QTL analysis of carotid atherosclerosis

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DESCRIPTION (provided by applicant): Stroke is the third leading cause of mortality and the leading cause of disability in the United States, and a significant fraction of ischemic strokes are caused by carotid atherosclerosis, which results in stenosis of the vessels and blocks the blood flow to the brain. The goal of this proposal is to identify genetic factors that contribute to the development of carotid atherosclerosis, using the novel apolipoprotein E-deficient (apoE-/-) mouse model. ApoE-/- mice on the C57BL/6 (B6) genetic background develop all phases of atherosclerotic lesions seen in humans in carotid arteries. Our recent studies show that the lesions can be dramatically diminished by outcross with C3H/HeJ (C3H) mice, demonstrating the genetic control of the disease process in the mice. In vitro, endothelial cells of C3H mice are not as responsive to oxidized LDL as B6 endothelial cells. We hypothesize that a genetic alteration that influences the response to oxidized LDL contributes to the resistance of C3H mice to carotid atherosclerosis. To test this hypothesis, B6.apoE-/- mice will be crossed with C3H.apoE-/- mice to generate F1 mice, which will be subsequently intercrossed to generate F2 mice. Starting at 6 weeks of age, the F2 mice, together with the F1 and the two parental strains, will be fed a Western diet for 12 weeks. Atherosclerotic lesions in carotid arteries will be measured by light microscopy. Blood will be collected for fasting lipid profiles and inflammatory markers. Genome wide scan will be performed using microsatellite markers to define the genetic loci that are linked to differences in phenotypes between B6 and C3H strains. Statistical associations of the markers and the phenotypes will be performed to identify loci underlying the traits. After the genome screen has detected chromosomal regions that show linkage with atherosclerotic lesions, we will type additional closely spaced polymorphic markers. One to two major QTLs for atherosclerotic lesions will be dissected through construction of congenic strains.