title: Demethylation of Circulating Estrogen Receptor Alpha Gene in Cerebral Ischemic Stroke.
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.
authors.affiliation: Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Neurology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Hsiu-Fen
authors.initials: HF
authors.lastname: Lin
authors.affiliation: Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Medical Genetics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Edward
authors.initials: E
authors.lastname: Hsi
authors.affiliation: Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Yi-Chu
authors.initials: YC
authors.lastname: Liao
authors.affiliation: Department of Human Biology, Stanford University, Stanford, California, United States of America.
authors.forename: Brian
authors.initials: B
authors.lastname: Chhor
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, United States of America.
authors.forename: Jessica
authors.initials: J
authors.lastname: Hung
authors.affiliation: Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Medical Genetics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Suh-Hang H
authors.initials: SH
authors.lastname: Juo
authors.affiliation: Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Neurology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Ruey-Tay
authors.initials: RT
authors.lastname: Lin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018899:CpG Islands; D019175:DNA Methylation; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012737:Sex Factors; D020521:Stroke / Q000235:genetics* / Q000378:metabolism*
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha