title: Estrogen receptor alpha gene polymorphisms and first-ever intracerebral hemorrhage.
abstract: BACKGROUND
  Signaling through estrogen receptor alpha (ER alpha) regulates vasodilatation and atherogenesis. Since hypertension and atherosclerosis are major mechanisms in stroke development, we hypothesized that genetic variants of the ER alpha gene (ESR1) are determinants of future ischemic stroke or intracerebral hemorrhage (ICH).
  
  
  METHODS
  In a population-based prospective nested case-control study, the relationships between ESR1 polymorphisms (c.454-397T>C and c.454-351A>G) and ischemic stroke and ICH were examined in univariate and multivariate models using conditional logistic regression, which included established risk factors.Definitive first-ever stroke events (n = 388), including ischemic stroke (n = 320), ICH (n = 61), and unspecified stroke (n = 7) cases, and controls without cardiovascular disease (n = 773), matched for age, sex, and geographical region were included.
  
  
  RESULTS
  Carriers of the c.454-397T/T genotype had a significantly (p = 0.017) increased risk of ICH (OR 2.31, 95% CI 1.16-4.60) in a univariate analysis. This association persisted (OR 3.94, 95% CI 1.54-10.03), after adjustment for stroke risk determinants. Carriers of c.454-397T/T or c.454-397T/C genotypes had significantly (p = 0.002 and p = 0.004, respectively) higher mean systolic blood pressure (SBP), than carriers of c.454-397C/C, and a similar relationship was observed for diastolic blood pressure (DBP). The combinations of c.454-397T/T genotype and hypertension (OR 21.46, 95% CI 5.20-88.51), or high SBP (OR 18.17, 95% CI 4.91-67.31) or DBP (OR 11.94, 95% CI 3.75-38.03), were strongly associated with increased risk of ICH.
  
  
  CONCLUSIONS
  In this population,the c.454-397T/T genotype associates with first-ever ICH, particularly in combination with hypertension. This implies that alterations in ER alpha-mediated signaling may be involved in the pathophysiology of this disease, with a putative impact on primary prevention.
authors.affiliation: Department of Public Health and Clinical Medicine, Medicine, University, Umeå, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Strand
authors.forename: Ingegerd
authors.initials: I
authors.lastname: Söderström
authors.forename: Per-Gunnar
authors.initials: PG
authors.lastname: Wiklund
authors.forename: Göran
authors.initials: G
authors.lastname: Hallmans
authors.forename: Lars
authors.initials: L
authors.lastname: Weinehall
authors.forename: Stefan
authors.initials: S
authors.lastname: Söderberg
authors.forename: Tommy
authors.initials: T
authors.lastname: Olsson
mesh_terms: D000368:Aged; D001483:Base Sequence; D001794:Blood Pressure / Q000235:genetics; D002545:Brain Ischemia / Q000150:complications*; D016022:Case-Control Studies; D002543:Cerebral Hemorrhage / Q000209:etiology / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D006973:Hypertension / Q000150:complications; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D020521:Stroke / Q000209:etiology* / Q000235:genetics*
chemical_list: D047628:Estrogen Receptor alpha