DEFINITION
Methylenetetrahydrofolate reductase (MTHFR) is an enzyme that in humans is encoded by the MTHFR gene.
THE GENE
Prevalence
Methylenetetrahydrofolate reductase (MTHFR): incidence of mutations C677T and A1298C in Brazilian population and its correlation with plasma homocysteine levels in spina bifida. 2003
MTHFR blog
Here are possible combinations:
Normal/Normal for both 677 and 1298 :)
Heterozygous 1298 / Normal 677 (i.e. one parent passed down a single 1298 mutation)
Homozygous 1298 / Normal 677 (i.e. both parents passed down the 1298 mutation)
Heterozygous 677 / Normal 1298 (i.e. one parent passed down a single 677 mutation)
Homozygous 677 / Normal 1298 (i.e. both parents passed down the 677 mutation)
Heterozygous 677 / Homozygous 1298 (one parent passed down the 677 mutation; both passed down the 1298)
Homozygous 677 / Heterozygous 1298 (both parents passed down the 677 mutation; one passed down the 1298)
Heterozygous 677 / Heterozygous 1298 (Compound Heterozygous: one parent passed 677; one passed 1298)
Homozygous 677 / Homozygous 1298 (Compound Homozygous, meaning you have two 677, two 1298)
Molecular Biology of Methylenetetrahydrofolate Reductase (MTHFR) and Overview of Mutations/Polymorphisms, 2014 book
CHEMICAL STRUCTURE AND IMAGES
When relevant for the function
- Primary structure
- Secondary structure
- Tertiary structure
- Quaternary structure
MTHFR and Protein arginine methyltransferase 1
The high ratio Glu/Gln corresponds to a high pO2 and MTHFR evolved after aromatase but before ANM1
SYNTHESIS AND TURNOVER
mRNA synthesis
protein synthesis
post-translational modifications
degradation
CELLULAR FUNCTIONS
cellular localization: cytoplasm
MTHFR plays a central role in the one carbon unit metabolism
Methylene tetrahydrofolate reductase (MTHFR) metabolizes 5,10-MTHF (important in DNA synthesis) to 5-MTHF (contributes to downstream methylation reactions by regeneration of methionine from homocysteine)
REGULATION
Endoplasmic reticulum stress increases the expression of methylenetetrahydrofolate reductase through the IRE1 transducer. 2007
Ire1+inositol
DIAGNOSTIC USE
Effect on MCV
The relation between erythrocyte volume and folate levels is influenced by a common mutation in the methylenetetrahydrofolate reductase (MTHFR) gene (C677T) 2000
VV subjects in the lowest folate quartile exhibited significantly higher mean erythrocyte volumes (MCV) and a tendency towards higher erythrocyte hemoglobin content (MCH) than AA and AV subjects (P = 0.008 and 0.069, respectively). Although MCV was not influenced by folate levels in AA and AV subjects, in VV subjects a significant inverse correlation with folate levels could be demonstrated (P = 0.544 and 0.020, respectively). CONCLUSION: We demonstrate an association between the C677T polymorphism, folate levels, and hematological parameters.
Reduced choline synthesis
Reduction of choline synthesis will lead to reduced acetylcholine synthesis
Significance of (C677T) MTHFR Gene Polymorphism in Buerger Disease and Improving Effects of Folic Acid Administration on Neurological Symptoms (MHLW, S) 2002
Language;Japanese
Abstract;Buerger disease is a cause-unknown peripheral arterial obstructive disease found in male heavy smokers. A hypothesis that lowered folic acid and hyperhomocysteinemia by smoking is involved with expression of neurological symptoms of the above disease was examined. Folic acid was administered for 7 patients with Buerger disease for one month and improvement in neurological symptoms was examined. Five cases were improved, and including overlapping items, fugitive phlebitis was improved in one case, pain of the sole in 4 cases, strong swollen feeling in one case and Raynaud symptom in one case. Pain of the legs and sole was exacerbated in one case when the folic acid was discontinued. Improvement in intermittent limping was not recognized. It is considered that pathology of the Buergur disease is complicated by overlapping of the symptoms of arteritis of its own with the various ones accompanying hyperhomocystinemia caused by folic acid metabolism abnormality due to smoking. Neurological symptoms considered to be caused by combined hyperhomocystinemia can be improved by folic acid administration.
Paraneoplastic Raynaud Phenomenon With Digital Necrosis Associated With Hyperhomocysteinemia and Antiphospholipid Antibodies 2007
J Rheumatol. 2000 Nov;27(11):2621-3.
Homocysteine concentration in primary and systemic sclerosis associated Raynaud's phenomenon.
