FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 346:967-974 March 28, 2002 Number 13 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Editorial by Krauss, R. M. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

ABSTRACT

Background Sequence variants in the gene encoding estrogen receptor (ER-) may modify the effects of hormone-replacement therapy on levels of high-density lipoprotein (HDL) cholesterol and other outcomes related to estrogen treatment in postmenopausal women.

Methods We characterized 309 women with coronary artery disease who were enrolled in the Estrogen Replacement and Atherosclerosis trial with respect to eight previously described and two newly identified ER- polymorphisms, and we examined the association between these polymorphisms and the response of HDL cholesterol and other lipids to treatment with estrogen alone or estrogen plus progestin.

Results After adjustment for age, race, diabetes status, body-mass index, smoking status, alcohol intake, and frequency of exercise, the 18.9 percent of the women who had the IVS1–401 C/C genotype (i.e., with C on both chromosomes in intervening sequence 1 at position 401 before exon 2) had an increase in the HDL cholesterol level with hormone-replacement therapy that was more than twice the increase observed in the other women (13.1 mg per deciliter vs. 6.0 mg per deciliter, P for treatment-by-genotype interaction = 0.004); this effect was limited to changes in the HDL subfraction 3 (HDL₃) (P for interaction=0.04). Similar patterns of response were observed for three other highly linked ER- intron 1 polymorphisms close to the IVS1–401 site (range of P values for interaction = 0.07 to 0.005). The pattern of increased response of HDL cholesterol in women with the IVS1–401 C/C genotype was evident in both the women receiving estrogen and those receiving estrogen plus progestin, was preserved across racial and ethnic groups, and was significant among women who were compliant with the study medication (P<0.001).

Conclusions Postmenopausal women with coronary disease who have the ER- IVS1–401 C/C genotype, or several other closely related genotypes, have an augmented response of HDL cholesterol to hormone-replacement therapy.

Source Information

From the Departments of Internal Medicine (D.M.H., G.A.H., E.R.B.), Pediatrics (T.D.H., S.L.Z., D.A.M.), and Public Health Sciences (D.M.R., J.X.) and the Hypertension and Vascular Disease Center (K.B.B.), Wake Forest University School of Medicine, Winston-Salem, N.C.

Address reprint requests to Dr. Herrington at Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157-1045.

Full Text of this Article

Related Letters:

Estrogen-Receptor Polymorphism and Hormone-Replacement Therapy
Garrido J. A., Grant E. C.G., Herrington D. M., Reboussin D. M.
Extract | Full Text | PDF  
N Engl J Med 2002; 347:762-763, Sep 5, 2002. Correspondence

This article has been cited by other articles:

