Estrogen receptor alpha gene polymorphisms and first-ever intracerebral hemorrhage

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).

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.

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.

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.