-
1.
Assessment of the relationship between methylenetetrahydrofolate reductase polymorphism and acute lymphoblastic leukemia: Evidence from an updated meta-analysis.
Frikha, R
Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners. 2020;(7):1598-1610
Abstract
OBJECTIVE The methylenetetrahydrofolate reductase gene C677T polymorphism is closely related to the acute lymphoblastic leukemia. Several case-control studies have investigated this association; however, no conclusions could be drawn. A comprehensive updated meta-analysis is established to explain these contradictions and clarify the overall impact of this variant on the susceptibility to acute lymphoblastic leukemia. METHODS Electronic searches were conducted to select published studies prior to June 2018. Pooled odds ratios and stratification analysis were performed under different genetic comparison models, age, and ethnicity. RESULTS Totally, 66 case-control studies including 9619 acute lymphoblastic leukemia cases and 17,396 controls were selected. Our analyses showed that methylenetetrahydrofolate reductase C677T polymorphism was protective mainly in Asian and European countries, under all genetic models and regardless of age, but leukemogenic in mixed population. CONCLUSION Thus, C677T polymorphism may be a promising acute lymphoblastic leukemia biomarker, but they should be interpreted with caution considering other factors such as folic acid intake, gene-gene and gene-environment interactions.
-
2.
Mutations in MTHFR and POLG impaired activity of the mitochondrial respiratory chain in 46-year-old twins with spastic paraparesis.
Wiedemann, A, Chery, C, Coelho, D, Flayac, J, Gueguen, N, Desquiret-Dumas, V, Feillet, F, Lavigne, C, Neau, JP, Fowler, B, et al
Journal of human genetics. 2020;(2):91-98
Abstract
Hereditary spastic paraplegias (HSPs) are characterized by lower extremity spasticity and weakness. HSP is often caused by mutations in SPG genes, but it may also be produced by inborn errors of metabolism. We performed next-generation sequencing of 4813 genes in one adult twin pair with HSP and severe muscular weakness occurring at the same age. We found two pathogenic compound heterozygous variants in MTHFR, including a variant not referenced in international databases, c.197C>T (p.Pro66Leu) and a known variant, c.470G>A (p.Arg157Gln), and two heterozygous pathogenic variants in POLG, c.1760C>T (p.Pro587Leu) and c.752C>T (p.Thr251Ile). MTHFR and POLG mutations were consistent with the severe muscle weakness and the metabolic changes, including hyperhomocysteinemia and decreased activity of both N(5,10)methylenetetrahydrofolate reductase (MTHFR) and complexes I and II of the mitochondrial respiratory chain. These data suggest the potential role of MTHFR and POLG mutations through consequences on mitochondrial dysfunction in the occurrence of spastic paraparesis phenotype with combined metabolic, muscular, and neurological components.
-
3.
Targeting MTHFR for the treatment of migraines.
Rainero, I, Vacca, A, Roveta, F, Govone, F, Gai, A, Rubino, E
Expert opinion on therapeutic targets. 2019;(1):29-37
Abstract
Migraine is a common neurovascular disorder classified by the World Health Organization as one of the most debilitating diseases. Migraine is a complex disease and is a consequence of an interaction between genetic, epigenetic and environmental factors. The MTHFR gene is one of the few replicated genetic risk factors for migraine and encodes an enzyme that is crucial for the folate and the methionine cycles. Individuals carrying the T allele of the MTHFR C677T polymorphism have increased plasma concentrations of homocysteine which leads to endothelial cell injury and alterations in coagulant properties of blood. Areas covered: This review focuses on the recent advances in genetics and the role of the MTHFR gene and homocysteine metabolism in migraine etiopathogenesis. The article summarizes the potential of targeting MTHFR and homocysteine for disease prevention. Expert opinion: Determination of MTHFR C677T polymorphisms as well as measurement of homocysteine concentrations may be useful to migraine patients, particularly those suffering from migraine with aura. Preliminary studies support the use of folate, vitamin B6 and vitamin B12 for the prevention of migraine. However, the results of these studies await replication in larger randomized controlled clinical trials.
-
4.
Epigenetic Factors in Late-Onset Alzheimer's Disease: MTHFR and CTH Gene Polymorphisms, Metabolic Transsulfuration and Methylation Pathways, and B Vitamins.
Román, GC, Mancera-Páez, O, Bernal, C
International journal of molecular sciences. 2019;(2)
Abstract
DNA methylation and other epigenetic factors are important in the pathogenesis of late-onset Alzheimer's disease (LOAD). Methylenetetrahydrofolate reductase (MTHFR) gene mutations occur in most elderly patients with memory loss. MTHFR is critical for production of S-adenosyl-l-methionine (SAM), the principal methyl donor. A common mutation (1364T/T) of the cystathionine-γ-lyase (CTH) gene affects the enzyme that converts cystathionine to cysteine in the transsulfuration pathway causing plasma elevation of total homocysteine (tHcy) or hyperhomocysteinemia-a strong and independent risk factor for cognitive loss and AD. Other causes of hyperhomocysteinemia include aging, nutritional factors, and deficiencies of B vitamins. We emphasize the importance of supplementing vitamin B12 (methylcobalamin), vitamin B₉ (folic acid), vitamin B₆ (pyridoxine), and SAM to patients in early stages of LOAD.
-
5.
Association of Intake Folate and Related Gene Polymorphisms with Breast Cancer.
Chen, X, Ahamada, H, Zhang, T, Bai, Z, Wang, C
Journal of nutritional science and vitaminology. 2019;(6):459-469
Abstract
Breast cancer is one of the most common malignancies in women worldwide and is associated with a variety of risk factors. Folate and vitamin B12 are key elements of the one-carbon metabolism pathway where methylenetetrahydrofolate reductase (MTHFR) plays a significant role. Though many molecular and epidemiological studies have been performed to explore the relationship between intake folate, vitamin B12, MTHFR gene polymorphism and breast cancer risk, there is no consensus to date. By reviewing the relevant literatures and summarizing the potential effect of dietary folate intake on MTHFR genes polymorphism and breast cancer risk, we conclude that MTHFR C677T gene polymorphism is associated with breast cancer risk among Asian, but not Caucasians, and the MTHFR A1298C gene polymorphism is not a susceptibility factor of breast cancers. Concomitant low activity of MTHFR enzyme resulted from C677T gene polymorphism and low dietary folate intake is associated with increased breast cancer risk.
-
6.
Associations of the MTHFR rs1801133 polymorphism with coronary artery disease and lipid levels: a systematic review and updated meta-analysis.
Luo, Z, Lu, Z, Muhammad, I, Chen, Y, Chen, Q, Zhang, J, Song, Y
Lipids in health and disease. 2018;(1):191
Abstract
BACKGROUND The associations of the 5,10-methylenetetrahydrofolate reductase gene (MTHFR) rs1801133 polymorphism with coronary artery disease (CAD) and plasma lipid levels have been widely investigated, but the results were inconsistent and inconclusive. This meta-analysis aimed to clarify the relationships of the rs1801133 polymorphism with CAD and plasma lipid levels. METHODS By searching in PubMed, Google Scholar, Web of Science, Cochrane Library, Wanfang, VIP and CNKI databases, 123 studies (87,020 subjects) and 65 studies (85,554 subjects) were identified for the CAD association analysis and the lipid association analysis, respectively. Odds ratio (OR) and standardized mean difference (SMD) were used to determine the effects of the rs1801133 polymorphism on CAD risk and lipid levels, respectively. RESULTS The variant T allele of the rs1801133 polymorphism was associated with increased risk of CAD under allelic model [OR = 1.11, 95% confidence interval (CI) = 1.06-1.17, P < 0.01], additive model (OR = 1.25, 95% CI = 1.14-1.37, P < 0.01), dominant model (OR = 1.11, 95% CI = 1.04-1.17, P < 0.01), and recessive model (OR = 1.22, 95% CI = 1.12-1.32, P < 0.01). The T carriers had higher levels of total cholesterol (TC) (SMD = 0.04, 95% CI = 0.01-0.07, P = 0.02) and low-density lipoprotein cholesterol (LDL-C) (SMD = 0.07, 95% CI = 0.01-0.12, P = 0.01) than the non-carriers. CONCLUSIONS The meta-analysis suggested that the T allele of the rs1801133 polymorphism is a risk factor for CAD, which is possibly and partly mediated by abnormal lipid levels.
