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Demethylation of Circulating Estrogen Receptor Alpha Gene in Cerebral Ischemic Stroke.

Lin HF, Hsi E, Liao YC, Chhor B, Hung J, Juo SH, Lin RT - PLoS ONE (2015)

Bottom Line: However, the methylation level for the patients with small vessel subtype was not significant.The results showed that the significant association only existed in women (adjusted p = 0.011), but not in men (adjusted p = 0.300).The study implies that women suffering from ischemic stroke of specific subtype may undergo different protective mechanisms to reduce the brain injury.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Neurology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

ABSTRACT

Background: Estrogen is involved in neuron plasticity and can promote neuronal survival in stroke. Its actions are mostly exerted via estrogen receptor alpha (ERα). Previous animal studies have shown that ERα is upregulated by DNA demethylation following ischemic injury. This study investigated the methylation levels in the ERα 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 ERα 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 ERα methylation level than controls in all 14 CpG sites, and site 13 and site 14 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 site 5, site 9, site 12, site 13 and site 14 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 ERα 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.

No MeSH data available.


Related in: MedlinePlus

Sex-specific analysis for the association between estrogen receptor α promoter methylation level and large-artery atherosclerosis and cardio-embolic stroke subtypes.
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pone.0139608.g002: Sex-specific analysis for the association between estrogen receptor α promoter methylation level and large-artery atherosclerosis and cardio-embolic stroke subtypes.

Mentions: Since demethylation of the ERα gene following ischemic stroke was shown in female but not male rats [12], we further tested the sex-specific effect of ERα methylation status in the LAA/CE group. The methylation levels of five significant CpG sites shown in Table 3 (i.e. CpG site5, site9, site12, site13 and site14) were different between male and female patients (S2 Table). The average methylation levels of these five significant CpG sites were used for subsequent analysis. Compared with female controls, female cases had a significant lower methylation level in the ERα promoter (3.97% vs 4.68%, adjusted p = 0.011) (Fig 2). Although male cases also had a lower ERα methylation level compared with male controls, the difference was not statistically significant (4.07% vs 4.34%, adjusted p = 0.300).


Demethylation of Circulating Estrogen Receptor Alpha Gene in Cerebral Ischemic Stroke.

Lin HF, Hsi E, Liao YC, Chhor B, Hung J, Juo SH, Lin RT - PLoS ONE (2015)

Sex-specific analysis for the association between estrogen receptor α promoter methylation level and large-artery atherosclerosis and cardio-embolic stroke subtypes.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4589317&req=5

pone.0139608.g002: Sex-specific analysis for the association between estrogen receptor α promoter methylation level and large-artery atherosclerosis and cardio-embolic stroke subtypes.
Mentions: Since demethylation of the ERα gene following ischemic stroke was shown in female but not male rats [12], we further tested the sex-specific effect of ERα methylation status in the LAA/CE group. The methylation levels of five significant CpG sites shown in Table 3 (i.e. CpG site5, site9, site12, site13 and site14) were different between male and female patients (S2 Table). The average methylation levels of these five significant CpG sites were used for subsequent analysis. Compared with female controls, female cases had a significant lower methylation level in the ERα promoter (3.97% vs 4.68%, adjusted p = 0.011) (Fig 2). Although male cases also had a lower ERα methylation level compared with male controls, the difference was not statistically significant (4.07% vs 4.34%, adjusted p = 0.300).

Bottom Line: However, the methylation level for the patients with small vessel subtype was not significant.The results showed that the significant association only existed in women (adjusted p = 0.011), but not in men (adjusted p = 0.300).The study implies that women suffering from ischemic stroke of specific subtype may undergo different protective mechanisms to reduce the brain injury.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Neurology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

ABSTRACT

Background: Estrogen is involved in neuron plasticity and can promote neuronal survival in stroke. Its actions are mostly exerted via estrogen receptor alpha (ERα). Previous animal studies have shown that ERα is upregulated by DNA demethylation following ischemic injury. This study investigated the methylation levels in the ERα 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 ERα 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 ERα methylation level than controls in all 14 CpG sites, and site 13 and site 14 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 site 5, site 9, site 12, site 13 and site 14 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 ERα 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.

No MeSH data available.


Related in: MedlinePlus