We are going to see a lot of genetic breakthoughs in Iceland. Unique population with fantastic medical records. I don't want them to get too good. A stoke on the dancefloor is my preferred end. I love the line, "Vikings from Norway who stopped first in Ireland to gather several wives apiece." Rape, kidnapping and pillage, that's what it was.
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September 22, 2003
Scientists Discover First Gene Tied to Stroke Risk
By NICHOLAS WADE
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.
nytimes.com |
