This Article  • Full text  • PDF  • Correction  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on ISI (124)  • Contact me when this article is cited  Related Content  • Related article  • Similar articles in JAMA  Topic Collections  • Neurology  • Cerebrovascular Disease  • Stroke  • Cardiovascular System  • Women's Health  • Women's Health, Other  • Cardiovascular Disease/ Myocardial Infarction  • Genetics  • Genetic Disorders  • Alert me on articles by topic  Social Bookmarking   What's this?

Association Between Estrogen Receptor Gene Variation and Cardiovascular Disease

Amanda M. Shearman, PhD; L. Adrienne Cupples, PhD; Serkalem Demissie, PhD; Inga Peter, PhD; Christopher H. Schmid, PhD; Richard H. Karas, MD, PhD; Michael E. Mendelsohn, MD; David E. Housman, PhD; Daniel Levy, MD

JAMA. 2003;290:2263-2270.

Context  Estrogen and related hormone therapies activate estrogen receptors, which in turn regulate genes for several cardiovascular disease (CVD) risk factors. Relatively little is known, however, about the impact of genetic variation in estrogen receptor (ESR1) on CVD risk.

Objective  To investigate whether the ESR1 c.454-397T>C polymorphism is associated with CVD risk.

Design, Setting, and Participants  Prospective study of 1739 unrelated men and women from the population-based offspring cohort of the Framingham Heart Study, who were followed up from 1971 to 1998.

Main Outcome Measures  Total atherosclerotic CVD events, defined as recognized or unrecognized myocardial infarction (MI), angina pectoris, coronary insufficiency, intermittent claudication, coronary heart disease death, or atherothrombotic stroke (n = 178); major atherosclerotic CVD, defined as recognized acute MI, coronary insufficiency, coronary heart disease death, or atherothrombotic stroke (n = 83); and recognized acute MI (n = 59).

Results  Twenty percent of participants (n = 352) were homozygous for the ESR1 c.454-397C allele. After adjustment for covariates (age, sex, body mass index, hypertension, diabetes mellitus, total cholesterol, high-density lipoprotein cholesterol, and cigarette smoking), the CC genotype was significantly associated with major atherosclerotic CVD, with an odds ratio of 2.0 (95% confidence interval [CI], 1.3-3.2; P = .004) compared with individuals with the CT or TT genotypes. Participants with the CC genotype had 3.0-fold greater odds of MI (95% CI, 1.7-5.2; P<.001) compared with those with the CT or TT genotype. The results remained significant when analyses were restricted to men; too few women had events to study them separately.

Conclusions  Individuals with the common ESR1 c.454-397CC genotype have a substantial increase in risk of MI. Whether ESR1 c.454-397T>C is causally related to MI risk or in linkage disequilibrium with 1 or more causal variants remains to be determined. These findings support the importance of estrogen receptors in CVD susceptibility, especially in men. Estrogen receptor variation also has potential to explain recent conflicting data regarding the effects of hormone therapy on CVD susceptibility in women.

Author Affiliations: Center for Cancer Research, Massachusetts Institute of Technology, Cambridge (Drs Shearman and Housman); Department of Biostatistics, Boston University School of Public Health (Drs Cupples and Demissie), Biostatistics Research Center, Division of Clinical Care Research, Department of Medicine, Tufts–New England Medical Center (Drs Peter and Schmid), and Molecular Cardiology Research Institute, Department of Medicine, Tufts–New England Medical Center, and Tufts–New England Medical Center Specialized Center of Research in Ischemic Heart Disease (Drs Karas and Mendelsohn), Boston, Mass; and the National Heart, Lung, and Blood Institute Framingham Heart Study, Framingham, Mass (Dr Levy).

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati     What's this?

