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Original Contribution
November 5, 2003

Association Between Estrogen Receptor α Gene Variation and Cardiovascular Disease

Author Affiliations

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).

JAMA. 2003;290(17):2263-2270. doi:10.1001/jama.290.17.2263

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 α (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.