Common estrogen receptor polymorphism augments effects of hormone replacement therapy on E-selectin but not C-reactive protein.
BACKGROUND
The estrogen receptor-alpha (ER-alpha) IVS1-401 polymorphism identifies a group of women (approximately 20%) who have augmented effects of hormone replacement therapy (HRT) on levels of HDL cholesterol. This study sought to determine if this augmentation extends to HRT regulation of E-selectin and C-reactive protein (CRP) and to explore possible mechanisms by which this polymorphism might influence estrogen action.


RESULTS
Serum levels of soluble E-selectin and CRP were measured at baseline and 1 year in 264 postmenopausal women randomized to treatment with oral conjugated equine estrogen (0.625 mg/d), estrogen plus progestin (medroxyprogesterone acetate 2.5 mg/d), or placebo. Women with the ER-alpha IVS1-401 C/C genotype receiving HRT had nearly a 2-fold greater reduction in E-selectin compared with C/T or T/T women (P for interaction=0.02). In contrast, there was no augmentation of the HRT-associated increase in CRP among the C/C women compared with C/T or T/T women (P for interaction=0.54). Of luciferase reporter constructs containing sequences spanning the IVS1-401 T/C polymorphism, expression of the construct containing the C allele was enhanced >10-fold, with cotransfection of a constitutively expressed B-myb vector. In contrast, B-myb resulted in only a 2.5-fold increase in expression of the T allele construct.


CONCLUSIONS
Women with the ER-alpha IVS1-401 C/C genotype have greater reductions in E-selectin but no further increases in CRP with HRT. The C allele produces a functional binding site for the transcription factor B-myb. The impact of this polymorphism on ER-alpha transcription and other estrogen-sensitive intermediate and clinical end points has not yet been established.
Herrington
David M
DM
Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1045, USA. kklein@wfubmc.edu
Howard
Timothy D
TD
Brosnihan
K Bridget
KB
McDonnell
Donald P
DP
Li
Xiaolin
X
Hawkins
Gregory A
GA
Reboussin
David M
DM
Xu
Jianfeng
J
Zheng
Siqun L
SL
Meyers
Deborah A
DA
Bleecker
Eugene R
ER
D001483:Base Sequence; D002097:C-Reactive Protein / Q000032:analysis*; D002318:Cardiovascular Diseases / Q000517:prevention & control; D019040:E-Selectin / Q000097:blood*; D047628:Estrogen Receptor alpha; D015914:Estrogen Replacement Therapy; D005260:Female; D006801:Humans; D008875:Middle Aged; D011110:Polymorphism, Genetic; D017698:Postmenopause / Q000097:blood / Q000187:drug effects / Q000235:genetics*; D011960:Receptors, Estrogen / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation
D019040:E-Selectin; D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen; D002097:C-Reactive Protein