Atherosclerotic disease, the hardening of the arteries that underlies coronary heart disease, stroke and peripheral vascular disease, is responsible for about 40 percent of the deaths in the United States each year. It is a complex genetic disease involving multiple genes and important gene-environment interactions. Dr. Breslow’s laboratory explores the genetic basis of atherosclerosis, working to determine what makes certain individuals more or less susceptible to this disease, and pioneers novel therapies to fight it.
Dr. Breslow explores the genetic and environmental basis of atherosclerosis. Susceptibility to atherosclerosis is associated with abnormal levels of plasma lipoproteins, and his studies have focused on the apolipoproteins, which coat lipoprotein particles and determine their synthesis, processing, and breakdown.
Dr. Breslow’s laboratory cloned the genes for most of the apolipoproteins and, to study how these genes function in vivo, made induced mutant mouse models, including the first mouse model of atherosclerosis. This model was made by knocking out the gene for apolipoprotein E (apo E), which is found on the surface of several lipoproteins. By breeding the apo E knockout trait to different inbred genetic backgrounds, Dr. Breslow and his colleagues produced varying amounts of atherosclerosis and evidence for modifier genes. Using mouse crosses such as this, as well as quantitative trait locus mapping, the lab is identifying new genes and pathways involved in atherosclerosis susceptibility.
Dr. Breslow’s laboratory also has used gene expression microarrays to identify mouse liver genes whose expression is regulated by dietary cholesterol, work that uncovered a new subclass of genes linked to cholesterol transport within cells. Another cholesterol-regulated gene discovered by this approach codes for a protein called PCSK9. His laboratory showed that PCSK9 was capable of destroying the LDL receptor, which clears LDL from the bloodstream. Inhibitors of PCSK9 are now in phase III clinical trials for lowering LDL cholesterol levels and preventing coronary heart disease.
In a collaborative project with Rockefeller’s Jeffrey M. Friedman and investigators at Columbia, Harvard, MIT, and Yale, Dr. Breslow has studied an isolated population on the Micronesian island Kosrae. Through family data, clinical and laboratory tests, and determination of genetic markers in each adult Kosraen, the investigators have identified genes that predispose an individual to obesity, diabetes, abnormal lipid levels, and high blood pressure.
Other past accomplishments include discovering that human genetic variation in apo E resulted from three different apo E types. Specific patterns of inheritance of these apo E types are linked to LDL cholesterol levels, atherosclerosis, Alzheimer’s disease, and even longevity. Dr. Breslow was the first to identify at the molecular level a human mutation causing atherosclerosis susceptibility, an apo A-I mutation that caused HDL deficiency and premature coronary heart disease. Finally, his research has shown that overproduction of apo CIII is a major determinant of high triglyceride levels and that triglyceride-lowering drugs called fibrates act mainly by decreasing apo CIII production.