-
7.
Riboflavin, MTHFR genotype and blood pressure: A personalized approach to prevention and treatment of hypertension.
McNulty, H, Strain, JJ, Hughes, CF, Ward, M
Molecular aspects of medicine. 2017;:2-9
Abstract
Hypertension is the leading risk factor contributing to mortality worldwide, primarily from cardiovascular disease (CVD), while effective treatment of hypertension is proven to reduce CVD events. Along with the well recognized nutrition and lifestyle determinants, genetic factors are implicated in the development and progression of hypertension. In recent years genome-wide association studies have identified a region near the gene encoding the folate-metabolizing enzyme methylenetetrahydrofolate reductase (MTHFR) among eight loci associated with blood pressure. Epidemiological studies, which provide a separate line of evidence to link this gene with blood pressure, show that the 677C→T polymorphism in MTHFR increases the risk of hypertension by 24-87% and CVD by up to 40%, albeit with a large geographical variation in the extent of excess disease risk suggestive of a gene-environment interaction. Emerging evidence indicates that the relevant environmental factor may be riboflavin, the MTHFR co-factor, via a novel and genotype-specific effect on blood pressure. Randomized trials conducted in hypertensive patients (with and without overt CVD) pre-screened for this polymorphism show that targeted riboflavin supplementation in homozygous individuals (MTHFR 677TT genotype) lowers systolic blood pressure by 6 to 13 mmHg, independently of the effect of antihypertensive drugs. The latest evidence, that the blood pressure phenotype associated with this polymorphism is modifiable by riboflavin, has important clinical and public health implications. For hypertensive patients, riboflavin supplementation can offer a non-drug treatment to effectively lower blood pressure in those identified with the MTHFR 677TT genotype. For sub-populations worldwide with this genotype, better riboflavin status may prevent or delay the development of high blood pressure. Thus riboflavin, targeted at those homozygous for a common polymorphism in MTHFR, may offer a personalized treatment or preventative strategy for hypertension. Further investigations of this novel gene-nutrient interaction in relation to blood pressure, hypertension and hypertension in pregnancy are required.
-
8.
Genotyping the High Altitude Mestizo Ecuadorian Population Affected with Prostate Cancer.
López-Cortés, A, Cabrera-Andrade, A, Salazar-Ruales, C, Zambrano, AK, Guerrero, S, Guevara, P, Leone, PE, Paz-Y-Miño, C
BioMed research international. 2017;:3507671
Abstract
Prostate cancer (PC) is the second most commonly diagnosed type of cancer in males with 1,114,072 new cases in 2015. The MTHFR enzyme acts in the folate metabolism, which is essential in methylation and synthesis of nucleic acids. MTHFR C677T alters homocysteine levels and folate assimilation associated with DNA damage. Androgens play essential roles in prostate growth. The SRD5A2 enzyme metabolizes testosterone and the V89L polymorphism reduces in vivo SRD5A2 activity. The androgen receptor gene codes for a three-domain protein that contains two polymorphic trinucleotide repeats (CAG, GGC). Therefore, it is essential to know how PC risk is associated with clinical features and polymorphisms in high altitude Ecuadorian mestizo populations. We analyzed 480 healthy and 326 affected men from our three retrospective case-control studies. We found significant association between MTHFR C/T (odds ratio [OR] = 2.2; P = 0.009), MTHFR C/T+T/T (OR = 2.22; P = 0.009), and PC. The SRD5A2 A49T substitution was associated with higher pTNM stage (OR = 2.88; P = 0.039) and elevated Gleason grade (OR = 3.15; P = 0.004). Additionally, patients with ≤21 CAG repeats have an increased risk of developing PC (OR = 2.99; P < 0.001). In conclusion, genotype polymorphism studies are important to characterize genetic variations in high altitude mestizo populations.
