XbaI polymorphism of the estrogen receptor alpha gene influences the effect of raloxifene on the endothelial function

Abstract Objectives Cardiovascular disease is the leading cause of death in postmenopausal women and estrogen deficiency may be an important factor in its development. The selective estrogen receptor modulator, raloxifene, exerts a part of its actions through the estrogen receptor alpha (ESR1) activ...

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Published in:Maturitas 2010-09, Vol.67 (1), p.84-90
Main Authors: Zavratnik, Andrej, Žegura, Branka, Marc, Janja, Preželj, Janez, Pfeifer, Marija
Format: Article
Language:English
Subjects:
Aged
Biological and medical sciences
Cell adhesion molecules
E-Selectin - blood
Endothelium, Vascular - drug effects
Endothelium, Vascular - physiology
Endothelium-dependent vasodilatation
ESR1 polymorphisms
Estrogen Receptor alpha - genetics
Female
Gynecology. Andrology. Obstetrics
Humans
Intercellular Adhesion Molecule-1 - blood
Internal Medicine
Medical sciences
Middle Aged
Obstetrics and Gynecology
Osteoporosis - drug therapy
Polymorphism, Genetic
Postmenopausal women
Prospective Studies
Puberal and climacteric disorders (male and female)
Raloxifene
Raloxifene Hydrochloride - pharmacology
Raloxifene Hydrochloride - therapeutic use
Selective Estrogen Receptor Modulators - pharmacology
Selective Estrogen Receptor Modulators - therapeutic use
Vascular Diseases - genetics
Vascular Diseases - prevention & control
Vasodilation - drug effects
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Summary:Abstract Objectives Cardiovascular disease is the leading cause of death in postmenopausal women and estrogen deficiency may be an important factor in its development. The selective estrogen receptor modulator, raloxifene, exerts a part of its actions through the estrogen receptor alpha (ESR1) activation. We explored if polymorphisms of the ESR1 modify the effects of 6 months raloxifene treatment on endothelial function. Methods A total of 53 postmenopausal women, mean age 59.7 ± 6.2, finished the prospective clinical trial. The PvuII, XbaI, and P325P polymorphisms of the ESR1 gene were analyzed. In all subjects endothelium-dependent flow mediated dilatation (FMD) and cell adhesion molecules (CAM) ICAM-1, VCAM-1 and E-selectin were measured before and after 6 months of raloxifene treatment. Results There was no difference in FMD between the ESR1 genotypes, at baseline. After raloxifene treatment, the FMD was significantly greater in subjects with XX genotype of XbaI polymorphism compared to xx ( p = 0.03) and borderline greater when compared to Xx genotype ( p = 0.053). The FMD increased significantly with raloxifene treatment in women with Xx genotype of XbaI and Pp genotype of PvuII polymorphisms ( p = 0.027 and p = 0.034, respectively). The P325P polymorphism did not influence the FMD after raloxifene. None of the ESR1 gene polymorphisms had any impact on the levels of CAM before or after the treatment. When analysing the whole group, a significant decrease in E-selectin ( p < 0.001) and a small increase in ICAM-1 levels ( p = 0.029) was observed with raloxifene treatment, but no influence on VCAM-1 levels or FMD overall was seen. Conclusion Our data suggest that XbaI and possibly PvuII polymorphisms of the ESR1 gene influence the impact of raloxifene treatment on endothelial function. This effect could be of pharmacogenomic and clinical importance.
ISSN:0378-5122
1873-4111
DOI:10.1016/j.maturitas.2010.05.011