First gene linked to stroke

Researchers from Icelandic genomics company deCODE Genetics have discovered the first gene ever linked to ischaemic stroke, raising the hope that new drugs to treat the condition may be developed.

The study, due for publication in the October issue of Nature Genetics​, has found that variations in the gene coding for the phosphodiesterase 4D enzyme are associated with ischaemic stroke, the most common form of the disease. Within this gene, the deCODE​ team has identified haplotypes - or specific sets of genetic markers - that correspond both to an increase and a decrease in the risk of stroke.

Some variations on the gene increase an individual's risk of having a stroke by three to five times, according to the company.

Stroke remains one of the most significant unmet needs in medicine. The only approved therapy is the use of thrombolytic drugs such as tissue plasminogen activator to dissolve the blood clots that block the blood vessels in the brain. However, the requirement to deliver this therapy within a few hours of the onset of a stroke has rendered it useless in the majority of cases.

Other approaches to therapy, for example the use of drugs such as glutamate antagonists to interrupt the cascade of biochemical events that lead to the death of brain cells when they are deprived of oxygen, have failed to live up to early expectations.

deCODE's gene discovery program is based on an analysis of the genetic profile of the Icelandic population, an ideal group to study because of the country's reliable genealogical and medical records. In the latest study, the company enrolled 1,800 stroke patients and their unaffected relatives from across Iceland in its gene-hunting exercise.

The PDE4D gene appears to play a role in atherosclerosis, most likely by influencing the proliferation and migration of smooth muscle cells within arteries that is central to the biology of ischaemic stroke, according to deCODE.

" A drug that could inhibit PDE4D or one of its specific isoforms might therefore be useful in counteracting atherosclerosis, and thereby reducing the risk of stroke,"​ according to the researchers, headed by Solveig Gretarsdottir.

Roche taking project into development​

deCODE has a long-standing collaboration with Swiss drug major Roche for the exploitation of a number of its gene discoveries, and the latter company has already started medicinal chemistry efforts aimed at identifying lead compounds that could act as inhibitors of the PDE4D pathway.

The Icelandic firm signed a deal worth up to $200 million (€174m) with Roche in 1998 to look for genes that cause 12 common diseases, including stroke.

In tandem with the drug discovery effort, deCODE is also developing a DNA-based diagnostic test based upon the at-risk and protective haplotypes within the PDE4D gene.