-
9.
Methylenetetrahydrofolate reductase A1298C genetic variant& risk of schizophrenia: A meta-analysis.
Rai, V, Yadav, U, Kumar, P, Yadav, SK, Gupta, S
The Indian journal of medical research. 2017;(4):437-447
-
-
Free full text
-
Abstract
BACKGROUND & OBJECTIVES Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme of folate metabolism, whose role in schizophrenia is debatable. Numerous case-control studies have investigated the association of MTHFR A1298C polymorphism with schizophrenia, but results are controversial. The aim of the present study was to find the association between MTHFR A1298C gene polymorphism and schizophrenia. METHODS PubMed, Google Scholar, Science Direct and Springer link databases were searched for case-control association studies in which MTHFR A1298C polymorphism was investigated as a risk factor for schizophrenia. In all, 19 studies with 4049 cases and 5488 controls were included in this meta-analysis. Odds ratios (ORs) with 95 per cent confidence intervals (CIs) were used as an association measure. RESULTS The results of meta-analysis reported a significant association between A1298C polymorphism and schizophrenia risk in overall comparisons in all genetic models (C vs. A: OR=1.13, 95% CI=1.01-1.27, P=0.02; CC vs. AA: OR=1.20, 95% CI=1.03-1.39, P=0.02; AC vs. AA: OR=1.13, 95% CI=1.03-1.23, P=0.009; AC+CC vs. AA: OR=1.14, 95% CI=1.02-1.24, P=0.002; CC vs. AA+AC: OR=1.17, 95% CI=1.01-1.35, P=0.04). INTERPRETATION & CONCLUSIONS MTHFR A1298C polymorphism was found to be a risk factor for schizophrenia and might have played a significant role in the pathogenesis of schizophrenia.
-
10.
MTHFR A1298C polymorphisms reduce the risk of congenital heart defects: a meta-analysis from 16 case-control studies.
Yu, D, Zhuang, Z, Wen, Z, Zang, X, Mo, X
Italian journal of pediatrics. 2017;(1):108
Abstract
BACKGROUND Methylenetetrahydrofolate reductase (MTHFR) plays a crucial role in the hyperhomocysteinemia, which is a risk factor related to the occurrence of congenital heart defect (CHD). However, the association between MTHFR polymorphism and CHD has been inconclusive. METHODS We conducted an updated meta-analysis to provide comprehensive evidence on the role of MTHFR A1298C polymorphism in CHD. Databases were searched and a total of 16 studies containing 2207 cases and 2364 controls were included. RESULTS We detected that a significant association was found in the recessive model (CC vs. AA + AC: OR = 1.38, 95% CI: 1.10-1.73) for the overall population. Subgroup analysis showed that associations were found in patients without Down Syndrome in genetic models for CC vs. AA (OR = 1.47, 95% CI: 1.01-2.14), CC vs. AC (OR = 1.29, 95% CI: 1.00-1.66) and recessive model (OR = 1.44, 95% CI: 1.14-1.82). We conducted a meta-regression analysis, Galbraith plots and a sensitivity analysis to assess the sources of heterogeneity. CONCLUSIONS In summary, our present meta-analysis supports the MTHFR 1298C allele as a risk factor for CHD. However, further studies should be conducted to investigate the correlation of plasma homocysteine levels, enzyme activity, and periconceptional folic acid supplementation with the risk of CHD.