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EPIDEMIOLOGY Slow Metabolism of Alcohol Linked to Lower Heart Risk An apple a day keeps the doctor away" is an adage that provokes few quibbles. True or not, the recommendation can do little harm. But the finding, first made in the 1980s, that people who drink one or two glasses of wine or beer a day have a lower risk of heart disease has inspired nervous scientific debate. David Hunter, Meir Stampfer, Lisa Hines (l to r) and their colleagues discovered that moderate drinkers who, owing to their genetic makeup, metabolize alcohol slowly experience a greatly reduced risk of heart disease. Photo by Jeff Cleary "There's a substantial anxiety about ever saying anything good about alcohol because you don't want to be seen to be giving people permission to drink too heavily, with all the harmful consequences there," said David Hunter, HSPH professor of epidemiology. "So some have looked for alternative explanations." A few re-searchers have tried to explain the controversial finding by arguing that moderate drinkers are more likely to exercise or belong to a particular socioeconomic class and that these factors reduce coronary risk. Others have claimed that the benefit is due to an ingredient in wine and beer other than alcohol. Yet it is the alcohol and the body's response to it that is responsible for the beneficial effect, according to a new study by Lisa Hines, Hunter, and colleagues at HSPH and in the Department of Preventive Medicine at Brigham and Women's Hospital. A person's risk of developing heart disease is affected not only by how much alcohol is consumed but also by the rate at which alcohol is metabolized, the researchers report in the Feb. 22 New England Journal of Medicine. Slow Wins the Race The researchers evaluated about 1,100 men enrolled in the Physicians' Health Study, which is conducted through the Department of Preventive Medicine at BWH. They found that as a group, doctors who had one or two drinks daily had fewer heart attacks. But those who by virtue of their genetic constitution metabolized alcohol slowly had a significantly lower rate of heart disease than those who metabolized alcohol quickly. The moderate-drinking slow-metabolizers, who carry a particular version of the alcohol dehydrogenase 3 gene, had an even lower risk of developing coronary disease—more than 50 percent lower—than nondrinking fast-metabolizers, who have a different version of the gene. Hines, a graduate student in epidemiology at HSPH, and her colleagues found that the slow-metabolizing moderate drinkers also had the highest levels of high density lipoproteins (HDL), a form of cholesterol that protects against heart disease. The findings make a strong case that the alcohol in wine, beer, and liquor is responsible for the benefits conferred by moderate drinking. "I think this study provides more insight into the mechanism of the observed protective effect," said Hines. Balancing Risks "This study wasn't meant to say, 'Change your drinking pattern or don't change your drinking,'" she said. "At the same time, alcohol consumption is a risk factor for several other diseases, such as breast cancer, so you have to keep that broader perspective." In fact, Hines was initially interested in exploring how alcohol puts women at risk for developing breast cancer. One line of thought was that differences in alcohol metabolism affect hormone levels that, in turn, cause disease. She and her colleagues measured estrogen, testosterone, and other hormones in the blood of fast- and slow-metabolizing women enrolled in the Nurses' Health Study. They also measured HDL levels. While hormone levels appeared only modestly affected by the rate of alcohol metabolism, women who were homozygous for the slow version of the alcohol dehydrogenase 3 gene displayed significantly higher HDL levels. To investigate the link between the alcohol dehydrogenase 3 variants and heart disease, the researchers turned to the Physicians' Health Study, which by 1994 had registered 396 cases of myocardial infarction. They randomly matched two doctors without heart disease with each of the heart-attack patients—for a total of 770 controls—and then did blood tests to ascertain the ADH3 genotype and examined HDL levels for all the subjects. "We observed the same pattern we had seen with the women, where homozygotes for the slow oxidizing alcohol dehydrogenase 3 gene had the highest HDL level," she said. They also had the lowest risk of heart disease. Heterozygotes who consumed a drink or two a day had HDL levels in between the fast- and slow-metabolizing homozygotes, but they did not appear to have fewer heart attacks than the fast-metabolizing homozygotes who drank moderately. Will the day come when people have their genes screened to see if they are slow- or fast-metabolizers and drink accordingly? "That's what you read in Time or Newsweek every few months," Hunter said. "But the fact is even if we think we understand the mechanism, it's going to require an enormous amount of extra study to confirm any one relationship. Maybe in 10 or 20 years there will be enough data to address the risk–benefit." —Misia Landau