Association between estrogen receptor alpha gene variation and cardiovascular disease.
BACKGROUND
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 alpha (ESR1) on CVD risk.


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


METHODS
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.


METHODS
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.
Shearman
Amanda M
AM
Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Mass 02139, USA. shearman@mit.edu
Cupples
L Adrienne
LA
Demissie
Serkalem
S
Peter
Inga
I
Schmid
Christopher H
CH
Karas
Richard H
RH
Mendelsohn
Michael E
ME
Housman
David E
DE
Levy
Daniel
D
D002318:Cardiovascular Diseases / Q000453:epidemiology* / Q000235:genetics*; D047628:Estrogen Receptor alpha; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000453:epidemiology / Q000235:genetics; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D011960:Receptors, Estrogen / Q000235:genetics*; D012307:Risk Factors
D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen