Science Editor

As genome-wide association studies turn up new gene culprits on more or less a daily basis, one particular stretch of DNA on chromosome 9 appears to be shaping up as the equivalent of a serial killer.

In the past few weeks, independent papers have implicated the region as a risk factor for both Type II diabetes and coronary artery disease in Caucasians. To top things off, while the SNP in question does not code for a protein, it is upstream of two genes that are well known to cancer researchers for their involvement in that disease.

National Human Genome Research Institute Director Francis Collins called the findings "a stunner. This is like the seat of the soul of the genome. . . . This one place carries all of that weight" as a risk factor, he told reporters at a press briefing.

Collins and his colleagues were one of three groups that published papers in the April 26, 2007 issue of Sciencexpress that showed that a SNP upstream of the CDKN2A and B, was one of 10 that showed an association with diabetes risk. Only a week later, those findings were followed by two more papers in the May 3, 2007 issue of Sciencexpress, this time focusing on heart disease. Those found a variant of the same SNP raises the heart disease risk by as much as 60 percent for Caucasians.

So far, the stunner has produced an obvious question - phrased by Collins as "How can one region of the genome, and it is not even containing a gene, contain risk factors for both diabetes and heart attack?" But answers will take a while to come by.

Collins told BioWorld Today that the idea that the upstream SNP signifies an involvement of CDKN2A and B is currently "a hypothesis, because there are no other well annotated genes in the neighborhood." But it is possible, albeit unlikely, that there is either an as yet-undiscovered gene, or that the SNP in question is located on a regulatory region for a different gene. Either way, because the gene itself does not appear to have variants that are associated with differential risk, Collins said that the change must be in the quantity, not the quality, of the protein in question.

While diabetes is a risk factor for heart disease in its own right, the authors of the papers linking CDKN2A and B to heart disease say that the link between the two is direct, not via an elevated diabetes risk. They excluded individuals with diabetes from their study and used models to control for the confounding effects of known risk factors for coronary heart disease.

Another possibility is that certain variants of the SNP may predispose their carriers to metabolic syndrome - a collection of lipid abnormalities, hypertension, diabetes and obesity. Though he did not discount the possibility altogether, Collins noted that metabolic syndrome itself is somewhat of a conjecture at this point. Genome-wide association studies searching for genetic bases of metabolic syndrome have, to date, come up empty handed.

That, Collins said, has led some researchers to conclude that "maybe metabolic syndrome isn't a syndrome at all; it's just a collection of relatively common disorders that are going to happen together in enough people" to look like a syndrome. Still, he said that the findings were sure to spur a revisiting of the genome-wide association studies on metabolics to see whether any signals from the SNP now implicated in diabetes and heart disease had been overlooked.

Even once the link between diabetes and heart disease is clear, the role of the CDKN2A and B genes in cancer adds yet another piece that needs to fit into the puzzle somehow. The genes code for cyclin-dependent kinases, which are important in controlling progression through the cell cycle. Mutations in the genes have been implicated in several different cancers.

The links between cancer and metabolism have been getting renewed attention recently, with one of the plenary talks at the recent AACR meetings devoted to the idea that "most oncogenes and tumor suppressors evolved to regulate cellular metabolism." Collins said the findings on CDKN2A and B "certainly would suggest that there's more of a link than we realize," between cancer and metabolic disorders, though the nature of the relationship remains to be understood.

Still unclear is the function of many of the newly discovered diabetes genes. Collins said that "a lot of these, we really don't know what they do." But even without an understanding of the mechanistic link, the findings point to an obvious target for drug development efforts. "I would be quite surprised if there were not several pharmaceutical companies that are starting drug discovery efforts right now," Collins said. Regardless of mechanism, genome-wide association studies tell you "this is a molecule that's involved in pathogenesis, and that could be very exciting in terms of a totally new way" to target the disease.

He also noted that such efforts, if successful, would not be limited in scope to those carrying a high-risk allele. "Some people have in their head that if you found a variation in a gene that's associated with diabetes, and you're going to use that to develop a drug, the drug would only work for the people who have the variations. That's not right," he emphasized. "Even the people with a low-risk spelling may very well respond to a drug that's targeted to that particular pathway."