• Jin, Y., Hayes, D. F., Li, L., Robarge, J. D., Skaar, T. C., Philips, S., Nguyen, A., Schott, A., Hayden, J., Lemler, S., Storniolo, A. M., Flockhart, D. A., Stearns, V. (2008). Estrogen Receptor Genotypes Influence Hot Flash Prevalence and Composite Score Before and After Tamoxifen Therapy. JCO 26: 5849-5854 [Abstract] [Full Text]  
• Markoula, S., Xita, N., Lazaros, L., Giannopoulos, S., Kyritsis, A. P., Georgiou, I. (2008). Estrogen Receptor {alpha} Gene Haplotypes and Diplotypes in the Risk of Stroke. Stroke 39: e172-e173 [Full Text]  
• Klos, K. L. E., Boerwinkle, E., Ferrell, R. E., Turner, S. T., Morrison, A. C. (2008). ESR1 polymorphism is associated with plasma lipid and apolipoprotein levels in Caucasians of the Rochester Family Heart Study. J. Lipid Res. 49: 1701-1706 [Abstract] [Full Text]  
• Miller, V. M., Duckles, S. P. (2008). Vascular Actions of Estrogens: Functional Implications. Pharmacol. Rev. 60: 210-241 [Abstract] [Full Text]  
• Legro, R. S., Barnhart, H. X., Schlaff, W. D., Carr, B. R., Diamond, M. P., Carson, S. A., Steinkampf, M. P., Coutifaris, C., McGovern, P. G., Cataldo, N. A., Gosman, G. G., Nestler, J. E., Giudice, L. C., Ewens, K. G., Spielman, R. S., Leppert, P. C., Myers, E. R., for the Reproductive Medicine Network, (2008). Ovulatory Response to Treatment of Polycystic Ovary Syndrome Is Associated with a Polymorphism in the STK11 Gene. J. Clin. Endocrinol. Metab. 93: 792-800 [Abstract] [Full Text]  
• Kato, S., Lindholm, B., Axelsson, J., Qureshi, R. A., Barany, P., Heimburger, O., Gustafsson, J.-A., Stenvinkel, P., Nordfors, L. (2007). Association between oestrogen receptor {alpha} gene polymorphism and mortality in female end-stage renal disease patients. Nephrol Dial Transplant 22: 2571-2577 [Abstract] [Full Text]  
• Altmae, S., Haller, K., Peters, M., Hovatta, O., Stavreus-Evers, A., Karro, H., Metspalu, A., Salumets, A. (2007). Allelic estrogen receptor 1 (ESR1) gene variants predict the outcome of ovarian stimulation in in vitro fertilization. Mol Hum Reprod 13: 521-526 [Abstract] [Full Text]  
• Gallagher, C. J., Langefeld, C. D., Gordon, C. J., Campbell, J. K., Mychalecky, J. C., Bryer-Ash, M., Rich, S. S., Bowden, D. W., Sale, M. M. (2007). Association of the Estrogen Receptor-{alpha} Gene With the Metabolic Syndrome and Its Component Traits in African-American Families: The Insulin Resistance Atherosclerosis Family Study. Diabetes 56: 2135-2141 [Abstract] [Full Text]  
• Arnett, D. K., Baird, A. E., Barkley, R. A., Basson, C. T., Boerwinkle, E., Ganesh, S. K., Herrington, D. M., Hong, Y., Jaquish, C., McDermott, D. A., O'Donnell, C. J. (2007). Relevance of Genetics and Genomics for Prevention and Treatment of Cardiovascular Disease: A Scientific Statement From the American Heart Association Council on Epidemiology and Prevention, the Stroke Council, and the Functional Genomics and Translational Biology Interdisciplinary Working Group. Circulation 115: 2878-2901 [Abstract] [Full Text]  
• Wierman, M. E., Kohrt, W. M. (2007). Review Article: Vascular and Metabolic Effects of Sex Steroids: New Insights Into Clinical Trials. Reproductive Sciences 14: 300-314 [Abstract]  
• Alevizaki, M, Saltiki, K, Cimponeriu, A, Kanakakis, I, Xita, N, Alevizaki, C C, Georgiou, I, Sarika, H-L (2007). Severity of cardiovascular disease in postmenopausal women: associations with common estrogen receptor {alpha} polymorphic variants. Eur J Endocrinol 156: 489-496 [Abstract] [Full Text]  
