Quantitative trait locus analysis of carotid atherosclerosis in an intercross between C57BL/6 and C3H apolipoprotein E-deficient mice.

Abstract

Inbred mouse strains C57BL/6J (B6) and C3H/HeJ (C3H) exhibit marked differences in atherosclerotic lesion formation in the carotid arteries on the apolipoprotein E-deficient (apoE(-/-)) background when fed a Western diet. Quantitative trait locus analysis was performed on an intercross between B6.apoE(-/-) and C3H.apoE(-/-) mice to determine genetic factors contributing to variation in the phenotype. Female B6.apoE(-/-) mice were crossed with male C3H.apoE(-/-) mice to generate F(1) hybrids, which were intercrossed to generate 241 female F(2) progeny. At 6 weeks of age, F(2) mice were started on a Western diet. After being fed the diet for 12 weeks, F(2) mice were analyzed for phenotypes such as lesion size in the left carotid arteries and plasma lipid levels and typed for 154 genetic markers spanning the mouse genome. One significant quantitative trait locus, named CAth1 (25 cM, log of the odds score: 4.5), on chromosome 12 and 4 suggestive quantitative trait loci, on chromosomes 1, 5, 6, and 11, respectively, were identified to influence carotid lesion size. One significant quantitative trait locus on distal chromosome 1 accounted for major variations in plasma low-density lipoprotein/very-low-density lipoprotein, high-density lipoprotein cholesterol, and triglyceride levels. Carotid lesion size was not significantly correlated with plasma low-density lipoprotein/very-low-density lipoprotein or high-density lipoprotein cholesterol levels. These data indicate that the loci for carotid lesions do not overlap with those for aortic lesions as identified in a previous cross derived from the same parental strains, and carotid atherosclerosis and plasma lipids are controlled by separate genetic factors in the B6 and C3H mouse model.