Marasini B, Casari S, Bestetti A, Maioli C, Cugno M, Zeni S, Turri O, Guagnellini E, Biondi ML.
Department of Medicine, Surgery and Dentistry, Institute of Radiological Sciences, San Paolo Hospital, Italy. bianca.marasini1@unimi.it
OBJECTIVE: To investigate whether patients with systemic sclerosis (SSc) have raised homocysteine (Hcy) plasma levels, thought to be an independent risk factor for vascular disease, and to study the relationship between Hcy and endothelial damage, and between Hcy and methylene-tetrahydrofolate reductase (MTHFR) genotypes, and patients' vitamin nutritional status, which are among the more frequent causes of hyperhomocysteinemia. METHODS: We measured Hcy, von Willebrand factor (vWF), folic acid, and vitamin B12 plasma levels and analyzed the frequencies of MTHFR mutations in 30 patients with SSc and 12 patients with primary Raynaud's phenomenon (RP); 29 healthy subjects served as controls. RESULTS: Patients with SSc had higher Hcy and vWF concentrations than those with RP (p < 0.01 and p < 0.02, respectively) or controls (p < 0.02 and p < 0.0001, respectively). Folic acid and vitamin B12 were lower in SSc than in RP (p < 0.01 and p < 0.02, respectively) or controls (p < 0.05). MTHFR genotype did not influence Hcy, folate, or vitamin B12 concentrations, but patients homozygous for the mutant gene had higher vWF levels. CONCLUSION: Patients with SSc, but not those with RP, had significantly higher Hcy and vWF plasma levels. Nutritional rather than inherited factors seem to have a pathogenic role in SSc hyperhomocysteinemia.
PMID: 11093443 [PubMed - indexed for MEDLINE]
Genetic factors in the etiology of systemic sclerosis and Raynaud phenomenon. 2000
The genetics of systemic sclerosis. 2002
Google Search mthfr polymorphism reynaud
Google Search mthfr polymorphism raynaud
Raynaud
Autonomic neuropathy
Increasing homocysteine levels and diabetic autonomic neuropathy. 2001
Relation between homocysteinaemia and diabetic neuropathy in patients with Type 2 diabetes mellitus. 2001
Viral infections
HCV
Hyperhomocysteinemia and the MTHFR C677T polymorphism promote steatosis and fibrosis in chronic hepatitis C patients. 2005
- The factors and mechanisms implicated in the development of hepatitis C virus (HCV)-related steatosis are unknown. Hyperhomocysteinemia causes steatosis, and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism induces hyperhomocysteinemia. We investigated the role of these factors in the development of HCV-related steatosis and in the progression of chronic hepatitis C (CHC). One hundred sixteen CHC patients were evaluated for HAI, fibrosis and steatosis grades, body mass index, HCV genotypes, HCV RNA levels, homocysteinemia, and the MTHFR C677T polymorphism. Hyperhomocysteinemia was associated with the TT genotype of MTHFR (r = 0.367; P = .001). Median values of homocysteine in the CC, CT, and TT genotypes of the MTHFR gene were 9.3, 12.2, and 18.6 micromol/L, respectively (P = .006). Steatosis correlated with the MTHFR polymorphism, homocysteinemia, HAI and fibrosis. Steatosis above 20% was significantly associated with fibrosis. Prevalence and high grade (>20%) of steatosis were 41% and 11% in CC, 61% and 49% in CT, and 79% and 64% in TT, respectively (P = .01). Relative risk of developing high levels of steatosis was 20 times higher for TT genotypes than CC genotypes. According to multivariate analysis, steatosis was independently associated with hyperhomocysteinemia (OR = 7.1), HAI (OR = 3.8), liver fibrosis (OR = 4.0), and HCV genotype 3 (OR = 4.6). On univariate analysis, fibrosis was associated with age, steatosis, MTHFR, homocysteinemia and HAI; however, on multivariate analysis, liver fibrosis was independently associated with age (P = .03), HAI (P = .0001), and steatosis (P = .007). In conclusion, a genetic background such as the MTHFR C677T polymorphism responsible for hyperhomocysteinemia plays a role in the development of higher degree of steatosis, which in turn accelerates the progression of liver fibrosis in CHC.
Homocysteine levels and sustained virological response to pegylated-interferon α2b plus ribavirin therapy for chronic hepatitis C: a prospective study 2009
- Chronic hepatitis C affects about 3% of the world's population. Pegylated interferon (IFN) α plus ribavirin is the gold standard treatment. Methylenetetrahydrofolate reductase(MTHFR) is a key enzyme in the metabolism of homocysteine. MTHFR gene polymorphisms and high levels of homocysteine are associated with a high degree of steatosis and fibrosis, conditions associated with a low sustained virological response (SVR) rate.