RELATED ARTICLE

Estrogen Receptor 1 Variants and Coronary Artery Disease: Shedding Light Into a Murky Pool
Paul N. Hopkins and Eliot A. Brinton
JAMA. 2003;290(17):2317-2319.
EXTRACT | FULL TEXT  

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Circulating Estradiol and Mortality in Men With Systolic Chronic Heart Failure
Jankowska et al.
JAMA 2009;301:1892-1901.
ABSTRACT | FULL TEXT  

Variation in Estrogen-Related Genes Associated with Cardiovascular Phenotypes and Circulating Estradiol, Testosterone, and Dehydroepiandrosterone Sulfate Levels
Peter et al.
J. Clin. Endocrinol. Metab. 2008;93:2779-2785.
ABSTRACT | FULL TEXT  

Genetic Association Studies
Lunetta
Circulation 2008;118:96-101.
FULL TEXT  

Vascular Actions of Estrogens: Functional Implications
Miller and Duckles
Pharmacol. Rev. 2008;60:210-241.
ABSTRACT | FULL TEXT  

Variation in the Estrogen Receptor {alpha} Gene and Risk of Stroke: The Rotterdam Study
Bos et al.
Stroke 2008;39:1324-1326.
ABSTRACT | FULL TEXT  

Polymorphisms and Haplotypes of the Estrogen Receptor-{beta} Gene (ESR2) and Cardiovascular Disease in Men and Women
Rexrode et al.
Clin. Chem. 2007;53:1749-1756.
ABSTRACT | FULL TEXT  

Low Serum Testosterone and High Serum Estradiol Associate With Lower Extremity Peripheral Arterial Disease in Elderly Men: The MrOS Study in Sweden
Tivesten et al.
J Am Coll Cardiol 2007;50:1070-1076.
ABSTRACT | FULL TEXT  

Association between oestrogen receptor {alpha} gene polymorphism and mortality in female end-stage renal disease patients
Kato et al.
Nephrol Dial Transplant 2007;22:2571-2577.
ABSTRACT | FULL TEXT  

Estrogen Receptors {alpha} and {beta} Mediate Distinct Pathways of Vascular Gene Expression, Including Genes Involved in Mitochondrial Electron Transport and Generation of Reactive Oxygen Species
O'Lone et al.
Mol. Endocrinol. 2007;21:1281-1296.
ABSTRACT | FULL TEXT  

Age-Related Changes in Echocardiographic Measurements: Association With Variation in the Estrogen Receptor-{alpha} Gene
Peter et al.
Hypertension 2007;49:1000-1006.
ABSTRACT | FULL TEXT  

Nonvalidation of Reported Genetic Risk Factors for Acute Coronary Syndrome in a Large-Scale Replication Study
Morgan et al.
JAMA 2007;297:1551-1561.
ABSTRACT | FULL TEXT  

Severity of cardiovascular disease in postmenopausal women: associations with common estrogen receptor {alpha} polymorphic variants
Alevizaki et al.
Eur J Endocrinol 2007;156:489-496.
ABSTRACT | FULL TEXT  

Estrogen Receptor {alpha} Gene Polymorphisms Associated with Incident Aging Macula Disorder
Boekhoorn et al.
IOVS 2007;48:1012-1017.
ABSTRACT | FULL TEXT  

Compromised Aortic Vasoreactivity in Male Estrogen Receptor-{alpha}-Deficient Mice during Acute Lipopolysaccharide-Induced Inflammation
Corbacho et al.
Endocrinology 2007;148:1403-1411.
ABSTRACT | FULL TEXT  

Estrogen Receptor {alpha} Polymorphism and Risk of Cardiovascular Disease, Cancer, and Hip Fracture: Cross-Sectional, Cohort, and Case-Control Studies and a Meta-Analysis
Kjaergaard et al.
Circulation 2007;115:861-871.
ABSTRACT | FULL TEXT  

Increasing Evidence That Estrogen Is an Important Modulator of Bone Marrow-Mediated Cardiac Repair After Acute Infarction
Dawn and Bolli
Circulation 2006;114:2203-2205.
FULL TEXT  

Circulating Estradiol Is an Independent Predictor of Progression of Carotid Artery Intima-Media Thickness in Middle-Aged Men
Tivesten et al.
J. Clin. Endocrinol. Metab. 2006;91:4433-4437.
ABSTRACT | FULL TEXT  

Estrogen and Different Aspects of Vascular Disease in Women and Men
Pepine et al.
Circ. Res. 2006;99:459-461.
FULL TEXT  

