BioWorld International Correspondent

LONDON - 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 Inc. in Reykjavik, Iceland, who made the discovery are collaborating with F. Hoffmann-La Roche Ltd. in Basel, Switzerland, on finding a drug that could be used to reduce the risk of stroke in those carrying the variant.

Solveig Gretarsdottir, leader of the stroke project at deCode, told BioWorld International that she envisaged in the future being able to screen people for the high-risk variant and offering them advice to reduce their risk. "The gene we have found could explain a considerable fraction of the observed cases of stroke, so obviously if we are able to develop a drug, this could have great use for many people," she said.

Gudmar Thorleifsson, head of the cardiovascular statistics group at deCode, described the study as "a beautiful example of the use of population genetics to identify a gene involved in a complex disease."

An account of the study appears in Nature Genetics, published online Sept. 21, 2003, in a paper titled "The gene encoding phosphodiesterase 4D confers risk of ischemic stroke."

Stroke is a common and serious disease. In the developed world, it is the leading cause of severe disability and the third leading cause of death.

There are many different kinds of stroke, but atherosclerosis plays a role in most of them, either by narrowing blood vessels, or by giving rise to blood clots, which then migrate to the brain. In carotid stroke, the cause is atherosclerosis of the carotid arteries. Cardiogenic stroke occurs when a blood clot blocks an artery in the brain, usually in the presence of abnormal heart rhythm or ischemic heart disease.

Five years ago, deCode put in place a strategy of carrying out genome-wide studies on patients who had suffered strokes, and comparing the data generated with those from a similar number of controls. More than a year ago, company scientists identified a region on chromosome 5 they thought could harbor an interesting gene.

The Nature Genetics paper describes what they found when they decided to investigate this region further by studying 864 Icelandic affected individuals and 908 controls. Their initial work led them to concentrate on the gene encoding the enzyme phosphodiesterase 4D (PDE4D).

They were unable to find any functional mutations in the coding regions of PDE4D. When they found, however, that affected individuals had significantly lower levels of messenger RNA from PDE4D than controls they decided to carry on investigating the role of that gene in stroke.

By comparing which chromosomal markers were present, the researchers were able to identify people who had inherited slightly different versions, or haplotypes, of the PDE4D gene. Haplotypes covering the first exon of PDE4D fell into three groups, each with distinct levels of risk.

About 16 percent of the general population carries one copy of the high-risk variant, and that group's risk of suffering either cardiogenic or carotid stroke is about 1.8 times higher than the general population. Just less than 1 percent of the general population has two copies of the high-risk variant, and the researchers calculate their risk as being about 3.8 times that of the general population.

Gretarsdottir said: "Based on our results, we propose that the functional variation may be involved in transcriptional regulation. Our next step will be to find out what causes the effect we see in the patients."

She and her colleagues suggest that phosphodiesterase 4D may have a role in the vascular biology of atherosclerosis. In Nature Genetics, they write: "Phosphodiesterase 4D selectively degrades second messenger cAMP, which has a central role in signal transduction and regulation of physiological responses. It is expressed in most cell types important to the pathogenesis of atherosclerosis, including vascular smooth muscle cells, endothelial cells, T lymphocytes, macrophages and monocytes. Cyclic AMP is a key signaling molecule in these cells."

They conclude that inhibition of PDE4D by a small-molecule drug might decrease the risk of stroke in those predisposed to it by their PDE4D genotype.

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