Aims: To evaluate whether MTHFR polymorphisms and homocysteine levels are predictors of the outcome of treatment in 102 prospectively enrolled patients with chronic hepatitis C naive to treatment.
Methods: Patients were treated with pegylated interferon α-2b plus ribavirin. All patients underwent blood tests, assessment of homocysteine, vitamin B12, folate, hepatitis C virus (HCV)-RNA levels, screening for MTHFR gene polymorphisms and liver ultrasound examination. Results:Homocysteine levels were deranged (>16 μmol/L) in 10.5% of MTHFR wild-type patients vs 40.3% of non-wild-type patients (P=0.015). Homocysteine levels were 14.4 μmol/L in SVR patients and 15.5 μmol/L in non-SVR patients (P=0.049). The SVR rate was 40.0% in MTHFR wild-type patients, 52.0% in heterozygote mutants and 39.3% in homozygote mutants (P=0.467). At logistic regression analysis, genotypes 2 and 3 (odds ratio: 12.328, 95% confidence interval: 3.390-44.837, P=0.0001), homocysteine <16 μmol/L (odds ratio: 3.397, 95% confidence interval: 1.033-11.177, P=0.044) and aspartate aminotransferase (AST) levels <48 U/L (odds ratio: 3.262, 95% confidence interval: 1.125-9.458, P=0.029) were independent predictors of SVR. Conclusions:
In patients with chronic hepatitis C, homocysteine levels are associated with the outcome of pegylated-IFNα plus ribavirin treatment, while polymorphisms of MTHFR are not.
MTHFR and Cancer
Folati e polimorfismi Mthfr responsabili di Ca mammario
Elevati livelli plasmatici di folati incrementerebbero il rischio di cancro al seno in donne in cui è presente la variante allelica 677T del gene Mthfr (folate-metabolizing enzyme methylenetetrahydrofolate reductase). A stabilirlo è uno studio pubblicato su American Journal of Clinical Nutrition che ha, per la prima volta, valutato l'influenza del contenuto plasmatico di acido folico sul rischio di carcinoma mammario alla luce di specifici polimorfismi del gene Mthfr. L'indagine coordinata da Ulrika C. Ericson della Lund University di Malmoe in Svezia ha previsto il reclutamento di 313 pazienti affette da cancro al seno e di 626 donne sane, di età compresa tra 55 e 73 anni. In breve, la concentrazione plasmatica di folati è risultata significativamente più bassa in presenza del genotipo Mthfr 677TT, rispetto a quello Mthfr 677CC. In donne con Mthfr 677T, alte concentrazioni di folati sono associate a un aumento del rischio di tumore mammario (P=0,03). In aggiunta, gli autori hanno osservato una correlazione positiva tra livelli di folati e rischio di tumore mammario anche in donne con genotipo Mthfr 1298AA, ma solo in presenza dell'allele 677T. (L.A.)
American Journal of Clinical Nutrition 2009, 90, 1380-1389
Localized depletion: the key to colorectal cancer risk mediated by MTHFR genotype and folate? 2006
Abstract Dietary folate has been consistently associated with reduced risk of colorectal cancer (CRC). One of the known biochemical roles of folate is donation of methyl moieties. DNA hypomethylation is an early and almost ubiquitous occurrence in tumor tissue. Therefore, it was originally suggested that adequate folate intake contributed to reduced risk of CRC by facilitating methyl-mediated silencing of oncogenes. Methylene tetrahydrofolate reductase (MTHFR) metabolizes 5,10-MTHF (important in DNA synthesis) to 5-MTHF (contributes to downstream methylation reactions by regeneration of methionine from homocysteine). A common polymorphism in the MTHFR gene (C677T) results in a thermolabile phenotype associated with increased homocysteine levels and DNA hypomethylation. Consistent with the folate/methylation hypothesis, it was originally proposed that C677T may increase risk of CRC due to hypomethylation of oncogenes . However, most subsequent studies have reported a reduced risk associated with this polymorphism. This is inconsistent with methylation as the mechanism by which folate and MTHFR genotype mediate CRC risk. The hypothesis presented here proposes that localized folate depletion combined with the effect of the C677T polymorphism on enzyme stability, impacts on the DNA synthesis pathway and accounts for the observed variation in risk associated with genotype and folate status.
MTHFR is a tumor suppressor?
RA (rheumatoid arthritis)
Plasma total homocysteine level and methylenetetrahydrofolate reductase 677C>T genetic polymorphism in Japanese patients with rheumatoid arthritis. 2009 Biomarkers. 2009 Feb;14(1):49-54.
