Plasma estrogen levels, estrogen receptor gene variation, and ischemic arterial disease in postmenopausal women: the three-city prospective cohort study.

Abstract : In older postmenopausal women, high levels of endogenous estrogen have been related to adverse health outcomes including ischemic arterial disease (IAD). Whether estrogen receptor-α (ESR1) and -β (ESR2) polymorphisms modulate the effects of estrogens on IAD has not been investigated. In the Three-City prospective cohort study among subjects older than 65 years, we used a case-cohort design in which plasma levels of total and bioavailable 17β-estradiol were measured. After exclusion of postmenopausal women using hormone therapy, a random subcohort of 533 women and 105 incident cases of first IAD events over 4 years of follow-up were analyzed. Five common polymorphisms of ESR1 and ESR2 were genotyped. Hazard ratios (HRs) of IAD for a 1-SD increase in hormones levels by the genotypes were estimated from Cox models after adjustment for cardiovascular risk factors and a correction for multiple testing. We also investigated the role of hemostasis and inflammation as potential mediators. Neither estrogens nor IAD risk was significantly associated with estrogen receptor polymorphisms. Overall, IAD risk increased with total estradiol [HR1.40, 95% confidence interval (CI) 1.11-1.77]. Stratified analysis by genotypes showed that total estradiol was positively related to IAD risk in women with ESR1 rs9340799-AA genotype but not in women with the AG/GG genotype (HR 1.62, 95% CI 1.22-2.17 and HR 1.03, 95% CI 0.81-1.30, respectively; P for interaction <.05). An additional adjustment for hemostatic variables reduced the HR by about one third in women carrying the rs9340799-AA genotype (HR 1.41, 95% CI 1.06-1.90). The ESR1 rs9340799 genotype may modify the IAD risk related to high endogenous estrogens levels in older postmenopausal women. Hypercoagulability may act as a mediator.