The study included 188 elderly persons (65-93 years), of which 68 (36.2%) were men and 120 (63.8%) were women. Variants were detected by polymerase chain reaction-©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 12 (3): 3698-3707 (2013) restriction fragment length polymorphism analysis, and subsequent electrophoresis on an 8% polyacrylamide gel stained with silver nitrate. The study population was in Hardy-Weinberg equilibrium for the 3 loci. Of the individuals analyzed, none carried variants of FV or FII (0%), and 24.7% had the MTHFR C677T polymorphism: 59 subjects (31.4%) were heterozygous (CT) and 17 subjects (9%) were homozygous (TT). Based on the analysis of these particular genes, we conclude that the study population does not present an increased risk for the development of VTE. Faced with a growing aging population worldwide, similar studies in other countries will help in the prevention of VTE in older individuals.

Isolated renal vein thrombosis is very rare without the presence of nephrotic syndrome. It is more common in the newborns and infants. Whereas major risk factors in adults are the procoagulant states such as protein C or S deficiency, factor V Leiden mutation, primary or secondary antiphospholipid syndrome, severe hypothyroidism, and trauma. Here, we report a case of isolated renal vein thrombosis associated with MTHFR-1298 and PAI-1 4G gene mutations. It should be noted that the presence of MTHFR-1298 and PAI-1 4G gene mutations together might be one of the examples of genetic mutation combinations that increase the likelihood of a thrombotic event.

Rheumatic heart disease (RHD) is a serious complication of rheumatic fever (RF). Plasma homocysteine (Hcy) levels are increased in RHD patients. MTHFR catalyzes the irreversible conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate and plays a vital role in Hcy metabolism. We hypothesize that the MTHFR C677T polymorphism is associated with a risk of RHD. Eighty-six patients with RHD and 130 matched controls without a history of RHD were eligible for the study. The diagnosis of RHD was made according to modified Jones&#39; criteria and echocardiography. Using echocardiography, RHD patients were further divided into mitral valve lesion (MVL) and combined valve lesion (CVL) groups. MTHFR C677T polymorphisms were genotyped by DNA sequencing. The chi-squared test was used to evaluate differences in genotypes. Control genotypes were in Hardy-Weinberg equilibrium. The C677T homozygous genotype (OR = 4.09; 95% CIs 1.16-14.44; p = 0.020) and recessive model (TT vs. CC+CT; ...

BACKGROUNDSingle‐nucleotide polymorphisms (SNPs) in inflammation, one‐carbon metabolism, and skin cancer genes might influence susceptibility to arsenic‐induced skin lesions.METHODSA case‐control study was conducted in Pabna, Bangladesh (2001‐2003), and the drinking‐water arsenic concentration was measured for each participant. A panel of 25 candidate SNPs was analyzed in 540 cases and 400 controls. Logistic regression was used to estimate the association between each SNP and the potential for gene‐environment interactions in the skin lesion risk, with adjustments for relevant covariates. Replication testing was conducted in an independent Bangladesh population with 488 cases and 2,794 controls.RESULTSIn the discovery population, genetic variants in the one‐carbon metabolism genes phosphatidylethanolamine N‐methyltransferase (rs2278952, P for interaction = .004; rs897453, P for interaction = .05) and dihydrofolate reductase (rs1650697, P for interaction = .02), the inflammation gene...