• Gallagher, C. J., Keene, K. L., Mychaleckyj, J. C., Langefeld, C. D., Hirschhorn, J. N., Henderson, B. E., Gordon, C. J., Freedman, B. I., Rich, S. S., Bowden, D. W., Sale, M. M. (2007). Investigation of the Estrogen Receptor-{alpha} Gene With Type 2 Diabetes and/or Nephropathy in African-American and European-American Populations. Diabetes 56: 675-684 [Abstract] [Full Text]  
• Bray, P. F., Howard, T. D., Vittinghoff, E., Sane, D. C., Herrington, D. M. (2007). Effect of genetic variations in platelet glycoproteins Ib{alpha} and VI on the risk for coronary heart disease events in postmenopausal women taking hormone therapy. Blood 109: 1862-1869 [Abstract] [Full Text]  
• Kjaergaard, A. D., Ellervik, C., Tybjaerg-Hansen, A., Axelsson, C. K., Gronholdt, M.-L. M., Grande, P., Jensen, G. B., Nordestgaard, B. G. (2007). Estrogen Receptor {alpha} Polymorphism and Risk of Cardiovascular Disease, Cancer, and Hip Fracture: Cross-Sectional, Cohort, and Case-Control Studies and a Meta-Analysis. Circulation 115: 861-871 [Abstract] [Full Text]  
• Dahlman-Wright, K., Cavailles, V., Fuqua, S. A., Jordan, V. C., Katzenellenbogen, J. A., Korach, K. S., Maggi, A., Muramatsu, M., Parker, M. G., Gustafsson, J.-A. (2006). International Union of Pharmacology. LXIV. Estrogen Receptors. Pharmacol. Rev. 58: 773-781 [Full Text]  
• Pepine, C. J., Nichols, W. W., Pauly, D. F. (2006). Estrogen and Different Aspects of Vascular Disease in Women and Men. Circ. Res. 99: 459-461 [Full Text]  
• Riancho, J. A, Zarrabeitia, M. T, Valero, C., Sanudo, C., Mijares, V., Gonzalez-Macias, J. (2006). A gene-to-gene interaction between aromatase and estrogen receptors influences bone mineral density.. Eur J Endocrinol 155: 53-59 [Abstract] [Full Text]  
• Lawlor, D. A., Timpson, N., Ebrahim, S., Day, I. N.M., Smith, G. D. (2006). The association of oestrogen receptor {alpha}-haplotypes with cardiovascular risk factors in the British Women's Heart and Health Study. Eur Heart J 27: 1597-1604 [Abstract] [Full Text]  
• Christian, R. C., Liu, P. Y., Harrington, S., Ruan, M., Miller, V. M., Fitzpatrick, L. A. (2006). Intimal Estrogen Receptor (ER){beta}, But Not ER{alpha} Expression, Is Correlated with Coronary Calcification and Atherosclerosis in Pre- and Postmenopausal Women. J. Clin. Endocrinol. Metab. 91: 2713-2720 [Abstract] [Full Text]  
• Shearman, A. M. (2006). Oestrogen receptor genetics: a needle that cuts through many haystacks?. Eur Heart J 27: 1519-1520 [Full Text]  
• de Maat, M. P.M., Bladbjerg, E.-M., Kluft, C., Winkler, U.H., Rekers, H., Skouby, S.O., Jespersen, J. (2006). Estrogen receptor 1 haplotype does not regulate oral contraceptive-induced changes in haemostasis and inflammation risk factors for venous and arterial thrombosis. Hum Reprod 21: 1473-1476 [Abstract] [Full Text]  
• Ouyang, P., Michos, E. D., Karas, R. H. (2006). Hormone Replacement Therapy and the Cardiovascular System: Lessons Learned and Unanswered Questions. J Am Coll Cardiol 47: 1741-1753 [Abstract] [Full Text]  
• Shearman, A. M., Cooper, J. A., Kotwinski, P. J., Miller, G. J., Humphries, S. E., Ardlie, K. G., Jordan, B., Irenze, K., Lunetta, K. L., Schuit, S. C. E., Uitterlinden, A. G., Pols, H. A. P., Demissie, S., Cupples, L. A., Mendelsohn, M. E., Levy, D., Housman, D. E. (2006). Estrogen Receptor {alpha} Gene Variation Is Associated With Risk of Myocardial Infarction in More Than Seven Thousand Men From Five Cohorts. Circ. Res. 98: 590-592 [Abstract] [Full Text]  
