Common estrogen receptor polymorphism augments effects of hormone replacement therapy on E-selectin but not C-reactive protein

Circulation. 2002 Apr 23;105(16):1879-82. doi: 10.1161/01.cir.0000016173.98826.88.


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.

Methods and 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.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Base Sequence
  • C-Reactive Protein / analysis*
  • Cardiovascular Diseases / prevention & control
  • E-Selectin / blood*
  • Estrogen Receptor alpha
  • Estrogen Replacement Therapy*
  • Female
  • Humans
  • Middle Aged
  • Polymorphism, Genetic
  • Postmenopause / blood
  • Postmenopause / drug effects
  • Postmenopause / genetics*
  • Receptors, Estrogen / genetics*
  • Receptors, Estrogen / metabolism
  • Transcriptional Activation


  • E-Selectin
  • Estrogen Receptor alpha
  • Receptors, Estrogen
  • C-Reactive Protein