November 5, 2003

Estrogen Receptor 1 Variants and Coronary Artery DiseaseShedding Light Into a Murky Pool

Author Affiliations

Author Affiliations: Department of Cardiovascular Genetics, University of Utah, Salt Lake City).

JAMA. 2003;290(17):2317-2319. doi:10.1001/jama.290.17.2317

The article by Shearman et al1 in this issue of THE JOURNAL brings intriguing genetic data to bear on several issues of considerable current controversy—the relationship between coronary artery disease (CAD) and estrogen action, the general utility of CAD associations with variants in candidate genes, and the challenges of identifying causative gene variants for common disease. In this interesting hybrid of a case-control and prospective design, the investigators extracted DNA from blood samples of a subset of unrelated members of the Framingham offspring cohort who were alive at examination 6 (approximately 27 years after the baseline examination). The subset was selected to achieve an approximately equal number of representative men and women from the cohort. The effects of several estrogen receptor α (ESR1) gene variants were tested using primarily a case-control analysis in which offspring who had developed atherosclerotic disease by the sixth examination were considered cases and the remainder controls. A 3.0-fold increase in risk of myocardial infarction (MI) (P<.001) was associated with the CC genotype of the ESR1 c.454-397T>C variant (compared with the TT and CT genotypes combined) after correction for multiple risk factors. Lower odds ratios were associated with broader end points. Virtually identical results were obtained when data were analyzed as a prospective survival study.

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