In a four-year study published in the January 15 advance online publication of Nature Genetics, researchers at The Institute for Genomic Research (TIGR) and the Medical College of Wisconsin (MCW) systematically bred and studied 43 designer rats with and without high blood pressure, in order to pinpoint candidate genes behind heart disease. In total, the scientists built 2,200 microarray gene expression profiles from these designer rats--providing a valuable new online resource now available to researchers worldwide.
Scientists have long used rat models to study heart disease in the lab. But those studies have yet to answer key questions: Which genes, on which chromosomes, combine to cause this complex condition? Why, and how, do some animals become hypertensive when consuming high-salt diets, while others stay healthy? To turn the tools of genomics onto these questions, the National Heart, Lung, and Blood Institute, part of the National Institutes of Health, funded the new study.
In the first part of the study, MCW researchers began with a strain of rats bearing high blood pressure, a hallmark of heart disease. The researchers then bred an almost identical designer rat, with one important change: they substituted one chromosome from the parental, hypertensive rat with the homologous chromosome from a healthy rat. Continuing this way, the team generated 22 unique designer rat strains, each bearing one distinct healthy chromosome substitution. Some of these new designer rats were disease-free, implying that their replaced chromosomes carried genes for high blood pressure and related conditions.
In the second part of the study, TIGR molecular biologist Norman Lee led the team in using a DNA microarray technique to compare the expression of more than 22,000 genes among the hypertensive, healthy, and designer rats. By studying the physical characteristics and gene expression of more than 800 rats, the team identified candidate genes that may contribute to cardiovascular disease, including some genes not previously associated with the condition.
"This information offers an unprecedented amount of data for cardiovascular researchers to now mine," remarks Lee, senior author of the study. Lead author Renae Malek, also a molecular biologist at TIGR, notes that the data point to promising genes for salt-sensitive hypertension, among other conditions. The online database resulting from the study, dubbed TREX, is available free of charge at: http://pga.tigr.org/.
TIGR continues to study the panels of designer rat strains, and Lee hopes in the future to knock out specific candidate heart disease genes, directly testing their effects. "With all this information in hand, science is moving from a microscopic to global perspective of heart disease," Lee says. "This will generate research projects for years down the line."