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
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
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.