• Hall, W. L, Vafeiadou, K., Hallund, J., Bugel, S., Reimann, M., Koebnick, C., Zunft, H-J F., Ferrari, M., Branca, F., Dadd, T., Talbot, D., Powell, J., Minihane, A.-M., Cassidy, A., Nilsson, M., Dahlman-Wright, K., Gustafsson, J.-A., Williams, C. M (2006). Soy-isoflavone-enriched foods and markers of lipid and glucose metabolism in postmenopausal women: interactions with genotype and equol production. Am. J. Clin. Nutr. 83: 592-600 [Abstract] [Full Text]  
• Hall, W. L, Vafeiadou, K., Hallund, J., Bugel, S., Koebnick, C., Reimann, M., Ferrari, M., Branca, F., Talbot, D., Dadd, T., Nilsson, M., Dahlman-Wright, K., Gustafsson, J.-A., Minihane, A.-M., Williams, C. M (2005). Soy-isoflavone-enriched foods and inflammatory biomarkers of cardiovascular disease risk in postmenopausal women: interactions with genotype and equol production. Am. J. Clin. Nutr. 82: 1260-1268 [Abstract] [Full Text]  
• Ginsburg, G. S., Donahue, M. P., Newby, L. K. (2005). Prospects for Personalized Cardiovascular Medicine: The Impact of Genomics. J Am Coll Cardiol 46: 1615-1627 [Abstract] [Full Text]  
• Bittner, V. (2005). Perspectives on Dyslipidemia and Coronary Heart Disease in Women. J Am Coll Cardiol 46: 1628-1635 [Abstract] [Full Text]  
• Johansson, M, Arlestig, L, Moller, B, Smedby, T, Rantapaa-Dahlqvist, S (2005). Oestrogen receptor {alpha} gene polymorphisms in systemic lupus erythematosus. Ann Rheum Dis 64: 1611-1617 [Abstract] [Full Text]  
• Herrington, D. (2005). Eliminating the Improbable: Sherlock Holmes and Standards of Evidence in the Genomic Age. Circulation 112: 2081-2084 [Full Text]  
• Shearman, A. M., Cooper, J. A., Kotwinski, P. J., Humphries, S. E., Mendelsohn, M. E., Housman, D. E., Miller, G. J. (2005). Estrogen Receptor {alpha} Gene Variation and the Risk of Stroke. Stroke 36: 2281-2282 [Abstract] [Full Text]  
• Shearman, A. M., Demissie, S., Cupples, L. A., Peter, I., Schmid, C. H., Ordovas, J. M., Mendelsohn, M. E., Housman, D. E. (2005). Tobacco smoking, estrogen receptor {alpha} gene variation and small low density lipoprotein level. Hum Mol Genet 14: 2405-2413 [Abstract] [Full Text]  
• Schuit, S. C E, de Jong, F. H, Stolk, L., Koek, W N. H, van Meurs, J. B J, Schoofs, M. W C J, Zillikens, M C., Hofman, A., van Leeuwen, J. P T M, Pols, H. A P, Uitterlinden, A. G (2005). Estrogen receptor alpha gene polymorphisms are associated with estradiol levels in postmenopausal women. Eur J Endocrinol 153: 327-334 [Abstract] [Full Text]  
• Yoshida, R., Fukami, M., Sasagawa, I., Hasegawa, T., Kamatani, N., Ogata, T. (2005). Association of Cryptorchidism with a Specific Haplotype of the Estrogen Receptor {alpha} Gene: Implication for the Susceptibility to Estrogenic Environmental Endocrine Disruptors. J. Clin. Endocrinol. Metab. 90: 4716-4721 [Abstract] [Full Text]  
• Yahata, T., Quan, J., Tamura, N., Nagata, H., Kurabayashi, T., Tanaka, K. (2005). Association between single nucleotide polymorphisms of estrogen receptor {alpha} gene and efficacy of HRT on bone mineral density in post-menopausal Japanese women. Hum Reprod 20: 1860-1866 [Abstract] [Full Text]  
