Estrogen receptor alpha gene polymorphisms and risk of myocardial infarction.
BACKGROUND
The role of estrogens in ischemic heart disease (IHD) is uncertain. Evidence suggests that genetic variations in the estrogen receptor alpha (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.


METHODS
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.


METHODS
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.
Schuit
Stephanie C E
SC
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
Oei
Hok-Hay S
HH
Witteman
Jacqueline C M
JC
Geurts van Kessel
Corine H
CH
van Meurs
Joyce B J
JB
Nijhuis
Rogier L
RL
van Leeuwen
Johannes P T M
JP
de Jong
Frank H
FH
Zillikens
M Carola
MC
Hofman
Albert
A
Pols
Huibert A P
HA
Uitterlinden
André G
AG
D000368:Aged; D047628:Estrogen Receptor alpha; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000453:epidemiology / Q000235:genetics* / Q000401:mortality; D017202:Myocardial Ischemia / Q000453:epidemiology / Q000235:genetics / Q000401:mortality; D011110:Polymorphism, Genetic; D017698:Postmenopause; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011960:Receptors, Estrogen / Q000235:genetics*; D012307:Risk Factors
D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen