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Estrogen and heart disease in men
Association between polymorphism and severity of disease
Edward R. Winstead

Researchers are reporting an association between the estrogen receptor gene and heart disease in a population of Finnish men. Men in the study with the long variant of the alpha estrogen receptor gene had a significantly greater number of severely narrowed coronary arteries, larger areas of complicated lesions, and more calcification of the coronary arteries than did men with other forms of the gene. The study appeared in a recent issue of the British Medical Journal.

In humans, the activity of the alpha estrogen receptor gene is regulated by a DNA sequence containing a dinucleotide polymorphism: two letters that are repeated at varying lengths in different individuals. Previous studies have linked the length of this polymorphism with bone mineral density, suggesting that the activity of this gene may influence bone health. These findings led researchers at the University of Tampere in Finland to investigate a link between the polymorphism and coronary artery disease in men.

"We are speculating that males who have the long variant may have a less-active alpha estrogen receptor gene and benefit less from the cardiovascular protective effect of the estrogen receptors," says Pekka J. Karhunen, who led the research. "As far as we know this is one of the first studies to look at the protective effects of estrogen in this context."

Should men at risk for heart disease take estrogen?

Females have a distribution of polymorphisms in the alpha estrogen receptor gene similar to males, according to Karhunen. "We suppose that some females benefit more from estrogen's protective effects because they have more estrogen receptor molecules," he says, noting that his group does not have biochemical evidence of this phenomenon.

Should men at risk for heart disease take estrogen? The researchers have been asked that question many times since presenting their results at a conference earlier this year. The answer is no, says Karhunen, because of estrogen's feminizing side effects, such as breast development. Nonetheless, he says, studying the protective effects of estrogen in men may help researchers understand the mechanisms involved.

Unable to carry out the study in living humans, the researchers obtained subjects from the Helsinki Sudden Death Study, a series of autopsies of white Finnish men who died suddenly of coronary heart disease, violent death or accident, and other diseases. Karhunen and his colleagues evaluated the coronary health of 119 subjects using a variety of means, including computer tools and plastic casts that assess coronary narrowing.

DNA from the 119 subjects was then analyzed. Individuals were assigned to one of three groups based on the number of repeats in their polymorphism: those with short versions (two copies of the gene with <19 repeats), those with long versions (two copies of the gene with > or =19 repeats), and those with mixed versions (one short and one long). The researchers found that changes in the narrowing of the arteries of individuals in the mixed group were not significantly different from those in the short or long groups. Other measures were used to compare the three groups, but none produced statistically significant results after factors such as age, body mass, smoking, alcohol consumption, and hypertension were taken into account.

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Kunnas, T.A. et al. Association of polymorphism of human a oestrogen receptor gene with coronary artery disease in men: A necropsy study. Br Med J 321, 273-274 (July 29, 2000).

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