Individuals with a common genetic variation in one of two known estrogen receptors have a threefold increase in the risk of having a heart attack, MIT researchers report in the Nov. 5 issue of the Journal of the American Medical Association (JAMA).
Estrogens activate the estrogen receptors, which in turn regulate genes for several cardiovascular disease (CVD) risk factors. The estrogen receptors affect gene expression by both estrogen-dependent and estrogen-independent mechanisms. Relatively little is known, however, about the impact of inherited variation in the estrogen receptor genes on CVD risk.
Amanda M. Shearman, research scientist in the MIT Center for Cancer Research, and colleagues conducted a study to determine if a certain variant in the estrogen receptor alpha gene (ESR1) is associated with CVD risk. The study included 1,739 unrelated men and women from the population-based offspring group of the Framingham Heart Study, who were followed up from 1971-98.
"I think that how genetics plays a role in estrogen action is an important area with considerable potential for shedding light on our understanding of cardiovascular disease and several other common diseases," Shearman said. "One of the strengths of our results is that they provide confirmation of earlier observations. However, it is still important that we determine whether the substantial genetic risk factor that we have identified for myocardial infarction [MI, or heart attack] can be generalized to other, genetically distinct populations. We also need to see if the same result holds true in women, because although we included women in our study, there were insufficient cardiovascular events among these individuals for us to say whether our findings apply to women as well as to men."
The article's co-authors include MIT biology professor David E. Housman.
The researchers found that in the study population, 20 percent of participants had a certain estrogen receptor variant on both copies of a chromosome. After adjustment for age, sex, body mass index, hypertension, diabetes mellitus, total cholesterol, high-density lipoprotein cholesterol and cigarette smoking, this genotype was significantly associated with three times the risk for heart attack compared with individuals with other genotypes.
The results remained significant when analyses were restricted to men; too few women had events to study them separately.
"These findings underscore a potentially important role of ESR1 in influencing the development of atherosclerosis and/or in accelerating the transition from subclinical atherosclerosis to plaque rupture and acute thrombotic CVD events such as MI and stroke. The frequency of the [ESR1] genotype was 20 percent in the entire study sample ... but ... it was 31 percent in individuals with major atherosclerotic CVD, and 37 percent in individuals with recognized myocardial infarction (heart attack). For the latter 2 end points, there was statistically significant evidence of association," the authors write.
"These findings support the importance of estrogen receptors in CVD susceptibility, especially in men. Estrogen receptor variation also has potential to explain recent conflicting data regarding the effects of hormone therapy on CVD susceptibility in women," the authors conclude.
In an accompanying JAMA editorial, University of Utah researchers write that the study brings "intriguing genetic data" to bear on the relationship between coronary artery disease (CAD) and estrogen action. "That the study ... confirms prior observations is of paramount importance in light of current thinking about genetic association studies, which are often considered untrustworthy because of the frequent inability to confirm initially reported positive associations," they write.
This work was supported by the National Heart, Lung, and Blood Institute (NHLBI) Specialized Center of Research in Ischemic Heart Disease. This work also is supported by the NHLBI's Framingham Heart Study.
A version of this article appeared in MIT Tech Talk on November 5, 2003.
