8-Humans: Decode project discover first gene tied to stroke risk

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TITLE:  Scientists Discover First Gene Tied to Stroke Risk
SOURCE: The New York Times, USA, by Nicholas Wade
        http://www.nytimes.com/2003/09/22/science/22STRO.html
DATE:   Sep 22, 2003

------------------- archive: http://www.genet-info.org/ -------------------


Scientists Discover First Gene Tied to Stroke Risk

Researchers in Iceland say they have discovered the first gene that
underlies common forms of stroke, a disease that affects more than
600,000 people a year in the United States.

People with a particular version of the gene have a three to five times
greater risk of stroke, said the researchers, who are at Decode Genetics,
a company based in Reykjavik. This is as large as or larger than known
environmental risk factors like high blood pressure, high cholesterol and
smoking.

Dr. Kari Stefansson, the chief executive of Decode, said that the new
gene makes an enzyme that is a good target for drugs, and that the Roche
pharmaceutical company in Switzerland was already testing several such
drugs in laboratory rats.

The new gene was identified by a team led by Dr. Solveig Gretarsdottir.
The gene had not previously been implicated in stroke, and its detection
may open new insights into the mechanisms of the disease. Decode's work,
reported today in the journal Nature Genetics, is a "tour de force" and
"highly, highly significant for the stroke field," said Dr. Jonathan
Rosand, a stroke specialist at Massachusetts General Hospital.

But the study is unlikely to yield new treatments any time soon and needs
to be confirmed by other researchers in other populations, Dr. Rosand added.

Decode Genetics has identified 15 genes involved in 12 common diseases
and has mapped the general locations on the genome for an additional 20,
Dr. Stefansson said last week. All have been identified among the
Icelandic population, which is particularly suitable for genetic studies
because of its excellent genealogical records and uniform health care
system, and some have also been identified in other populations.

Some diseases, like sickle cell anemia or cystic fibrosis, are caused by
mutations in a single gene, and are relatively rare. Common diseases like
stroke, diabetes and cancer are thought to be promoted by several
different genes acting in concert.

Since each of the contributing genes in these multigenic diseases has a
small effect, they are hard to pick up from family pedigrees. Identifying
such genes was expected to be one of the major fruits of the Human Genome
Project, which was financed by the United States government and other
countries. But so far only a handful of such genes have been identified,
with Decode's reported tally being far larger than anyone else's.

Dr. Rosand said the company had several advantages, including its use of
extremely sophisticated technology, and the helpful genetic history of
the Icelandic population, which ensures that many patients with a given
disease may have inherited the same genetic variation from a single
ancestor in the distant past. The population is a mix of Norwegian and
Celtic, as the country was founded in the 10th century by Vikings from
Norway who stopped first in Ireland to gather several wives apiece.

Dr. Stephen T. Warren, editor of The American Journal of Human Genetics,
said other groups were making good progress in detecting the genes for
specific complex diseases, but Decode was more visible because it was
working on many diseases at once.

The disease-causing version of the new stroke gene has come to light
among Icelanders, but its finders hope it may have a wider significance.

"My prediction is that we will find this in all populations we look at
because," Dr. Stefansson said only partly in jest, "I am convinced that
Icelanders are a good animal model for Homo sapiens." Other populations
will have different genetic changes, but in the same gene, he suggested.

In addition, the drugs Roche is developing to target the stroke gene's
enzyme might be useful for everyone at risk of stroke, whether or not
they carry the same genetic variant found among Icelanders, said Dr.
Jonathan Knowles, Roche's president of global research. Roche paid for
some of Decode's research and has rights to certain discoveries.

Decode's data from its Icelandic patients shows that certain variations
in the new stroke gene are highly associated with both the carotid artery
and heart-associated forms of stroke. The gene is known as
phosphodiesterase 4D, or "dunce" because it was first discovered in fruit
flies with learning issues. But it is not yet clear how the variant form
of the gene is involved in stroke. The dunce gene operates in the cell's
internal signaling system and causes certain types of cells to be
activated. These include the smooth muscle cells of the arteries.

Dr. Stefansson says he believes that in patients with the variant form of
the dunce gene the muscle cells of the artery walls may proliferate,
causing the blockage known as plaque. Dr. Knowles said that or other
mechanisms were possible. Dr. Rosand said the variant gene might instead
impair the brain's normal response to a stroke, which is to increase
blood flow to regions affected by a blockage.

Many genetic diseases are caused by mutations, or changes in the DNA
sequence of a gene, that make it produce a dysfunctional protein product.
The change in the dunce gene is more subtle. The gene produces several
different proteins, known as isoforms, depending on which of its subunits
is involved in the protein manufacturing process. Decode's researchers
could find no defects in these isoforms. The only change attributable to
the variant form of the dunce gene was that it made different quantities
of three of the gene's isoforms. This minute change is apparently enough
to lead to disease. It is not yet clear what features in the variant gene
cause the different production of its isoforms.

Dr. Stefansson said that there were probably several other genes involved
in stroke, but that the dunce gene variant made the strongest
contribution. His method of gene hunting is not powerful enough to pick
up every gene relevant to a disease, but the ones it does flag are likely
to be the most important, he said.

Discovery of the dunce gene's role at least gives researchers a new
starting point for trying to understand the mechanism of stroke, even
though the exact chain of cause and effect remains unclear.

"Genetics doesn't tell you the answer; it tells you that somewhere in
here an answer lies," Dr. Knowles said.




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