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Designer Rats Reveal Possible Heart Disease Genes

Heart disease claims about 7 million lives every year, according to the WHO. Scientists have been trying to identify the precise genes that are behind this complex disease. Now they have a new research ally: the designer rat. //

In a 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) conducted systematic breeding and study of 43 designer rats with and without high blood pressure, to pinpoint candidate genes behind heart disease.

In total, the scientists built 2,200 microarray gene expression profiles from these designer rats. They have provided a highly valuable new online resource now available to researchers worldwide. The National Heart, Lung, and Blood Institute, part of the National Institutes of Health funded this study.

Scientists have been using rat models to study heart disease in the lab. But these studies have yet to answer key questions: Which genes, on which chromosomes, combine to cause this complex condition? How, and why, do some animals become hypertensive when consuming high-salt diets, while others stay healthy?

In the first part of the four-year study, MCW researchers began with a strain of rats with high blood pressure, a hallmark of heart disease. Then they bred an almost identical designer rat, with one important change: one chromosome from the parental, hypertensive rat was substituted with the homologous chromosome from a healthy rat. In 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 comparing the expression of over 22,000 genes among the hypertensive, healthy, and designer rats using a DNA microarray technique. By studying the physical characteristics and gene expression of over 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. Lee hopes to knock out specific candidate heart disease genes in future, 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."

The Institute for Genomic Research (TIGR) is a not-for-profit center dedicated to deciphering and analyzing genomes. Since 1992, TIGR, based in Rockville, Md., has been a genomics leader, conducting research critical to medicine, agriculture, energy, the environment and biodefence.


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