The effect of polymorphisms of MTHFR C677T, A1298C, MS A2756G and CBS 844ins68bp on plasma total homocysteine level and the risk of ischemic stroke in Thai children

Hyperhomocysteinemia is strongly associated with cardiovascular diseases. Previous studies have shown that phytoestrogenα-zearalanol can protect cardiovascular system from hyperhomocysteinemia and ameliorate the level of plasma total homocysteine; however, the underlying mechanisms remain to be clarified. The aim of this research is to investigate the possible molecular mechanisms involved in ameliorating the level of plasma homocysteine byα-zearalanol. By the successfully established diet-induced hyperhomocysteinemia rat models, we found that, afterα-zearalanol treatment, the activity of cystathionineβ-synthase, the key enzyme in homocysteine metabolism, was significantly elevated and level of nitrative stress in liver was significantly reduced. In correlation with this, results also showed a decreased nitration level of cystathionineβ-synthase in liver. Together data implied that alleviation of plasma homocysteine level by phytoestrogenα-zearalanol might be related to the reduction of cystathionineβ-synthase nitration.

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An evidence-based approach to globally assess the covariate-dependent effect of MTHFR SNP rs1801133 on plasma homocysteine: a systematic review and meta-analysis

10.1101/204487 ◽

2017 ◽

Author(s):

Huifeng Jin ◽

Haojie Cheng ◽

Wei Chen ◽

Xiaoming Sheng ◽

Mark Brown ◽

...

Keyword(s):

Methylenetetrahydrofolate Reductase ◽

Meta Analysis ◽

Mthfr C677t ◽

Evidence Based ◽

Single Nucleotide ◽

Dependent Effect ◽

The Public ◽

Modifying Effect ◽

Total Homocysteine ◽

Plasma Total Homocysteine

BackgroundThe single nucleotide polymorphism (SNP) of the gene Methylenetetrahydrofolate Reductase (MTHFR) C677T (or rs1801133) is the most established genetic factor that increases plasma total homocysteine (tHcy) and consequently results in hyperhomocysteinemia. Yet given the limited penetrance of this genetic variant, it is necessary to individually predict the risk of hyperhomocysteinemia for a rs1801133 carrier.ObjectiveWe hypothesized that variability of this genetic risk is largely due to the presence of factors (covariates) that serve as effect modifiers and/or confounders, such as folic acid (FA) intake, and aimed to assess this risk in the complex context of these covariates.DesignWe systematically extracted from published studies the data of tHcy, rs1801133, and any previously reported rs1801133 covariates. The resulting meta-dataset was first used to analyze the covariates’ modifying effect by meta regression and other statistical means. Subsequently, we stratified tHcy data by the rs1801133 genotypes and analyzed under each genotype the variability of the risk resulted from the covariates’ confounding.ResultsThe dataset contains data of 36 rs1801133 covariates that were collected from 114,448 subjects and 249 qualified studies, among which 6 covariates (sex, age, race, FA intake, smoking, and alcohol consumption) are the most frequently informed and therefore included for statistical analysis. The effect of rs1801133 on tHcy exhibits significant variability that can be attributed to effect modification and, to a larger degree, confounding by these covariates. Via statistical modeling, we predicted the covariate-dependent risk of tHcy elevation and hyperhomocysteinemia in a systematic manner.Conclusionswe demonstrated an evidence-based approach that globally assesses the covariate-dependent effect of rs1801133 on tHcy. The results should assist clinicians in interpreting the rs1801133 data from genetic testing for their patients. Such information is also important for the public that increasingly receives genetic data from commercial services without interpretation of its clinical relevance.

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