Advancing the Study of Stroke in Women: Summary and Recommendations for Future Research From an NINDS-Sponsored Multidisciplinary Working Group
Bushnell et al.
Stroke 2006;37:2387-2399.
ABSTRACT | FULL TEXT  

Endogenous sex hormones and cardiovascular disease incidence in men.
Arnlov et al.
ANN INTERN MED 2006;145:176-184.
ABSTRACT | FULL TEXT  

The association of oestrogen receptor {alpha}-haplotypes with cardiovascular risk factors in the British Women's Heart and Health Study
Lawlor et al.
Eur Heart J 2006;27:1597-1604.
ABSTRACT | FULL TEXT  

Oestrogen receptor genetics: a needle that cuts through many haystacks?
Shearman
Eur Heart J 2006;27:1519-1520.
FULL TEXT  

Estrogen receptor 1 haplotype does not regulate oral contraceptive-induced changes in haemostasis and inflammation risk factors for venous and arterial thrombosis
de Maat et al.
Hum Reprod 2006;21:1473-1476.
ABSTRACT | FULL TEXT  

Hormone Replacement Therapy and the Cardiovascular System: Lessons Learned and Unanswered Questions
Ouyang et al.
J Am Coll Cardiol 2006;47:1741-1753.
ABSTRACT | FULL TEXT  

Acute responses to phytoestrogens in small arteries from men with coronary heart disease
Cruz et al.
Am. J. Physiol. Heart Circ. Physiol. 2006;290:H1969-H1975.
ABSTRACT | FULL TEXT  

Contribution of Clinical Correlates and 13 C-Reactive Protein Gene Polymorphisms to Interindividual Variability in Serum C-Reactive Protein Level
Kathiresan et al.
Circulation 2006;113:1415-1423.
ABSTRACT | FULL TEXT  

Estrogen Receptor {alpha} Gene Variation Is Associated With Risk of Myocardial Infarction in More Than Seven Thousand Men From Five Cohorts
Shearman et al.
Circ. Res. 2006;98:590-592.
ABSTRACT | FULL TEXT  

Estrogen and mitochondria: a new paradigm for vascular protection?
Duckles et al.
Mol. Interv. 2006;6:26-35.
ABSTRACT | FULL TEXT  

Mechanisms of estrogenic vascular protection
Jayachandran and Miller
Am. J. Physiol. Heart Circ. Physiol. 2006;290:H507-H508.
FULL TEXT  

Metabolite ligands of estrogen receptor-{beta} reduce primate coronary hyperreactivity
Mishra et al.
Am. J. Physiol. Heart Circ. Physiol. 2006;290:H295-H303.
ABSTRACT | FULL TEXT  

Eu-estrogenemia
Kerber et al.
J. Appl. Physiol. 2005;99:2471-2472.
FULL TEXT  

Estrogen Receptor {alpha} Gene Polymorphisms Are Associated with the Angiographic Extent of Coronary Artery Disease
Rokach et al.
J. Clin. Endocrinol. Metab. 2005;90:6556-6560.
ABSTRACT | FULL TEXT  

Sex-Specific Association between Estrogen Receptor-{alpha} Gene Variation and Measures of Adiposity: The Framingham Heart Study
Fox et al.
J. Clin. Endocrinol. Metab. 2005;90:6257-6262.
ABSTRACT | FULL TEXT  

Oestrogen receptor {alpha} gene polymorphisms in systemic lupus erythematosus
Johansson et al.
Ann Rheum Dis 2005;64:1611-1617.
ABSTRACT | FULL TEXT  

Eliminating the Improbable: Sherlock Holmes and Standards of Evidence in the Genomic Age
Herrington
Circulation 2005;112:2081-2084.
FULL TEXT  

No Replication of Association Between Estrogen Receptor {alpha} Gene Polymorphisms and Susceptibility to Myocardial Infarction in a Large Sample of Patients of European Descent
Koch et al.
Circulation 2005;112:2138-2142.
ABSTRACT | FULL TEXT  

Estrogen Receptor {alpha} Gene Variation and the Risk of Stroke
Shearman et al.
Stroke 2005;36:2281-2282.
ABSTRACT | FULL TEXT  