The effect of a rat carotid endarterectomy (CEA) on homocysteine and the metabolic enzymes methylenetetrahydrofolate reductase (MTHFR) and cystathionine ␤-synthase (CBS) was studied. Methods: Rats were placed into 7 groups: (1) no anesthesia (NA), (2) anesthesia only (AO), (3) skin opened and closed (O/C), (4) skin opened with exposure of the carotid artery and closed (O/E/C), (5) carotid isolated and clamped (CO), (6) open CEA, and (7) open femoral endarterectomy (FEA). End points included homocysteine, hepatic MTHFR, and CBS activity. Results: Homocysteine in the NA, AO, O/C, O/E/C, and FEA were low and not different. CEA produced a 6-fold increase in homocysteine when compared with non-CEA groups. Specifically, CEA produced an increase in homocysteine versus the AO group at 2 weeks (11.3 ؎ 0.7 vs 2.1 ؎ 0.9 mol/L; P < .001), 4 weeks (8.9 ؎ 0.7 vs 3.5 ؎ 0.9 mol/L; P ‫؍‬ .004) and 6 weeks (7.7 ؎ 0.9 vs 3.1 ؎ 1.5 mol/L; P ‫؍‬ .03). The CO group had increased homocysteine versus the O/C, O/E/C, and FEA, but was lower than the CEA group. CEA produced an increase in MTHFR and CBS versus the AO group. Conclusions: CEA resulted in elevated levels of homocysteine; however, when broken down into its component parts, no elevation was observed except for a small increase with the CO procedure. Manipulation of the femoral artery did not raise homocysteine levels. The increase in homocysteine is possibly due to the combination of vessel wall damage and changes in cerebral blood flow dynamics. ( J Vasc Surg 2004;40:796-803.) Clinical Relevance: Our lab has identified increased plasma homocysteine, induced by diet modification, as a risk factor in the development of intimal hyperplasia. To date, the effect of an operative procedure on plasma homocysteine has not been evaluated. In this study, a carotid endarterectomy performed in the rat resulted in an elevation of plasma homocysteine. If, as we have previously shown, elevated plasma homocysteine produces and "exaggerated" intimal hyperplasia response after a vascular procedure, then the possibility that the operation itself can elevate homocysteine levels could be clinically important. A patient who presents with a mild increase in homocysteine could advance to a markedly elevated plasma level after undergoing a vascular operation. This elevation in plasma homocysteine could in turn result in the formation of clinically relevant intimal hyperplasia that may negate the effect of the operation.

En varios estudios se ha analizado la asociación entre el genotipo del gen metilentetrahidrofolato reductasa ( MTHFR) y las concentraciones de homocisteína plasmática, pero muy pocos estudios se han realizado en niños. Determinar la concentración plasmática de homocisteína total, ácido fólico, folato intraeritrocitario (FCR) y vitamina B 12 en un grupo de niños sanos y ver su posible r elación con el genotipo MTHFR. Formaron parte del estudio 83 participantes (45 chicos y 38 chicas) de edad comprendida entre 1 semana y 18 años. Las muestras de plasma y sangre completa se almacenaron a -80 °C para su posterior determinación de los parámetros bioquímicos y moleculares. La determinación de homocisteína total se realizó mediante ensayo de inmunofluorescencia polarizada; mientras que la concentración sérica de ácido fólico, folato intraeritrocitario y vitamina B 12 se determinó mediante inmunoanálisis electroquimioluminiscente. El análisis molecular se realizó mediante reacción en cadena de la polimerasa (PCR), y posterior digestión enzimática, del ADN obtenido de las muestras de sangre. Las concentraciones plasmáticas de homocisteína se correlacionaron negativamente con las de ácido fólico, vitamina B 12 y FCR, pero positivamente con la edad (p < 0,005). Se ha encontrado una interacción entre la edad-genotipo MTHFR y las concentraciones de ácido fólico, vitamina B 12 y FCR, pero no con las concentraciones de homocisteína. Nuestras observaciones sugier en que la concentración de homocisteína en la población pediátrica sana está más influida por factores bioquímicos como el ácido fólico, que genéticos.

Introduction: A large body of evidence links plasma homocysteine (Hcy) concentrations and cardiovascular disease. A common MTHFR polymorphism (C677T) leads to a variant with reduced activity and associated with increased Hcy levels. Coronary surgery precipitates a significant and sustained increase in the blood concentrations of Hcy and elevated levels of plasma Hcy have been associated to saphenous vein (SV) graft disease after CABG. However, the effects of MTHFR genotypes in the incidence of cardiovascular events after CABG have not been investigated prospectively. Here, we investigate whether MTHFR gene variants are associated with an increased cardiovascular risk in individuals submitted to CABG. We also propose a molecular mechanism to explain our findings. Methods: We performed MTHFR C677T genotypes in 558 patients with two or three vessel-disease and normal left ventricular function prospectively followed in the MASS II Trial, a randomized study to compare treatments for multivessel CAD and preserved left ventricle function. Follow-up time was 5 years. Survival curves were calculated with the Kaplan-Meier method, and evaluated with the log-rank statistic. We assessed the relationship between baseline variables and the composite end-point of death, myocardial infarction and refractory angina using a Cox proportional hazards survival model. Finally, using an ex-vivo organ culture we have reproduced the arterialization of SV implants by culturing human SV either under venous hemodynamic condition (flow: 5 mL/min; no pressure) or arterial hemodynamic

