Estrogen Receptor Alpha Gene Variants Up Risk Of MI In Women

NEW YORK (Reuters Health) - Women who carry a frequently occurring variation in the estrogen receptor alpha (ESR1) gene face an increased risk of myocardial infarction after menopause, independent of known cardiovascular risk factors, researchers report in the June 23/30 issue of the Journal of the American Medical Association.

Dr. Stephanie C. E. Schuit and colleagues from Erasmus Medical Center in Rotterdam, the Netherlands evaluated 2617 men and 3791 postmenopausal women in the Rotterdam Study to see if the ESR1 haplotype created by the c.454-397T>C and c.454-351A>G polymorphisms is associated with incident MI and ischemic heart disease (IHD).

Roughly 29% of women and 28.2% of men were homozygous for the ESR1 haplotype 1, while 49% of women and 50% of men were heterozygous carriers, and 22% and 21.4% of men and women, respectively, were noncarriers.

During a mean 7-year follow up period, 115 women and 170 men experienced MI and 168 women and 272 men had an IHD event, 97 of which were fatal.

In analyses adjusting for established cardiovascular risk factors, female heterozygous carriers of the ESR1 haplotype 1 had a 2.23 increased relative risk of MI compared with noncarriers. In female homozygous carriers, the relative risk of MI was 2.48.

For IHD events, including MI, revascularization procedures, and IHD mortality, the team observed similar associations in women.

In men, there was no apparent association between the ESR1 haplotypes and MI or IHD risk. Actually, the trend was for a protective effect.

The authors of an editorial note that this finding is at odds with another "well-designed and well-implemented" study that showed a three-fold increased risk of MI in male carriers of two copies of the ESR1 C allele. (see Reuters Health report November 4, 2003).

"While there are some differences between the studies, a review of the available criteria points to no firm conclusion regarding which of the associations should be regarded as most valid," Dr. Christopher J. O'Donnell of the NHLBI Framingham Heart Study and another Massachusetts-based colleague write. The two studies "provide a strong rationale for further research," they conclude.

It should be noted, Dr. Schuit and colleagues emphasize, that 78% of the population carries the ESR1 haplotype 1 allele. "Perhaps we should view this not as a 'risk' allele but consider the noncarriers as having a protective allele."

Once the gene variant is detected, there is no direct treatment to alleviate the increased risk, Dr. Schuit noted. However, it has been suggested that postmenopausal women who carry the ESR1 gene variant may respond differently to estrogen replacement therapy than women who do not carry the gene variant. (see Reuters Health report March 27, 2002)

As for the underlying mechanism, Dr. Schuit noted that "the sensitivity to available estrogen is influenced by the estrogen receptor alpha gene variant."

"Due to decreased sensitivity to estrogen, the heart's coping mechanism in response to coronary artery occlusion is less effective and a heart attack is more likely to take place," she explained. Postmenopausal women are most at risk due to low circulating estrogen levels and "therefore differences in sensitivity for estrogen become clinically relevant. However, sufficient studies have not been performed to prove this theory," she added.

Source: JAMA 2004;291:2969-2977,3008-3010. [ Google search on this article ]

MeSH Headings: Receptors, Estrogen : Receptors, Steroid : Transcription Factors : Receptors, Cytoplasmic and Nuclear

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