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

• Published in: Circulation (New York, N.Y.) N.Y.), 2002-04, Vol.105 (16), p.1879-1882
• Main Authors: HERRINGTON, David M, HOWARD, Timothy D, BLEECKER, Eugene R, BROSNIHAN, K. Bridget, MCDONNELL, Donald P, XIAOLIN LI, HAWKINS, Gregory A, REBOUSSIN, David M, JIANFENG XU, ZHENG, Siqun L, MEYERS, Deborah A
• Format: Article
• Language: English
• Subjects: Base Sequence; Biological and medical sciences; C-Reactive Protein - analysis; Cardiovascular Diseases - prevention & control; E-Selectin - blood; Estrogen Receptor alpha; Estrogen Replacement Therapy; Female; Hormones. Endocrine system; Humans; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Polymorphism, Genetic; Postmenopause - blood; Postmenopause - drug effects; Postmenopause - genetics; Receptors, Estrogen - genetics; Receptors, Estrogen - metabolism; Transcriptional Activation
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.0000016173.98826.88

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. 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. 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.