Collaborative research reveals ABCs of cholesterol disease

A pan-Canadian collaboration between the country's leading geneticists and research institutions has identified the gene responsible for the regulation of "good" cholesterol, or HDL cholesterol, in the human body. Experts say the discovery opens the door to the development of new treatments for heart disease, one of the most common and fatal diseases in the western world.

The gene, known as ABC1, is responsible for regulating levels of HDL cholesterol, which is necessary for transporting excess cholesterol out of cells and to the liver for elimination. When the ABC1 gene is flawed, cholesterol accumulates in the tissues and arteries, increasing the risk of coronary artery disease.

The discovery of ABC1 was a result of collaboration involving Xenon Bioresearch Inc. and a consortium of Canadian and international research institutions. Funding came from Xenon and the Medical Research Council, as well as from the Networks of Centres of Excellence Program via the Canadian Genetic Diseases Network (CGDN).

Researchers uncovered the role of ABC1 while studying families from Quebec and the Netherlands with histories of heart disease, as well as people with Tangier disease, a rare illness characterized by very low HDL levels. These studies revealed that ABC1, when flawed, was the root of both diseases.

Dr. Michael Hayden, who led the research team, says that isolating the genetic cause of HDL deficiencies "represented a frontier in the prevention of coronary artery disease that had not yet been overcome."

"Although medical science has developed effective methods to lower LDL or 'bad' cholesterol, until now we have not understood crucial mechanisms which elevate levels of HDL or 'good' cholesterol," he says.

The gene hunt involved teams from Halifax to Victoria, including Toronto, Montreal and Vancouver, as well as researchers at the Academic Medical Centre in Amsterdam, led by Dr. John Kastelein.

"Holland, because of its size and population, is ideally suited for genetics research," says Dr. Kastelein, adding that large families and well-equipped clinical facilities give the country an excellent research base in genetic diseases. "When you add CGDN's and Xenon's capacities in genetics and molecular biology to those family collections, you have a very strong combination, and that has enormously helped the HDL discovery," he says.

Details of the discovery were published in the August 1999 issue of Nature Genetics, as well as in newspapers and scientific journals around the world. Since then, a number of pharmaceutical and biotechnology companies have approached Xenon Bioresearch Inc., which has intellectual property rights to the gene, about developing drugs for people with low levels of good cholesterol.

Frank Holler, president and CEO of Xenon, says it could take two to three years before such drugs can be advanced into clinical testing, but adds that the time and effort will have been worth it.

He says that while low levels of good cholesterol are found in one half of all patients with coronary artery disease, there are currently no effective drugs to boost HDL levels in humans.

Dr. Hayden stresses that a key factor in the cholesterol breakthrough was the collaborative spirit across the country.

"Our competitive edge in research in Canada is the cooperation, the collegiality, the ability to work across this country as a single unit when we have to. We do that very well," says the director of CGDN. "When we use the model of research propagated by the Networks, we are powerful."

CGDN is a not-for-profit corporation and nation-wide centre of research excellence. It links 50 of Canada's leading geneticists and their teams based in 18 universities, hospitals, and research centres across Canada with public and private sector organizations. CGDN is one of 15 federal Networks of Centres of Excellence (NCE). In 1999-2000, the NCE funds going to CGDN represent an investment of $4.5 million in Canadian research and development.

The NCE program is jointly funded by NSERC (the Natural Sciences and Engineering Research Council), the Social Sciences and Humanities Research Council, and the Medical Research Council, in partnership with Industry Canada.

For more information please visit the CGDN Web site.