So far, Framingham researchers speak guardedly about the results of their first scan, saying only that it confirmed the effects of some genes that were already suspected of contributing to various conditions and provided “interesting leads” to generate hypotheses about where to search for others. “Did we find something terribly exciting? No,” says Larry Atwood, professor of neurology at Boston University and a geneticist for FHS. “But this is basic science and we have to creep along incrementally.”
Nor is it possible to draw conclusions from one scan. “It’s the nature of statistics that some results that seem biologically significant will turn out to be random fluctuations,” Atwood says. And the greater the number of SNPs tested, the more likely that is to occur. But that’s another area in which Framingham’s family-based study provides an advantage. When researchers know that several generations show the same genetic variation, they can be much more confident in their findings.
Still, Atwood cautions that it may take years before scientists fully understand the genetic architecture of some diseases. Whereas genome scans for diabetes, for example, have seemed relatively definitive, revealing as many as eight genes that appear to have a significant effect on blood glucose, hypertension remains a genetic mystery. “Many systems in the body appear to have an effect on blood pressure, which means there may be very many genes involved,” Atwood says.
There’s also the matter of determining the relative effect of implicated genes. “If the eight we’ve identified for diabetes have a large effect on the disease, then we’re nearly done with the search,” Atwood says. “But if there are 40 more, each affecting variation in blood glucose in a small way, we’re still looking at an extremely difficult problem.”
In the decades since Framingham first introduced disease risk factors to medical parlance and practice, death rates for coronary heart disease and stroke have dropped 60% and 66%, respectively. Studies suggest that about half that reduction has been the result of preventive medicine and a population that has consciously altered its behavior; better medical procedures and treatments are credited with the rest of the improvement. Now there’s the matter of how discoveries about genetics may intersect with the risk factors on which Framingham has built its legacy. “It’s a good question and one that Framingham would be perfect to research,” O’Donnell says. “I suspect we’ll find that a genetic predisposition to certain diseases, like other risk factors, can still be countered by lifestyle changes; but it may mean those changes have to be particularly aggressive.”
It’s possible that the study will recruit a fourth generation of Framingham participants, perhaps even before they reach adulthood, to find the seeds of disease long before they take root. “It’s not reasonable to assume that the Framingham Heart Study will go on forever,” Levy says. “But as long as it continues to ask the right questions, identifies methods to answer them and generates information to improve public health, it will last.” Adds Wolf: “There’s a lot of gold in Framingham left to mine.” 
Dossier
1. A Change of Heart: Unraveling the Mysteries of Cardiovascular Disease, by Daniel Levy and Susan Brink (Vintage Books, 2005). A behind-the-scenes history of the people, science, politics and culture that created one of the longest-running epidemiology studies.
2. “You Changed America’s Heart: A 50th Anniversary Tribute to the Participants in the Framingham Heart Study” [nhlbi.nih.gov/about/framingham/fhsbro.pdf]. A report that both enumerates the medical accomplishments of the study and offers the human side with anecdotes from participants.