• Dubey, R. K., Imthurn, B., Barton, M., Jackson, E. K. (2005). Vascular consequences of menopause and hormone therapy: Importance of timing of treatment and type of estrogen. Cardiovasc Res 66: 295-306 [Abstract] [Full Text]  
• Gennari, L., Merlotti, D., De Paola, V., Calabro, A., Becherini, L., Martini, G., Nuti, R. (2005). Estrogen Receptor Gene Polymorphisms and the Genetics of Osteoporosis: A HuGE Review. Am J Epidemiol 161: 307-320 [Abstract] [Full Text]  
• Boyapati, S. M., Shu, X. O., Ruan, Z. X., Cai, Q., Smith, J. R., Wen, W., Gao, Y.-T., Zheng, W. (2005). Polymorphisms in ER-{alpha} Gene Interact with Estrogen Receptor Status in Breast Cancer Survival. Clin. Cancer Res. 11: 1093-1098 [Abstract] [Full Text]  
• Dubey, R. K., Imthurn, B., Zacharia, L. C., Jackson, E. K. (2004). Hormone Replacement Therapy and Cardiovascular Disease: What Went Wrong and Where Do We Go From Here?. Hypertension 44: 789-795 [Abstract] [Full Text]  
• Lee, Y J, Shin, K S, Kang, S W, Lee, C K, Yoo, B, Cha, H S, Koh, E M, Yoon, S J, Lee, J (2004). Association of the oestrogen receptor {alpha} gene polymorphisms with disease onset in systemic lupus erythematosus. Ann Rheum Dis 63: 1244-1249 [Abstract] [Full Text]  
• Koh, K. K., Sakuma, I. (2004). Should Progestins Be Blamed for the Failure of Hormone Replacement Therapy to Reduce Cardiovascular Events in Randomized Controlled Trials?. Arterioscler. Thromb. Vasc. Bio. 24: 1171-1179 [Abstract] [Full Text]  
• Gibbons, G. H., Liew, C. C., Goodarzi, M. O., Rotter, J. I., Hsueh, W. A., Siragy, H. M., Pratt, R., Dzau, V. J. (2004). Genetic Markers: Progress and Potential for Cardiovascular Disease. Circulation 109: IV-47-IV-58 [Full Text]  
• Schuit, S. C. E., Oei, H.-H. S., Witteman, J. C. M., Geurts van Kessel, C. H., van Meurs, J. B. J., Nijhuis, R. L., van Leeuwen, J. P. T. M., de Jong, F. H., Zillikens, M. C., Hofman, A., Pols, H. A. P., Uitterlinden, A. G. (2004). Estrogen Receptor {alpha} Gene Polymorphisms and Risk of Myocardial Infarction. JAMA 291: 2969-2977 [Abstract] [Full Text]  
• Newton-Cheh, C., O'Donnell, C. J. (2004). Sex Differences and Genetic Associations With Myocardial Infarction. JAMA 291: 3008-3010 [Full Text]  
• Jansen, M. S., Nagel, S. C., Miranda, P. J., Lobenhofer, E. K., Afshari, C. A., McDonnell, D. P. (2004). Short-chain fatty acids enhance nuclear receptor activity through mitogen-activated protein kinase activation and histone deacetylase inhibition. Proc. Natl. Acad. Sci. USA 101: 7199-7204 [Abstract] [Full Text]  
• Khosla, S., Riggs, B. L., Atkinson, E. J., Oberg, A. L., Mavilia, C., Del Monte, F., Melton, L. J. III, Brandi, M. L. (2004). Relationship of Estrogen Receptor Genotypes to Bone Mineral Density and to Rates of Bone Loss in Men. J. Clin. Endocrinol. Metab. 89: 1808-1816 [Abstract] [Full Text]  
• Eriksson, A.-L., Skrtic, S., Niklason, A., Hulten, L. M., Wiklund, O., Hedner, T., Ohlsson, C. (2004). Association between the low activity genotype of catechol-O-methyltransferase and myocardial infarction in a hypertensive population. Eur Heart J 25: 386-391 [Abstract] [Full Text]  
• Pollak, A., Rokach, A., Blumenfeld, A., Rosen, L. J, Resnik, L., Dresner Pollak, R. (2004). Association of oestrogen receptor alpha gene polymorphism with the angiographic extent of coronary artery disease. Eur Heart J 25: 240-245 [Abstract] [Full Text]  
