The phenotype of small dense low density lipoprotein (LDL) appears to play an important role in human atherosclerosis and diabetes. Most human diabetics have small dense LDL particles. Furthermore, a human gene that determines a phenotype of small dense LDL has been found. The allele causing the abnormal phenotype occurs in about 30% of individuals and is associated with upper body obesity, insulin resistance, and a 3-fold increased risk of heart disease. The human gene is named ATHS for atherosclerosis susceptibillty, and we have just mapped this gene to human chromosome 19 at or very near the gene for the LDL receptor. The objective of this grant proposal is to identify and characterize the genetic factor in the mouse responsible for the phenotype of small LDL and to investigate its interaction with other genetic factors controlling atherosclerosis, diabetes and obesity. First we will identify the genetic factor that determines production of small LDL in C57BL/Ks diabetes mice. If we identify the gene, we will sequence it and characterize the mutation causing the small dense LDL. Second, we want to determine the relationship between the small dense LDL genotype and the diabetogenic and atherogenic factors found in the BKs strain. That is, we will determine whether the gene for small dense LDL and the atherogenic or diabetogenic factor are linked or are even the same gene. Should we find, for instance, that small LDL and the atherogenic factor are the same gene, this would show, for the first time directly, that small LDL can lead to atherosclerosis. And third, we plan to determine the relationship between the small dense LDL phenotype and other phenotypic characteristics of the obese-diabetic syndrome in BKs. In particular, we want to answer the question whether the small LDL phenotype is dependent on the diabetic state. Finally, as a long term goal in our work, we want to study the interaction of the genes whose interplay results in the obese-diabetic syndrome. As each gene that determines small dense LDL, the atherosclerotic factor and the diabetogenic factor is defined, we will construct congenics by placing one allele of each gene on a C57BL/6 background. The construction of congenic strains will greatly facilitate future studies on the physiology and the mechanism of action of each gene. Our finding of a mouse model that displays many characteristics of human ATHS phenotype. will make it possible to answer many questions that cannot be resolved in the human system.
