Genetic modifiers of atherosclerosis in mice.

Common atherosclerosis has a genetic component, but it is difficult to determine the specific genes that play a role in atherosclerosis susceptibility in humans. We have used the apoE-deficient mouse as a model system to examine the effects of candidate genes on atherosclerosis as well as to perform genomic experiments to map and isolate other genes giving rise to atherosclerosis susceptibility. We have tested the effects of mutations in the MCSF and VCAM-1 genes on atherosclerosis, and in both of these cases mutations led to gene dosage-dependent decreases in atherosclerosis. By successive back breeding, we have established apoE-deficiency on the C57BL/6 and FVB/N inbred mouse strains. Lesions in C57BL/6 mice are about eightfold larger than those in FVB/ N mice, and lesions in F1 hybrids are intermediate in size. We have performed quantitative trait locus mapping on two F2 cohorts and discovered atherosclerosis susceptibility loci on chromosomes 10, 14, and 19.