Demethylation of Circulating Estrogen Receptor Alpha Gene in Cerebral Ischemic Stroke

作者:Lin Hsiu Fen; Hsi Edward; Liao Yi Chu; Chhor Brian; Hung Jessica; Juo Suh Hang H; Lin Ruey Tay*
来源:PLos One, 2015, 10(9): e0139608.
DOI:10.1371/journal.pone.0139608

摘要

Background Estrogen is involved in neuron plasticity and can promote neuronal survival in stroke. Its actions are mostly exerted via estrogen receptor alpha (ER alpha). Previous animal studies have shown that ER alpha is upregulated by DNA demethylation following ischemic injury. This study investigated the methylation levels in the ERa promoter in the peripheral blood of ischemic stroke patients. Methods The study included 201 ischemic stroke patients, and 217 age-and sex-comparable healthy controls. The quantitative methylation level in the 14 CpG sites of the ERa promoter was measured by pyrosequencing in each participant. Multivariate regression model was used to adjust for stroke traditional risk factors. Stroke subtypes and sex-specific analysis were also conducted. Results The results demonstrated that the stroke cases had a lower ERa methylation level than controls in all 14 CpG sites, and site13 and site14 had significant adjusted p-values of 0.035 and 0.026, respectively. Stroke subtypes analysis showed that large-artery atherosclerosis and cardio-embolic subtypes had significantly lower methylation levels than the healthy controls at CpG site5, site9, site12, site13 and site14 with adjusted p = 0.039, 0.009, 0.025, 0.046 and 0.027 respectively. However, the methylation level for the patients with small vessel subtype was not significant. We combined the methylation data from the above five sites for further sex-specific analysis. The results showed that the significant association only existed in women (adjusted p = 0.011), but not in men (adjusted p = 0.300). Conclusions Female stroke cases have lower ER alpha methylation levels than those in the controls, especially in large-artery and cardio-embolic stroke subtypes. The study implies that women suffering from ischemic stroke of specific subtype may undergo different protective mechanisms to reduce the brain injury.

  • 出版日期2015-9-30