P&S Journal: Spring 1997, Vol.17, No.2
New Mouse Mimics Disorder Leading to Premature Heart Disease
P&S researchers led a team that developed a mouse model for the most common genetic cause of a lipid disorder associated with premature heart disease. The study appeared in Science in January.
Familial combined hyperlipidemia (FCHL) is a common inherited disorder that causes high cholesterol and high triglyceride levels in 1 percent to 2 percent of the Western population. People with FCHL frequently develop heart disease before age 55. The mouse model may provide clues to the origin of human FCHL and allow the study of drugs to treat the disorder.
The exact genetic mutation that causes FCHL is not yet known, but this study suggests that the apolipoprotein C-III (APOC3) gene is involved, says senior author Dr. Alan R. Tall, the Tilden Weger Bieler Professor of Preventive Medicine and chief of the Specialized Center for Research in Molecular Medicine and Atherosclerosis.
"Independent human genetic studies have pointed to the APOC3 gene as the cause of this disorder in some families," says Dr. Tall, "so the fact that we can produce a phenocopy of the human disorder in the mouse strengthens the theory that APOC3 genetic variations underlie this disease."
The study suggests that an over expression of the APOC3 gene product results in the high levels of very low density lipoprotein and low density lipoprotein that characterize the disease. "Our study suggests a new hypothesis of how FCHL develops," says Dr. Tall. "If the APOC3 connection to FCHL holds true, it may open the way to the production of drugs to better treat the disorder."
Approximately 5 percent all individuals with coronary heart disease have FCHL. Ten percent of people with premature heart disease are thought to have the disorder.
Other authors on the study were Drs. Lori Masucci-Magoulas, Ira J. Goldberg, and Humaira Serajuddin of P&S; Dr. Charles L. Bisgaier, Parke-Davis Pharmaceutical Research; Dr. Omar L. Francone, Pfizer Inc.; and Dr. Jan L. Breslow, Rockefeller University.