Landmark Discovery Achieved In Cardiovascular Gene Project

December 16, 1997

An international team of researchers has discovered most of the genes in the cardiovascular system. The results of the four-year research project led by Professor C. C. Liew of the University of Toronto are published in the Dec. 16 issue of Circulation.

"Through categorizing genes of the heart and blood vessels we have been able to establish a database for identifying cardiovascular genes, a critical step to understanding the complex genetic mechanisms underlying cardiovascular disease and the development and evolution of the cardiovascular system," says Liew of U of T's department of laboratory medicine and pathobiology and The Toronto Hospital. "Although cardiovascular disease is a leading cause of death worldwide the genetic factors leading to this disease are largely unknown."

An estimated 75,000 to 100,000 unique genes are located in DNA in the human body. Although all DNA throughout the human body contain the same genes, the genes that are active vary according to each organ or tissue. For example, the cardiovascular system has an estimated 30,000 to 50,000 genes active in the development and normal functioning of the human heart and its blood vessels.

Five years ago, fewer than 3,000 human genes had been identified and little was known about which of these genes might be actively involved in cardiovascular function and disease. The team of researchers from the Banting Institute at the University of Toronto, the Centre for Cardiovascular Research of The Toronto Hospital, the Chinese University of Hong Kong and the China National Center for Biotechnology Development in Beijing, China, has now identified as many as 80 per cent of the genes active in the cardiovascular system.

"This is the most comprehensive analysis of cardiovascular genes done to date and it has created one of the largest existing databases for a single human organ," Liew explains. "Through a computer-based analysis we can learn how these genes work together in the normal cardiovascular system or their impact on conditions such as coronary artery disease, stroke, hypertension and heart failure."

"We are now able to look at the genetic basis for diseases involving more than one gene. This is important because the vast majority of cardiovascular conditions likely involve interactions between many different genes, rather than only being caused by one," Liew explains. By comparing genes active in tissue from people with congestive heart failure to those free of heart disease, Liew's team has already found about 100 different genes which may be involved in congestive heart failure. This information changes our understanding of cardiovascular disease and may lead to improved drug therapies and diagnostic tests, says Liew.

"The success of the research team's work involved the timely marriage of the cutting-edge technology of the Human Genome Project with more conventional molecular biology," says Liew. To locate active genes, researchers looked for the presence of RNA, which represents copies of active genes occurring in the cytoplasm of the cell. Since RNA is significantly more difficult to work with than DNA, the investigators extracted RNA from tissue samples, purified it in vitro and then used it to make a complementary DNA (cDNA) library for analysis.

Using the cDNA library, the investigators then deciphered small segments of cDNA sequences of individual genes from heart and blood vessel walls of both healthy and diseased tissue samples to create a database of active genes in the cardiovascular system. These partial DNA sequences are referred to as expressed sequence tags (ESTs) because the genes are activated or expressed in the tissue from which they were derived. To date, the research team has generated over 46,000 of these gene tags from hearts in various stages of development and disease. Together with U of T graduate students David Hwang, Adam Dempsey and Ruoxiang Wang, the team has also been able to identify the chromosomal locations of over 1,000 these genes. This information may assist other investigators in their efforts to identify disease-causing genes.

The cardiovascular gene project received major funding from Spectral Diagnostics Incorporated of Toronto and additional support from the Canadian Genome Analysis and Technology Program, the Ontario Heart and Stroke Foundation and the Medical Research Council of Canada.

University of Toronto

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