By DAVID LEFF and SHARON KINGMAN
BBI Science Writers

Researchers in Iceland have discovered a variant of a gene that can almost quadruple someone's risk of suffering a stroke. The gene, which encodes a protein thought to play a role in the development of atherosclerosis, is the first to be identified that is associated with increased risk of the common forms of stroke.

Scientists at deCode Genetics (Reykjavik, Iceland), who made the discovery, are collaborating with F. Hoffmann-La Roche (Basel, Switzerland), on finding a drug that could be used to reduce the risk of stroke in those carrying the variant.

Their findings appear in the issue of Nature Genetics released online Sept. 22 and scheduled for publication in October. The article is titled, "The gene encoding phosphodiesterase 4D [PDE4D] confers risk of ischemic stroke." Its co-senior author is medical geneticist and neurologist Kari Stefansson, chairman, chief executive officer and president of deCode Genetics.

Stefansson said the basic findings reported in the paper are the discovery of a gene that he said "contains variants predisposed to the common form of stroke [and] that we have protein made by this gene, which in this instance is a good drug target."

In collaboration with Roche, the deCode researchers started a drug discovery program on the basis of these molecules. "We have gone to high-throughput screening and are very optimistic that it's going to lead us in the end, years down the road, to a drug that will prevent the genetic predisposition from being turned into stroke," Stefansson said.

"The other category of implications allows us to identify the individuals who have a particular predisposition to the development of stroke," he said, terming that important "because it can help to focus and contain stroke risks [such as] hypertension." And, he added, "they would also be the target population for the drugs designed against this particular protein."

So, said Stefansson, "these are the two industrial implications: the possibilities of facilitating drug development and of developing diagnoses. It is the first gene isolated in a disease of this complexity."

The article's lead author, geneticist Solveig Gretarsdottir, and fellow researchers at deCode last year mapped that PDE4D stroke-susceptibility gene to the long arm of human chromosome 5. In the present study, working with doctors and researchers at Iceland's National University and its Heart Association, they report a large-scale screening to identify the gene in question, involving sampling 1,800 Icelandic adults who had suffered a stroke both patients and unaffected relatives from across Iceland, which has a total population of just under 278,000.

"Within this PDE4D gene," Stefansson observed, "our team identified haplotypes (specific sets of genetic markers) that correspond to both increased risk of stroke and significantly decreased risk. Expression and functional analyses of the gene strongly suggest that PDE4D plays an important role in atherosclerosis. This most likely is by influencing the proliferation and migration of smooth muscle cells within arteries, which is central to the biology of ischemic stroke."

Stefansson said, "A drug that could inhibit PDE4D or one of its specific isoforms might therefore be useful in counteracting atherosclerosis, and thereby reduce the risk of stroke." He said deCode and Roche "have initiated medicinal chemistry work on compounds we have identified as active against targets in the PDE4D pathway."

Separately, deCode also is developing a DNA-based diagnostic test based upon the at-risk and protective haplotypes within the PDE4D gene.

Although there are no variants in the gene itself connected to stroke, the authors did show that three different isoform variants of the gene were expressed at lower levels in patients affected by the disease.

"Stroke is among the diseases that has highest incidence in old age," Stefansson noted, "and therefore it's becoming more and more common a disease in our society, probably the most common cause of disability."

Environmental factors contribute to stroke, Stefansson noted. "It happens at the intersection between genes and environment. Any increase in blood pressure increases probability of stroke. Certain drugs of abuse increase that probability," he said. "One of the commonest risk factors occurs in young people, who rarely develop stroke. The few instances when they do often follow heavy consumption of alcohol."

If you look at the role of genetics, he said, "the beauty of isolating the genes is that when you have the equation between two unknowns, one is the genetic component, the other environmental. When you have found No. 1, it is simpler to find No. 2."

Stefansson said deCode is now in a drug discovery phase, using the protein made by the gene as a target. "We are also into the development of diagnostic tests, based on genes. That is where we are putting most of our efforts these days," he said.

"We and Roche are jointly applying for patents to protect our investment for stroke medications," Stefansson said. "The big message now for biotechies is that we have technology that allows us to pull out genes in the common diseases." But also, he noted, "because it gives us a new insight into the possible ways of treating and diagnosing diseases, and even preventing them."

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