Context The role of estrogens in ischemic heart disease (IHD) is uncertain.
Evidence suggests that genetic variations in the estrogen receptor α (ESR1) gene may influence IHD risk, but the role of common
sequence variations in the ESR1 gene is unclear.
Objective To determine whether the ESR1 haplotype created
by the c.454-397T>C (PvuII)
and c.454-351A>G (XbaI)
polymorphisms is associated with myocardial infarction (MI) and IHD risk.
Design, Setting, and Participants In 2617 men and 3791 postmenopausal women from The Rotterdam Study (enrollment
between 1989-1993 and follow-up to January 2000), a population-based, prospective
cohort study of participants aged 55 years and older, ESR1
c.454-397T>C and c.454-351A>G haplotypes were
determined. Detailed interviews and physical examinations were performed,
blood samples were obtained, and cardiovascular risk factors were assessed.
Main Outcome Measure The primary outcome was MI and IHD defined as MIs, revascularization
procedures, and IHD mortality.
Results Approximately 29% of women and 28.2% of men were homozygous carriers
of the ESR1 haplotype 1 (−397 T and −351 A) allele, 49% of women and
50% of men were heterozygous carriers, and 22% of women and 21.4% of men were
noncarriers. During a mean follow-up of 7.0 years, 285 participants (115 women;
170 men) had MI, and 440 (168 women; 272 men) had an IHD event, of which 97
were fatal. After adjustment for known cardiovascular risk factors, female
heterozygous carriers of haplotype 1 had an increased risk of MI (event rate,
2.8%; relative risk [RR], 2.23; 95% confidence interval [CI], 1.13-4.43) compared
with noncarriers (event rate, 1.3%), whereas homozygous carriers had an increased
risk (event rate, 3.2%; RR, 2.48; 95% CI, 1.22-5.03). For IHD events, we observed
a similar association. In women, the effect of haplotype 1 on fatal IHD was
larger than on nonfatal IHD. In men, the ESR1 haplotypes
were not associated with an increased risk of MI (event rate, 5.7%; RR, 0.93;
95% CI, 0.59-1.46 for heterozygous carriers; and event rate, 5.1%; RR, 0.82;
95% CI, 0.49-1.38 for homozygous carriers) compared with noncarriers (event
rate, 5.8%) and were not associated with an increased risk of IHD.
Conclusions In this population-based, prospective cohort study, postmenopausal women
who carry ESR1 haplotype 1 (c.454-397
T allele and c.454-351 A allele) have an increased
risk of MI and IHD, independent of known cardiovascular risk factors. In men,
no association was observed.