Fujimaki C, Hayashi H, Tsuboi S, Matsuyama T, Kosuge K, Yamada H, Inoue K, Itoh K.
- Hyperhomocysteinemia is a known risk factor of cardiovascular disease. Homocysteine has been also linked to inflammation in rheumatoid arthritis (RA). In this study, we investigated the relationship between plasma homocysteine levels and single nucleotide polymorphism (SNP) of the gene coding for methylenetetrahydrofolate reductase (MTHFR), an enzyme involved in the biosynthesis of homocysteine, and the correlation between the plasma homocysteine levels and generally used inflammatory markers (C-reactive protein, erythrocyte sedimentation rate and matrix metalloproteinase-3) in 96 Japanese patients with RA. Plasma homocysteine levels in patients with the MTHFR 677TT genotype were significantly higher than in those with the 677CC genotype (p < 0.05). In addition, plasma homocysteine levels were increased along with the elevation of general inflammatory markers. Therefore, we conclude that homocysteine might affect the inflammatory status of patients, and the MTHFR 677C>T SNP could be a predictive factor of hyperhomocysteinemia in patients with RA.
Depression
The folic acid endophenotype and depression in an elderly population. 2010
MTHFR and Uric Acid production
more MTFH more DNA synthesis more Uric Acid
Significant association between methylenetetrahydrofolate reductase 677T allele and hyperuricemia among adult Japanese subjects. 2009
Hyperuricaemia and risk of cardiovascular disease and overall death. A 12-year follow-up of participants in the population study of women in Gothenburg, Sweden.
Acta Med Scand. 1988;224(6):549-55
Bengtsson C, Lapidus L, Stendahl C, Waldenström J.
Serum uric concentration was determined in a series of 1462 women, aged 38-60 when first examined in 1968-69, as the first phase of a longitudinal population study in Gothenburg, Sweden. Serum uric acid concentration was positively correlated to the 12-year overall mortality in univariate analysis. No relationship was observed between initial serum uric acid values and incidence of myocardial infarction, angina pectoris, ECG changes indicating ischaemic heart disease or stroke. The association between serum uric acid concentration and mortality was independent of age, body mass index, systolic blood pressure, adipose tissue distribution, smoking habits, serum cholesterol concentration, serum triglyceride concentration, serum creatinine concentration, serum calcium concentration, use of diuretics, and haematological disease. The increased mortality could not be explained by any increase in malignant neoplastic disease.
MTHFR wound healing
Stromelysin-1 5A/6A and eNOS T-786C polymorphisms, MTHFR C677T and A1298C mutations, and cigarette-cannabis smoking: a pilot, hypothesis-generating study of gene-environment pathophysiological associations with Buerger's disease.
Atherosclerosis. 2004 Jun;174(2):315-22.
The 5,10-methylenetetrahydrofolate reductase C677T polymorphism interacts with smoking to increase homocysteine.
Brown KS, Kluijtmans LA, Young IS, Murray L, McMaster D, Woodside JV, Yarnell JW, Boreham CA, McNulty H, Strain JJ, McPartlin J, Scott JM, Mitchell LE, Whitehead AS.
Department of Pharmacology and Center for Pharmacogenetics, University of Pennsylvania School of Medicine, 153 Johnson Pavilion, 3620 Hamilton Walk, Philadelphia, PA 19104-6084, USA.
Elevated homocysteine is a risk marker for several human pathologies. Risk factors for elevated homocysteine include low folate and homozygosity for the T allele of the 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism. Because nitric oxide may inhibit folate catabolism and endothelial nitric oxide synthase activity is reduced in smokers, we postulated that smoking status might modify the impact of the MTHFR C677T polymorphism on homocysteine (tHcy) concentrations. We tested this hypothesis in a healthy young adult population for which MTHFR C677T genotypes and tHcy concentrations were previously reported. The MTHFR 677TT genotype was significantly associated with elevated tHcy concentrations in smokers (P = 0.001) but not in non-smokers (P = 0.36). Among smokers, the MTHFR 677TT genotype was significantly associated with high tHcy in heavy smokers (P = 0.003) but not light smokers (P = 0.09), in men (P = 0.003) but not women (P = 0.11), and in subjects from the lowest serum folate quartile (P = 0.49) but not from folate quartiles 2-4 (P = 0.49). After adjustment for nutritional variables, interactions between MTHFR C677T genotype and NOS3 G894T genotype, and between MTHFR genotype, smoking status and gender were statistically significant. We propose that hyperhomocysteinemia in MTHFR 677TT homozygote smokers is the consequence of mild intracellular folate deficiency caused by a smoking-related reduction of NOS3 activity that is exacerbated when serum folate is low.
Hypertriglyceridemia and MTHFR
Hyperhomocysteinemia is associated with hypertriglyceridemia in mice with methylenetetrahydrofolate reductase deficiency. 2009
Our results suggest that HHcy is associated with hypertriglyceridemia and that MTHFR deficiency may exacerbate lipid accumulation in ApoE deficiency.
Cholesterol and MTHFR
Association of C677T polymorphism in MTHFR gene, high homocysteine and low HDL cholesterol plasma values in heterozygous familial hypercholesterolemia. 2009
significant differences in plasma HDL-C (CC 1.39+/-0.34, CT 1.33+/-0.39 and TT 1.14+/-0.26 mmol/L, p=0.028) between the C677T MTHFR genotypes, that were also found when gender age, and BMI were included as covariables. In addition, Hcy values were significantly different between C/T MTHFR genotypes (CC 11.75+/-2.9, CT 12.69+/-2.88, TT 15.34+/-2.1 micromol/L). The distribution of gender, smoking habit and LDLR gene mutations was similar among the three groups.A significant correlation was found between Hcy plasma values and plasma HDL-C (-0.370, p= 0.003),
Nutr Res. 2009 Nov;29(11):794-801.
Taurine-deficient diet up-regulated cystathionine beta-synthase monoallele in hemizygous cystathionine beta-synthase knockout mice.
Chao WH, Reynolds RD.
Impaired cystathionine beta-synthase (CBS) causes hyperhomocystinuria and hyperhomocysteinemia, both risk factors for cardiovascular diseases. Reduced CBS activity could decrease cysteine and taurine biosyntheses (metabolites of homocysteine degradation) and lead to less taurocholic acid production with a resultant increased cholesterol content. We hypothesized that a deficiency in CBS genetic material and enzyme activity would reduce taurine synthesis, which would lead to an elevated cholesterol concentration. Both sexes of hemizygous C57BL/6J-Cbs(tm1Unc) [CBS (+/-)] and wild-type C57BL/6J mice [CBS (+/+)] were divided into 2 groups. One group of CBS (+/-) and CBS (+/+) mice was fed a cysteine- and taurine-deficient diet for 8 weeks, and the other group was fed a cysteine, taurine, and vitamin B6-deficient diet for 8 weeks. Significantly higher plasma total homocysteine concentrations occurred in the CBS (+/-) mice than their CBS (+/+) cohorts. Female mice of both genotypes had significantly higher plasma total homocysteine concentrations and significantly lower relative CBS mRNA levels than did male mice. During vitamin B(6) deficiency, plasma total homocysteine concentrations were significantly elevated. Three important findings were a differential sex response of CBS mRNA to feeding the vitamin B(6) diet; CBS (+/-) mice had a significantly lower plasma cholesterol concentration, contrary to what was anticipated; and during feeding, the taurine- and cysteine-deficient diet, CBS mRNA levels in CBS (+/-) mice were reduced only 13% rather than the expected 50%. We conclude that the remaining CBS monoallele is up-regulated in mice when fed a taurine-deficient diet to produce additional CBS mRNA.
Plasma homocysteine in adolescents depends on the interaction between methylenetetrahydrofolate reductase genotype, lipids and folate: a seroepidemiological study. 2009
Arterioscler Thromb Vasc Biol. 2006 May;26(5):1043-50. Epub 2006 Feb 23.
Homocysteine activates cAMP-response element binding protein in HepG2 through cAMP/PKA signaling pathway.
Woo CW, Siow YL, O K.
Department of Animal Science, University of Manitoba, Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, Canada.
Comment in:
* Arterioscler Thromb Vasc Biol. 2006 Jul;26(7):e126-7.
OBJECTIVE: Hyperhomocysteinemia is an independent risk factor for cardiovascular disorders. Our previous studies demonstrated that hyperhomocysteinemia not only elicited inflammatory responses in the vascular endothelium but also induced fatty liver and hypercholesterolemia via transcriptional regulation. One of the transcription factors activated in the liver during hyperhomocysteinemia was cAMP-response element binding protein (CREB). CREB regulates the expression of many genes including those involved in lipid and glucose metabolism. In this study, we investigated the molecular mechanism by which Hcy activated CREB in rat liver and in hepatocytes (HepG2). METHOD AND RESULTS: Hyperhomocysteinemia was induced in rats by feeding high-methionine diet for 4 weeks. There was a significant increase in hepatic cAMP levels, protein kinase A (PKA) activity and an activation of CREB. Incubation of HepG2 cells with Hcy (50 to 100 micromol/L) significantly enhanced CREB phosphorylation and subsequently increased CREB/DNA binding activity. PKA was activated in Hcy-treated cells as a result of increased cellular cAMP level. Inhibition of adenylyl cyclase not only reduced the intracellular cAMP levels elevated by Hcy treatment but also inhibited PKA activation and prevented Hcy-induced CREB phosphorylation. CONCLUSIONS: These results suggest that the cAMP/PKA signaling pathway plays an important role in mediating Hcy-induced CREB activation in hepatocyte.
