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Estrogen Receptor Gene Polymorphisms and Risk of Myocardial Infarction

Stephanie C. E. Schuit, MD; Hok-Hay S. Oei, MD; Jacqueline C. M. Witteman, PhD; Corine H. Geurts van Kessel, MSc; Joyce B. J. van Meurs, PhD; Rogier L. Nijhuis, MD; Johannes P. T. M. van Leeuwen, PhD; Frank H. de Jong, PhD; M. Carola Zillikens, MD; Albert Hofman, MD, PhD; Huibert A. P. Pols, MD, PhD; André G. Uitterlinden, PhD

JAMA. 2004;291:2969-2977.

Context  The role of estrogens in ischemic heart disease (IHD) is uncertain. Evidence suggests that genetic variations in the estrogen receptor (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.

Author Affiliations: Departments of Internal Medicine (Drs Schuit, van Meurs, van Leeuwen, de Jong, Zillikens, Pols, and Uitterlinden and Ms Geurts van Kessel) and Epidemiology & Biostatistics (Drs Schuit, Oei, Witteman, Nijhuis, Hofman, and Pols), Erasmus Medical Center, Rotterdam, the Netherlands.

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