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


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Center for Research in Epidemiology and Population Health (V.S.-C., M.C., P.-Y.S.), Unité 1018, Department of Hormones and Cardiovascular Disease, 94807 Villejuif, France; Unité Mixte de Recherche en Santé 1018 (V.S.-C., M.C., P.-Y.S.), Université Paris-Sud, 94276 Le Kremlin-Bicêtre, France; Service de Génétique Moléculaire, Pharmacogénétique, et Hormonologie (S.B.-T., A.G.-M.), Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris, 94275 Le Kremlin-Bicêtre, France; INSERM Unité Mixte de Recherche en Santé 693 (S.B.-T., A.G.-M.), Université Paris-Sud, 94276 Le Kremlin-Bicêtre, France; INSERM Unité 1061 (M.-L.A.), University Montpellier, 34493 Montpellier, France; INSERM (C.M.), Institut de Santé Publique, d'Épidémiologie et de Développement, Center Unité 897, Department of Epidemiology-Biostatistic, 33076 Bordeaux, France; and Université Bordeaux (C.M.), 33076 Bordeaux, France.
Valérie
V
Scarabin-Carré
Sylvie
S
Brailly-Tabard
Marie-Laure
ML
Ancelin
Cécilia
C
Maubaret
Anne
A
Guiochon-Mantel
Marianne
M
Canonico
Pierre-Yves
PY
Scarabin
D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002947:Cities / Q000453:epidemiology; D003324:Coronary Artery Disease / Q000097:blood* / Q000235:genetics*; D004958:Estradiol / Q000097:blood*; D047628:Estrogen Receptor alpha / Q000235:genetics*; D047629:Estrogen Receptor beta / Q000235:genetics*; D005260:Female; D005602:France / Q000453:epidemiology; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D017698:Postmenopause / Q000097:blood* / Q000235:genetics
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004958:Estradiol