Am J Physiol Endocrinol Metab. 2005 May;288(5):E1002-10. Epub 2005 Jan 11.
Hyperhomocysteinemia induces hepatic cholesterol biosynthesis and lipid accumulation via activation of transcription factors.
Woo CW, Siow YL, Pierce GN, Choy PC, Minuk GY, Mymin D, O K.
Department of Physiology, St. Boniface Hospital Research Centre, Faculty of Medicine, R4032, 351 Tache Ave., Winnipeg, Manitoba, Canada R2H 2A6.
Hyperhomocysteinemia is an independent risk factor for cardiovascular disorders. Elevated plasma homocysteine (Hcy) concentration is associated with other cardiovascular risk factors. We previously reported that Hcy stimulated cholesterol biosynthesis in HepG2 cells. In the present study, we investigated the underlying mechanisms of Hcy-induced hepatic cholesterol biosynthesis in an animal model. Hyperhomocysteinemia was induced in Sprague-Dawley rats by feeding a high-methionine diet for 4 wk. The mRNA expression and the enzyme activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase were significantly increased in livers of hyperhomocysteinemic rats. There were marked hepatic lipid accumulation and an elevation of plasma cholesterol concentration in hyperhomocysteinemic rats. Three transcription factors, namely, sterol regulatory element-binding protein-2 (SREBP-2), cAMP response element-binding protein (CREB), and nuclear factor Y (NF-Y) were activated in livers of hyperhomocysteinemic rats. Upon Hcy treatment of hepatocytes, there was a significant increase in HMG-CoA reductase mRNA expression in these cells. The activation of SREBP-2, CREB, and NF-Y preceded the increase in HMG-CoA reductase expression in Hcy-treated cells. Pretreatment of hepatocytes with inhibitors for transcription factors not only blocked the activation of SREBP-2, CREB, and NF-Y but also attenuated Hcy-induced HMG-CoA reductase mRNA expression. These results suggested that hyperhomocysteinemia-induced activation of SREBP-2, CREB, and NF-Y was responsible for increased cholesterol biosynthesis by transcriptionally regulating HMG-CoA reductase expression in the liver leading to hepatic lipid accumulation and subsequently hypercholesterolemia. In conclusion, the stimulatory effect of Hcy on hepatic cholesterol biosynthesis may represent an important mechanism for hepatic lipid accumulation and cardiovascular disorder associated with hyperhomocysteinemia.
Homocysteine induces 3-hydroxy-3-methylglutaryl coenzyme a reductase in vascular endothelial cells: a mechanism for development of atherosclerosis? 2002 Fulltext
Circulation. 2002 Mar 5;105(9):1037-43.
Li H, Lewis A, Brodsky S, Rieger R, Iden C, Goligorsky MS.
BACKGROUND: It has been established that hyperhomocyst(e)inemia (HHCy) is an independent and graded risk factor for atherosclerosis, although the molecular link to the atherosclerotic process remains obscure. METHODS AND RESULTS: Screening human umbilical vein endothelial cells (HUVECs) with complementary DNA microarray for the gene expression modified by homocysteine (Hcy) revealed that 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) was upregulated. This effect was confirmed using quantitative reverse transcriptase-polymerase chain reaction. Actinomycin D studies revealed that Hcy stabilized HMGCR mRNA (tau(1/2), 9.5 +/- 1.0 versus 5.0 +/- 0.2 hours). Expression of immunodetectable HMGCR in both HUVECs and renal microvascular endothelial cells was increased in Hcy-treated cells in association with the increased abundance of caveolin. Application of a cell-permeable superoxide dismutase mimetic, Mn-TBAP, reversed the Hcy-induced expression of HMGCR. Additional biochemical analysis of the abundance of total cellular cholesterol showed that 0, 20, 50, and 100 micromol/L Hcy resulted in 22.2 +/- 7.3%, 39.5 +/- 1.2%, and 50.4 +/- 6.8% increase, respectively. Gas chromatography mass spectrometry analysis of extracted cholesterol from Hcy-treated HUVECs and from the culture medium showed 17.8 +/- 5.2% and 24.0 +/- 14.5% increases, respectively. Application of simvastatin to Hcy-treated cells reduced cellular cholesterol and prevented Hcy-induced suppression of NO production by HUVECs in a dose-dependent manner. CONCLUSIONS: Using a cDNA microarray, the data disclosed an unexpected link between Hcy and cholesterol dysregulation based on the finding of increased abundance of HMGCR mRNA and protein in endothelial cells, demonstrated the possible role of Hcy-induced oxidative stress in this response, and revealed the improvement of endothelial NO production in Hcy-treated HUVECs by statins. Collectively, these findings may provide a solid explanation for the observed proatherogenic effect of HHcy.
