MTHFR - Ala222Val Effects on Metabolic Syndrome Progression

Abstract

Objective: Methylene-tetrahydrofolate reductase (MTHFR) is involved in adapting metabolism to environmental challenges by various mechanisms, including the control of gene expression by epigenetic and post-translational changes of transcription factors. Though a metabolic syndrome candidate gene, association studies of its common polymorphism rs1801133 (MTHFR-Ala222Val) remain inconclusive with important ethnic differences, and the effect on disease progression was not addressed. Methods: 307 middle-aged metabolic syndrome patients in a central Romanian hospital setting were investigated metabolically, and genotyped by PCR-RFLP. Disease progression was assessed by the age of onset of metabolic components, as well as development of non-alcoholic fatty liver disease and atherosclerotic complications. Results: The minor allele frequency of rs1801133 was 30.13%. Metabolic parameters showed no statistically significant differences according to genotype, but variant carriers developed dysglycemia and dyslipidemia earlier (53.28±10.8 vs 59.44±9.31 years, p<0.05 and 58.57±11.31 vs 64.72±10.6 years, p<0.1).While the polymorphism did not influence hepatic complications, an inverse association was found for manifest atherosclerosis (OR=0.49, p=0.006, 95%CI:0.29-0.81), which may be folate-status dependent, and needs further investigations. Simultaneous analysis with transcription factor polymorphisms (rs1801282, rs8192678) showed that the more protective genotypes were present the later metabolic disturbances developed, and in the presence of the other two variants the apparent protective cardiovascular effect disappeared. Conclusions: The common functional polymorphism rs1801133 may influence metabolic syndrome progression, the age of onset of components and development of atherosclerotic complications. Besides simple additive effects, complex mitigating and aggravating variant interactions may exist, and the protective or predisposing outcome may depend on modifiable environmental factors.

Possibility of Dietary Induction of METHFR rs1801133 (SNP) and the Potential Preventive Effect of Curcumin and Metformin in the Presence of Metabolic Syndrome

“…organizations, including the World Health Organization (WHO), have reached a consensus regarding the factors contributing to MetS, but there is disagreement regarding the specific grouping of these factors and the specific threshold points for each factor that defines MetS because there are so many definitions for identifying MetSTable (1), which contributes to both false-positive and false-negative diagnoses [6].…”

“…Other derivatives of this active ingredient, guanidine Figure (1), were synthesized in laboratories and used also to lower blood glucose, in the 1920s and 1930s, metformin was used to cure diabetes, but it was discontinued due to its toxicity and the greater accessibility of insulin. In the 1940s, experiments to find a cure for malaria led to the rediscovery of metformin., Metformin gives a good impact on influenza when lowering blood glucose during clinical trials.…”

“…It controls methylation, a crucial mechanism for posttranslational changes and epigenetic control, as well as methionine synthesis, which entails the detoxification of homocysteine linked to increased oxidative stress. It also regulates the proportional use of one-carbon units in the synthesis of nucleic acids [1]. [30][31][32] Mostly in Asians and less in Caucasians, Rs1801133 is associated with elevated homocysteine levels and has been described inconclusively in relation toMetS components and other prevalent illnesses (such as Alzheimer's disease, and depression) [31].…”

“…It was clearly stated that metabolic syndrome has a relation with gene polymorphism induction, choosing MTHFR and its most popular SNP rs1801133 (MTHFR -Ala222Val) just to assess this relation through using many biochemical (fasting blood glucose, Insulin, HOMA-IR, Lipid profile), Anthropometrical (weight, Length, BodyMass Index) and molecular biological tests, exploring the most available published articles in this context to evaluate this relationship, especially in the presence of both curcumin and metformin as a natural source of treatment of metabolic syndrome [1].…”

“…The key enzyme in folate metabolism process is MTHFR (methylenetetrahydrofolate reductase) and its gene SNP rs1801133 is highly suspected to stimulate metabolic syndrome [1], it was well-defined that Type 2 diabetes mellitus (T2DM) risk is raised by five times, cardiovascular disease risk is increased by three times, and the chance of acquiring certain types of cancer is also elevated as a result of the presence of metabolic syndrome [2], in this article we tried to collect representative number of the available published papers about this issues in order to evaluate the dietary induction of MTHFR rs1801133 (MTHFR -Ala222Val) Single nucleotide polymorphism (SNP) which will be accompanied with the presence of diet induced metabolic syndrome and the potential preventive effect of metformin or curcumin.…”