Common Genetic Variation at the Endothelial Nitric Oxide Synthase Locus and Relations to Brachial Artery Vasodilator Function in the Community
Kathiresan et al.
Circulation 2005;112:1419-1427.
ABSTRACT | FULL TEXT  

Tobacco smoking, estrogen receptor {alpha} gene variation and small low density lipoprotein level
Shearman et al.
Hum Mol Genet 2005;14:2405-2413.
ABSTRACT | FULL TEXT  

Estrogen receptor alpha gene polymorphisms are associated with estradiol levels in postmenopausal women
Schuit et al.
Eur J Endocrinol 2005;153:327-334.
ABSTRACT | FULL TEXT  

Association of Cryptorchidism with a Specific Haplotype of the Estrogen Receptor {alpha} Gene: Implication for the Susceptibility to Estrogenic Environmental Endocrine Disruptors
Yoshida et al.
J. Clin. Endocrinol. Metab. 2005;90:4716-4721.
ABSTRACT | FULL TEXT  

Molecular and Cellular Basis of Cardiovascular Gender Differences
Mendelsohn and Karas
Science 2005;308:1583-1587.
ABSTRACT | FULL TEXT  

Is Atherosclerotic Cardiovascular Disease an Endocrinological Disorder? The Estrogen-Androgen Paradox
Phillips
J. Clin. Endocrinol. Metab. 2005;90:2708-2711.
ABSTRACT | FULL TEXT  

Vascular consequences of menopause and hormone therapy: Importance of timing of treatment and type of estrogen
Dubey et al.
Cardiovasc Res 2005;66:295-306.
ABSTRACT | FULL TEXT  

PGC-1{alpha} Gly482Ser Polymorphism Associates With Hypertension Among Danish Whites
Andersen et al.
Hypertension 2005;45:565-570.
ABSTRACT | FULL TEXT  

Correlating Androgen and Estrogen Steroid Receptor Expression with Coronary Calcification and Atherosclerosis in Men without Known Coronary Artery Disease
Liu et al.
J. Clin. Endocrinol. Metab. 2005;90:1041-1046.
ABSTRACT | FULL TEXT  

Polymorphisms in ER-{alpha} Gene Interact with Estrogen Receptor Status in Breast Cancer Survival
Boyapati et al.
Clin. Cancer Res. 2005;11:1093-1098.
ABSTRACT | FULL TEXT  

Hormone Replacement Therapy and Cardiovascular Disease: What Went Wrong and Where Do We Go From Here?
Dubey et al.
Hypertension 2004;44:789-795.
ABSTRACT | FULL TEXT  

Estrogen Receptor {alpha} Gene Polymorphisms and Risk of Myocardial Infarction
Schuit et al.
JAMA 2004;291:2969-2977.
ABSTRACT | FULL TEXT  

Sex Differences and Genetic Associations With Myocardial Infarction
Newton-Cheh and O'Donnell
JAMA 2004;291:3008-3010.
FULL TEXT  

Of Mice, Men, and Hormones
Miller et al.
Arterioscler. Thromb. Vasc. Bio. 2004;24:995-997.
FULL TEXT  

Susceptibility to Early Atherosclerosis in Male Mice Is Mediated by Estrogen Receptor {alpha}
Villablanca et al.
Arterioscler. Thromb. Vasc. Bio. 2004;24:1055-1061.
ABSTRACT | FULL TEXT  

Hormone Therapy: Physiological Complexity Belies Therapeutic Simplicity
Turgeon et al.
Science 2004;304:1269-1273.
ABSTRACT | FULL TEXT  

Estrogen-Receptor Gene Variant Linked with Increased CVD Risk
Journal Watch Cardiology 2004;2004:2-2.
FULL TEXT  

Hormonal Regulation of Normal Vascular Tone in Males
Mendelsohn and Rosano
Circ. Res. 2003;93:1142-1145.
FULL TEXT  

Other Noteworthy Papers This Week
Sci Aging Knowl Environ 2003;2003:nw151-151.
FULL TEXT  

Estrogen Receptor 1 Variants and Coronary Artery Disease: Shedding Light Into a Murky Pool
Hopkins and Brinton
JAMA 2003;290:2317-2319.
FULL TEXT