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The genetic background of apolipoprotein E (apoE) deficient mice influences atherosclerotic plaque development. We previously reported three quantitative trait loci (QTL),  Aath1–Aath3 , that affect aortic arch atherosclerosis independently of those in the aortic root in a cross between C57BL6 apoEKO mice (B6-apoE) and 129S6 apoEKO mice (129-apoE). To gain further insight into genetic factors that influence atherosclerosis at different vascular locations, we analyzed 335 F2 mice from an intercross between 129-apoE and apoEKO mice on a DBA/2J genetic background (DBA-apoE). The extent of atherosclerosis in the aortic arch was very similar in the two parental strains. Nevertheless, a genome-wide scan identified two significant QTL for plaque size in the aortic arch:  Aath4  on Chromosome (Chr) 2 at 137 Mb and  Aath5  on Chr 10 at 51 Mb. The DBA alleles of  Aath4  and  Aath5  respectively confer susceptibility and resistance to aortic arch atherosclerosis over 129 alleles. Both QTL are also independent of those affecting plaque size at the aortic root. Genome analysis suggests that athero-susceptibility of  Aath4  in DBA may be contributed by multiple genes, including  Mertk  and  Cd93 , that play roles in phagocytosis of apoptotic cells and modulate inflammation. A candidate gene for  Aath5  is  Stab2 , the DBA allele of which is associated with 10 times higher plasma hyaluronan than the 129 allele. Overall, our identification of two new QTL that affect atherosclerosis in an aortic arch-specific manner further supports the involvement of distinct pathological processes at different vascular locations.

plos one

Identification of Aortic Arch-Specific Quantitative Trait Loci for Atherosclerosis by an Intercross of DBA/2J and 129S6 Apolipoprotein E-Deficient Mice