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By Tony Strattner

November 15, 2003 | Scientists at deCODE Genetics, the Icelandic biotech company pursuing genes underlying complex diseases, have isolated the gene most strongly associated with two common forms of ischemic stroke: cardiogenic and carotid. In ischemic strokes, the flow of blood to the brain is choked, killing cerebral tissue and causing paralysis, loss of speech or vision, and other crippling effects.

Whereas deCODE scientists had previously mapped a stroke susceptibility gene (STRK1) to chromosome 5, this latest study, published in the October issue of Nature Genetics, finely maps the locus and documents specific mutations that are associated with stroke.

Scientists genotyped more than 1,700 people in Iceland, about half of whom had suffered strokes. Iceland’s paucity of immigration over the past 10 centuries and exhaustive genealogical records render the easily traceable gene pool ideal for DNA testing.

Solveig Gretarsdottir and colleagues found that the gene encoding the enzyme phosphodiesterase 4D (PDE4D) produces eight different protein isoforms, three of which are expressed at significantly lower levels in people who had strokes. Three single nucleotide polymorphisms (SNPs), which do not alter the PDE4D coding sequence, are correlated with the risk of stroke.

Expression and functional analyses of PDE4D strongly suggest that the enzyme plays a key role in atherosclerosis, in which arteries become clogged by a buildup of fatty substances. The study proposes that PDE4D influences the proliferation and migration of smooth muscle cells within arteries, “which is an early event in the formation of arterial plaque,” explains Kari Stefansson, deCODE CEO. “Too much [activity] of this enzyme contributes to atherosclerosis.” People with the PDE4D gene variants have a three times greater risk of stroke, he adds.

The Nature Genetics study is the first to definitively describe a genetic risk factor for common forms of stroke. Researchers believe that blocking PDE4D in people may protect them against stroke. Drugs using phosphodiesterase inhibitors are already available to treat asthma and other types of inflammation, but more study will be needed before a variant is developed for stroke-susceptible patients.

Test for Stroke Risk Coming
Hoffmann-La Roche isn’t waiting to see if investigators studying other populations can replicate deCODE’s results. The Swiss pharmaceutical giant, which extended its $200-million research collaboration deal with deCODE in 2002, has already begun testing phosphodiesterase inhibitors on lab rats.

Under terms of the research partnership, Roche has rights to develop drugs based on disease genes discovered by deCODE, while deCODE retains the rights to gene and antisense therapies. DeCODE is also developing a diagnostic test based on the at-risk and protective haplotypes (specific sets of genetic markers) within the PDE4D gene.

The DNA test, which will indicate whether an individual is susceptible to stroke, should be available “long before there is a drug on the market,” Stefansson notes, though he declined to say exactly when.

The payoff on a diagnostic test and drug for treatment will likely be huge. An estimated 700,000 Americans will suffer a stroke this year, and about 160,000 will die. Stroke is the third leading cause of death in industrialized countries behind heart disease and cancer -- and the leading cause of long-term disability, costing the United States between $30­ billion and $40 billion annually.

A Pill for ‘Thinness’?
In other tantalizing research, announced only via press release, deCODE says it has isolated a gene that, in one form, predisposes women to obesity, while another form predisposes women to be slender. This discovery is the newest deliverable under an alliance with Merck that combines the two companies’ research efforts in obesity. DeCODE gets a “milestone payment” from Merck for identifying the obesity gene, but, more importantly, scientists now know that a variant of that gene inclines women to thinness.

“The goal will be a drug that controls body mass,” Stefansson says, “or at least is a complement to exercise and diet.”


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