• Sowers, M., Jannausch, M. L., Liang, W., Willing, M. (2004). Estrogen Receptor Genotypes and Their Association with the 10-Year Changes in Bone Mineral Density and Osteocalcin Concentrations. J. Clin. Endocrinol. Metab. 89: 733-739 [Abstract] [Full Text]  
• Braunwald, E. (2003). Cardiology: the past, the present, and the future. J Am Coll Cardiol 42: 2031-2041 [Full Text]  
• Fitzpatrick, L. A. (2003). Hormones and the Heart: Controversies and Conundrums. J. Clin. Endocrinol. Metab. 88: 5609-5610 [Full Text]  
• Shearman, A. M., Cupples, L. A., Demissie, S., Peter, I., Schmid, C. H., Karas, R. H., Mendelsohn, M. E., Housman, D. E., Levy, D. (2003). Association Between Estrogen Receptor {alpha} Gene Variation and Cardiovascular Disease. JAMA 290: 2263-2270 [Abstract] [Full Text]  
• Hopkins, P. N., Brinton, E. A. (2003). Estrogen Receptor 1 Variants and Coronary Artery Disease: Shedding Light Into a Murky Pool. JAMA 290: 2317-2319 [Full Text]  
• McDonnell, D. P. (2003). Mining the Complexities of the Estrogen Signaling Pathways for Novel Therapeutics. Endocrinology 144: 4237-4240 [Full Text]  
• McCarthy, J J, Lehner, T, Reeves, C, Moliterno, D J, Newby, L K, Rogers, W J, Topol, E J (2003). Association of genetic variants in the HDL receptor, SR-B1, with abnormal lipids in women with coronary artery disease. J. Med. Genet. 40: 453-458 [Full Text]  
• Yaffe, K. (2003). Hormone Therapy and the Brain: Deja Vu All Over Again?. JAMA 289: 2717-2719 [Full Text]  
• Evans, W. E., McLeod, H. L. (2003). Pharmacogenomics -- Drug Disposition, Drug Targets, and Side Effects. NEJM 348: 538-549 [Full Text]  
• Herrington, D. M. (2003). Hormone Replacement Therapy and Heart Disease: Replacing Dogma With Data. Circulation 107: 2-4 [Full Text]  
• Schwartz, A. R., Gerin, W., Davidson, K. W., Pickering, T. G., Brosschot, J. F., Thayer, J. F., Christenfeld, N., Linden, W. (2003). Toward a Causal Model of Cardiovascular Responses to Stress and the Development of Cardiovascular Disease. Psychosom. Med. 65: 22-35 [Abstract] [Full Text]  
• Kuller, L. H. (2003). Hormone Replacement Therapy and Risk of Cardiovascular Disease: Implications of the Results of the Women's Health Initiative. Arterioscler. Thromb. Vasc. Bio. 23: 11-16 [Abstract] [Full Text]  
• Simon, T., Boutouyrie, P., Simon, J.M., Laloux, B., Tournigand, C., Tropeano, A.I., Laurent, S., Jaillon, P. (2002). Influence of Tamoxifen on Carotid Intima-Media Thickness in Postmenopausal Women. Circulation 106: 2925-2929 [Abstract] [Full Text]  
• Garrido, J. A., Grant, E. C.G., Herrington, D. M., Reboussin, D. M. (2002). Estrogen-Receptor Polymorphism and Hormone-Replacement Therapy. NEJM 347: 762-763 [Full Text]  
• (2002). Genetic Testing to Predict Cholesterol Response to Postmenopausal HT. JWatch Women's Health 2002: 1-1 [Full Text]  
• (2002). Genotype May Dictate Responsiveness to HRT. Journal Watch Cardiology 2002: 1-1 [Full Text]  
• (2002). Tailoring Drug Treatment to Genetics: An Evolving Estrogen Story?. JWatch General 2002: 5-5 [Full Text]  
• Krauss, R. M. (2002). Individualized Hormone-Replacement Therapy?. NEJM 346: 1017-1018 [Full Text]  
• Herrington, D. M., Howard, T. D., Brosnihan, K. B., McDonnell, D. P., Li, X., Hawkins, G. A., Reboussin, D. M., Xu, J., Zheng, S. L., Meyers, D. A., Bleecker, E. R. (2002). Common Estrogen Receptor Polymorphism Augments Effects of Hormone Replacement Therapy on E-Selectin but Not C-Reactive Protein. Circulation 105: 1879-1882 [Abstract] [Full Text]