DNA methylation and mRNA expression of glutathione S-transferase alpha 4 are associated with intracranial aneurysms in a gender-dependent manner

Abstract

Objective: We performed a case-control study to investigate the correlation between DNA methylation and mRNA expression of the glutathione S-transferase alpha 4 (GSTA4) gene and the risk of intracranial aneurysm (IA) in the Chinese Han population.Methods: After propensity score matching, 44 pairs of cases and controls were collected in this study. Fasting blood samples were collected for DNA and RNA extraction within 24 h of admission. Nine CpG dinucleotides were selected from the GSTA4 promoter region for DNA methylation pyrosequencing. mRNA expression of GSTA4 was measured by quantitative real-time polymerase chain reaction (RT-qPCR). In vitro cell experiments were conducted to verify the association between 5-aza-2′-deoxycytidine induced DNA hypomethylation and GSTA4 mRNA expression.Results: The mean methylation level of GSTA4 was much lower in IA patients, especially in IA patients, especially in unruptured IA (UIA), than that in controls (IA vs. Control, p < .001; ruptured IA (RIA) vs. Control, p = .005; UIA vs. Control, p < .001). With sex stratification, we further found that the association between GSTA4 methylation and IA risk presented only in women (mean methylation level: IA vs. Control, p < .001; RIA vs. Control, p = .009; UIA vs. Control, p < .001). GSTA4 mRNA expression was significantly higher in the IA group than in the control group (p < .01) and negatively correlated with DNA methylation in all individuals (r = −.746, p < .001). DNA hypomethylation can increase GSTA4 mRNA expression in human primary artery smooth muscle cells. The receiver operating characteristic (ROC) curve showed that GSTA4 mean methylation (AUC = .80, p < .001) was a reliable predictor of women intracranial aneurysm, among which CpG 1 exhibited the best predictive value (AUC = .89, p < .001). In addition, GSTA4 expression levels could also predict the risk of IA in women (AUC = .87, p = .005).Conclusion: Decreased DNA methylation and increased mRNA expression of the GSTA4 gene are associated with the risk of IA in women.

The Role of Epigenetics in Brain Aneurysm and Subarachnoid Hemorrhage: A Comprehensive Review

“…Still, these findings lacked replication and correction for multiple testing, casting uncertainty on their reliability. Additionally, a fourth study found lower DNAm levels and a higher mRNA expression of the glutathione S-transferase alpha 4 (GSTA4 ) gene involved in oxidative stress and phenotypic vascular smooth muscle cells (VSMC) transition, which is associated with IA risk, particularly in women [ 41 ].…”

DNA methylation regulator-mediated modification patterns and risk of intracranial aneurysm: a multi-omics and epigenome-wide association study integrating machine learning, Mendelian randomization, eQTL and mQTL data

“…Recent studies have shown that IA patients exhibit lower levels of MAP3K10 methylation, which could potentially serve as a predictor of IA risk, particularly among women [ 24 ]. Additionally, DNA methylation and mRNA expression of glutathione S-transferase alpha 4 have been shown to be correlated with IAs in a gender-specific manner [ 25 ]. In addition, the DNA methylation of the patatin-like phospholipase domain-containing protein 6 gene has been implicated in contributing to the risk of intracranial aneurysms, especially in males [ 26 ].…”