High MTHFR promoter methylation levels in men confer protection against ischemic stroke

Abstract

The MTHFR gene encodes methylenetetrahydrofolate reductase required for the metabolism of homocysteine (Hcy) – a previously reported independent risk factor for ischemic stroke (IS). In this study, we first aimed to clarify the association between DNA methylation levels in the MTHFR promoter and the risk of IS, followed by the analysis of potential interactions between environmental factors and DNA methylation levels that affect IS risk. We recruited 164 patients with hypertension and IS (case group) and 345 age- and sex-matched patients with hypertension only (control group). Demographic and clinical information was obtained using questionnaires, and blood samples were collected for biochemical analyses. Fluorescence quantitative methylation-specific PCR (qMSP) was used to detect MTHFR promoter methylation levels. A logistic regression analysis was performed to determine the relationship between environmental factors, MTHFR promoter methylation levels, and IS risk. We finally generated a receiver operating characteristic (ROC) curve to determine whether MTHFR promoter methylation levels can predict IS. The mean MTHFR methylation levels in case group (8.10 ± 6.14) were significantly lower than those in control group (17.44 ± 3.16; p < 0.05). MTHFR promoter methylation levels were also lower in patients with plasma Hcy levels ≥15 μmol/L (10.65 ± 4.05) than in those with Hcy levels <15 μmol/L (16.74 ± 4.26, p < 0.001). Finally, we found that MTHFR hypermethylation is a protective factor for IS, particular in men (OR in men: 0.07; 95% CI: 0.02–0.16; p < 0.001). Further, sex and MTHFR promoter methylation levels exhibited a preliminary interaction effect on IS risk. These results indicate that MTHFR promoter methylation status might have diagnostic value in IS.

Mitochondrial DNA and Epigenetics: Investigating Interactions with the One-Carbon Metabolism in Obesity

“…On the other hand, recent findings associated a reduction of MTHFR methylation with unfavorable conditions or diseases. For example, hypermethylation of the MTHFR promoter has been described as a protective factor against ischemic stroke [ 72 ]. Moreover, it has been demonstrated that MTHFR demethylation is more frequent in subjects that are physically inactive [ 73 ], and that homocysteine can induce demethylation in the promoter region of the MTHFR gene in human vascular smooth muscle cells [ 74 ].…”

Epigenetic mechanisms and potential therapeutic targets in stroke

“…[46][47][48] Additionally, blood methylation in dozens of genes have been associated with stroke risk and functional outcomes in stroke patients with comorbid diseases (hypertensive and obese). [49][50][51] Furthermore, additional profiling studies showed that biological age (DNAm age), which is measured by circulating levels 5mC, can predict stroke risk, outcome, and recurrence more accurately than chronological age. [52][53][54][55][56] Thus, these studies collectively indicate that blood levels of methylated DNA may serve as a biomarker for the diagnosis, prognosis and treatment of stroke.…”

The Role of DNA Methylation in Stroke Recovery

“…Elevated homocysteine levels can induce an excessive inflammatory response in the cerebral region [ 68 ]. Furthermore, high MTHFR promoter methylation levels are suggested to lower the risk of ischemic stroke [ 7 , 75 ]. These findings support the possibility of using the methylation status of MTHFR promoter as a predictive biomarker for ischemic stroke; however, additional studies are required to confirm this hypothesis.…”