The leading mechanism suggested for the adverse vascular effects of homocysteine on endothelial function involves oxidant stress resulting in a reduced bioavailability of NO.5,8
Homocysteine, like other thiol-containing amino acids, undergoes auto-oxidation with the generation of ROS. ROS, such as superoxide anion, interact with NO to form peroxynitrite,
leading to a depletion of biologically active NO
Decreased_circulating_plasma_lipids_in_HMC_1999
HMcy induces enzymes of lipid met 2007
Genet Test Mol Biomarkers. 2009 May 6;: 19419265
MTHFR 677TT Alone and IRF6 820GG Together with MTHFR 677CT, But Not MTHFR A1298C, Are Risks for Nonsyndromic Cleft Lip with or without Cleft Palate in an Indian Population.
Akhtar Ali, Subodh Kumar Singh, Rajiva Raman
1 Centre for Genetic Disorders, Banaras Hindu University , Varanasi, India .
Aim: To determine the association of three SNPs, IRF6 G820A, MTHFR C677T, and MTHFR A1298C, with nonsyndromic cleft lip with or without cleft palate (NSCL/P) in an Indian population. Method: A total of 323 NSCL/P patients, 116 of their mothers, 108 of their fathers, and 214 normal controls have been examined for the above three SNPs. Result: Frequency of IRF6 GG was 65% in controls, 78% in cases, 84% in case-fathers, and 80% in case-mothers. MTHFR 677T homozygosity was lower than 1% in controls and unaffected parents, while in the group of probands it was much higher (3.4%; OR 4.30). The frequency of CT genotype was also high in the cases and case-mothers (OR 1.89 and 2.2, respectively). MTHFR A1298C did not reveal a statistically significant deviation in allele and genotype frequencies. Conclusion: While MTHFR 677T homozygotes show a significant association with NSCL/P, heterozygotes 677CT are minor risk factors. MTHFR A1298C does not show a risk in any combination of alleles. IRF6 820GG too forms a minor risk. However, combined genotypes IRF6 GG/MTHFR 677CT together form greater risk for NSCL/P.
Microarray-Based Detection of CYP1A1, CYP2C9, CYP2C19, CYP2D6, GSTT1, GSTM1, MTHFR, MTRR, NQO1, NAT2, HLA-DQA1, and AB0 Allele Frequencies in Native Russians.
Olga Gra, Olga Mityaeva, Iryna Berdichevets, Zhanna Kozhekbaeva, Denis Fesenko, Olga Kurbatova, Irina Goldenkova-Pavlova, Tatyana Nasedkina
1 Engelhardt Institute of Molecular Biology, Russian Academy of Sciences , Moscow, Russian Federation.
Xenobiotic-metabolizing genes (e.g., Cytochromes P450, GST, NAT2, and NQO1), folate metabolism genes (e.g., MTHFR and MTRR), and major histocompatibility complex genes (e.g., HLA-DQA1) play multiple roles in the organism functioning. In addition, AB0 is the most clinically significant high-polymorphic gene in transfusion and transplantation medicine. Epidemiological data show that allele frequencies of these genes exhibit ethnic and geographic diversity. Besides, little is known about frequency distribution of the major polymorphic variants in native Russians. We developed biological microchips that allow us to analyze a spectrum of allelic variants in 12 different genes: CYP1A1, CYP2D6, CYP2C9, CYP2C19, GSTT1, GSTM1, MTHFR, MTRR, NQO1, NAT2, HLA-DQA1, and AB0. Using this composite methodological platform we have studied 352 DNA samples from healthy native Russian volunteers. The allelic frequencies of gene polymorphisms obtained are close to allelic frequencies observed in some European populations, as published earlier. These data were used in comparative studies to determine predisposition to tuberculosis, lymphoma, and leukemia in adults and to childhood acute leukemia. The HLA-DQA1 and AB0 allele frequencies were used to estimate forensic population parameters for these loci.
