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


CONCLUSIONS
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.
Zavratnik
Andrej
A
Department of Endocrinology, University Medical Centre, Ljubljanska 5, 2000 Maribor, Slovenia. Andrej.Zavratnik@ukc-mb.si
Zegura
Branka
B
Marc
Janja
J
Prezelj
Janez
J
Pfeifer
Marija
M
D000368:Aged; D019040:E-Selectin / Q000097:blood; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D008875:Middle Aged; D010024:Osteoporosis / Q000188:drug therapy; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D020849:Raloxifene Hydrochloride / Q000494:pharmacology* / Q000627:therapeutic use; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology* / Q000627:therapeutic use; D014652:Vascular Diseases / Q000235:genetics / Q000517:prevention & control*; D014664:Vasodilation / Q000187:drug effects*
D019040:E-Selectin; D047628:Estrogen Receptor alpha; D020845:Selective Estrogen Receptor Modulators; D018799:Intercellular Adhesion Molecule-1; D020849:Raloxifene Hydrochloride