Thromogenic gene mutations has been thought to be associated with recurrent pregnancy loss in women in Turkey. The aim of this study was to investigate the prevalence of thromogenic gene mutations such as factor V Leiden (FVL, G1691T), prothrombin (G20210A), and the methylene tetrahydrofolate reductase (MTHFR, C677T) mutation in women with recurrent pregnancy loss. This descriptive study was carried out in the Department of Obstetrics and Gynaecology, Harran University School of Medicine, and included a total of 1,507 women with histories of recurrent pregnancy loss between January 2010 and June 2013. The mutations were assessed by using the polymerase chain reaction. The homozygous mutation frequencies of FVL, prothrombin, and MTHFR were found to be 3 (0.20%), 0 and 125 (8.29%), and the heterozygous mutation frequencies were 83 (5.51%), 61 (4.05%), and 612 (40.61%), respectively. Among the 86 FVL mutation patients, 38 also had accompanying prothrombin and MTHFR mutations. Since the homozygous forms of the FVL-prothrombin gene mutations have low incidences and MTHFR mutation is similar to a healthy population, preconceptional thromogenic gene mutations screening seems to be controversial.

To explore the clinical presentation, course, treatment and impact of early treatment in patients with remethylation disorders from the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD) international web-based registry. This review comprises 238 patients (cobalamin C defect n = 161; methylenetetrahydrofolate reductase deficiency n = 50; cobalamin G defect n = 11; cobalamin E defect n = 10; cobalamin D defect n = 5; and cobalamin J defect n = 1) from 47 centres for whom the E-HOD registry includes, as a minimum, data on medical history and enrolment visit. The duration of observation was 127 patient years. In 181 clinically diagnosed patients, the median age at presentation was 30 days (range 1 day to 42 years) and the median age at diagnosis was 3.7 months (range 3 days to 56 years). Seventy-five percent of pre-clinically diagnosed patients with cobalamin C disease became symptomatic within the first 15 days of life. Total homocysteine (tHcy), amino a...

Periconceptional folic acid supplementation may reduce the risk of cleft lip with or without cleft palate (CL(P)). Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene reduce availability of 5methyltetrahydrofolate, the predominant circulating form of folate. To determine the effect of MTHFR C677T and MTHFR A1298C genotypes and haplotypes on CL(P) risk and the interaction with maternal periconceptional dietary folate and folic acid supplement intake, the authors conducted a case-control triad study in the Netherlands (1998)(1999)(2000) among 179 CL(P) and 204 control families. Infant and parental MTHFR C677T and MTHFR A1298C genotypes and haplotypes were not associated with CL(P) risk in the case-control and transmission disequilibrium test analyses. Mothers carrying the MTHFR 677TT genotype and who either did not use folic acid supplements periconceptionally or had a low dietary folate intake, or both, had an increased risk of delivering a CL(P) child (odds ratio (OR) = 5.9, 95% confidence interval (CI): 1.1, 30.9; OR = 2.8, 95% CI: 0.7, 10.5; OR = 10.0, 95% CI: 1.3, 79.1, respectively). No supplement use, low dietary folate intake, and maternal MTHFR 1298CC genotype increased the risk of CL(P) offspring almost sevenfold (OR = 6.5, 95% CI: 1.4, 30.2). Thus, the detrimental effect of low periconceptional folate intake on the risk of giving birth to a CL(P) child was more pronounced in mothers with the MTHFR 677TT or MTHFR 1298CC genotype. abnormalities; folic acid; genes; nutrition; pregnancy; vitamins Abbreviations: CI, confidence interval; CL(P), cleft lip with or without cleft palate; MTHFR, methylenetetrahydrofolate reductase; OR, odds ratio. Cleft lip with or without cleft palate (CL(P)) is a frequently occurring congenital malformation characterized by closure defects of the lip, alveolus, and/or palate. The suggested multifactorial etiology of nonsyndromic CL(P) is still not understood (1). In addition to genetic predisposition, environmental risk factors may play an important role in the