Autism
"MTHFR disturbi neurologici indotti dalle vaccinazioni": http://autoimmunityreactions.org/2016/06/25/mthfr-disturbi-neurologici-indotti-dalle-vaccinazioni/
Migraine
Migraine and MTHFR
Burocracy
Blog on MTHFR
Additional Polymorphisms interacting with MTHFR
Polymorphisms in serine hydroxymethyltransferase 1 and methylenetetrahydrofolate reductase interact to increase cardiovascular disease risk in humans. 2011
Role of the ACE ID and MTHFR C677T polymorphisms in genetic susceptibility of migraine in a north Indian population. , 2009
Genetic variants of angiotensin converting enzyme and methylenetetrahydrofolate reductase may act in combination to increase migraine susceptibility. 2005
THERAPY
Keeping homocysteine low
Folate supplementation
Folate supplementation biases
Folate supplementation biases
JAMA. 2010 Jun 23;303(24):2486-94.
Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. 2010
Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group, Armitage JM, Bowman L, Clarke RJ, Wallendszus K, Bulbulia R, Rahimi K, Haynes R, Parish S, Sleight P, Peto R, Collins R.
CONTEXT: Blood homocysteine levels are positively associated with cardiovascular disease, but it is uncertain whether the association is causal. OBJECTIVE: To assess the effects of reducing homocysteine levels with folic acid and vitamin B(12) on vascular and nonvascular outcomes. DESIGN, SETTING, AND PATIENTS: Double-blind randomized controlled trial of 12,064 survivors of myocardial infarction in secondary care hospitals in the United Kingdom between 1998 and 2008. INTERVENTIONS: 2 mg folic acid plus 1 mg vitamin B(12) daily vs matching placebo. MAIN OUTCOME MEASURES: First major vascular event, defined as major coronary event (coronary death, myocardial infarction, or coronary revascularization), fatal or nonfatal stroke, or noncoronary revascularization. RESULTS: Allocation to the study vitamins reduced homocysteine by a mean of 3.8 micromol/L (28%). During 6.7 years of follow-up, major vascular events occurred in 1537 of 6033 participants (25.5%) allocated folic acid plus vitamin B(12) vs 1493 of 6031 participants (24.8%) allocated placebo (risk ratio [RR], 1.04; 95% confidence interval [CI], 0.97-1.12; P = .28). There were no apparent effects on major coronary events (vitamins, 1229 [20.4%], vs placebo, 1185 [19.6%]; RR, 1.05; 95% CI, 0.97-1.13), stroke (vitamins, 269 [4.5%], vs placebo, 265 [4.4%]; RR, 1.02; 95% CI, 0.86-1.21), or noncoronary revascularizations (vitamins, 178 [3.0%], vs placebo, 152 [2.5%]; RR, 1.18; 95% CI, 0.95-1.46). Nor were there significant differences in the numbers of deaths attributed to vascular causes (vitamins, 578 [9.6%], vs placebo, 559 [9.3%]) or nonvascular causes (vitamins, 405 [6.7%], vs placebo, 392 [6.5%]) or in the incidence of any cancer (vitamins, 678 [11.2%], vs placebo, 639 [10.6%]). CONCLUSION: Substantial long-term reductions in blood homocysteine levels with folic acid and vitamin B(12) supplementation did not have beneficial effects on vascular outcomes but were also not associated with adverse effects on cancer incidence. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN74348595.
what about replacement therapy with choline?
Malaria
Increased Resistance to Malaria in Mice with Methylenetetrahydrofolate Reductase (Mthfr) Deficiency Suggests a Mechanism for Selection of the MTHFR 677C>T (c.665C>T) , 2014
- The polymorphism 677C>T (NM_005957.4:c.665C>T/p.Ala222Val, rs1801133:C>T) in methylenetetrahydrofolate reductase (MTHFR) results in mild enzymatic deficiency and increased risk for several complex traits including adverse reproductive outcomes, birth defects, and heart disease. Despite these deleterious effects, homozygosity is high (5%-15%) in many populations, and among the highest in Mediterranean regions, where malaria was historically endemic and may have conferred a selective advantage for other mutations. We infected Mthfr-deficient (Mthfr(+) (/-) ) and MTHFR overexpressing (MTHFR ) mice with Plasmodium berghei ANKA to induce cerebral malaria. Mthfr(+/-) mice survived longer (P < 0.02, log-rank test), and MTHFR mice died earlier (P < 0.05, log-rank test) after infection compared with wild-type littermates. Flow cytometry revealed increased lymphocyte populations and increased CCR4 NK cells in spleen of Mthfr(+) (/-) mice; MTHFR animals had decreased numbers of these NK cells. Interferon-γ and interleukin-10 immunoreactive proteins were increased and decreased, respectively, in brain of Mthfr(+/-) mice compared with wild-type. We suggest that mild MTHFR deficiency protects against malarial infection and that this phenomenon may have led to the high frequency of the 677C>T/c.665C>T vari
homocysteine+and+wound+healing
