Atherosclerosis in the carotid arteries is a major cause of ischemic stroke, which accounts for 85% of all stroke cases. Genetic factors contributing to carotid atherosclerosis remain poorly understood. The aim of this study was to identify chromosomal regions harboring genes contributing to carotid atherosclerosis in mice. 228 female F2 mice were generated from an intercross between BALB/cJ (BALB) and SM/J (SM) apolipoprotein E-deficient (Apoe-/-) mice and fed 12 weeks of western diet. Atherosclerotic lesion sizes in the left carotid artery were quantified. 149 genetic markers were genotyped across the entire genome. Quantitative trait locus (QTL) analysis revealed 8 loci for carotid lesion sizes, located on chromosomes 1, 5, 12, 13, 15, 16, and 18. Combined cross linkage analysis using data from this cross and two previous F2 crosses derived from BALB, C57BL/6J and C3H/HeJ strains identified 5 significant QTLs on chromosomes 5, 9, 12 and 13 and 9 suggestive QTLs for carotid atherosclerosis. Of them, the QTL on chromosome 12 had a high LOD score of 9.95. Bioinformatic analysis prioritized Arhgap5, Akap6, Mipol1, Clec14a, Fancm, Nin, Dact1, Rtn1, and Slc38a6 as probable candidate genes for this QTL. Atherosclerotic lesion sizes were significantly correlated with non-HDL cholesterol levels (r=0.254; p=0.00016) but inversely correlated with HDL cholesterol levels (r=-0.134; p=0.049) in the current cross. Thus, we demonstrated the polygenic control of carotid atherosclerosis in mice. The correlations of carotid lesion sizes with non-HDL and HDL suggest that genetic factors exert effect on carotid atherosclerosis partially through modulation of lipoprotein homeostasis.
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