Rationale: Apolipoprotein E-null mice with a 129S6/SvEvTac strain background (129-apoE) develop atherosclerotic plaques faster in the aortic arch but slower in the aortic root than those with a C57BL/6J background (B6-apoE). The shape of the aortic arch also differs in the 2 strains. Objective: Because circulating plasma factors are the same at both locations, we tested the hypothesis that genetic factors affecting vascular geometry also affect the location and extent of atherosclerotic plaque development. Methods and Results: Tests on the F2 progeny from a cross between 129-apoE-null and B6-apoE-null mice showed that the extent of atherosclerosis in the aortic arch is significantly correlated in males, but not in females, with the shape of arch curvature (r‫,43.0؍‬ P<0. A therosclerosis is a complex trait resulting from interactions between multiple genetic and environmental factors. The spatial distribution of development of atherosclerotic plaques along the vasculature varies between individuals and by gender in humans, although lesions tend to develop close to arterial bifurcations and bends. This suggests that local hemodynamic forces, including shear stress, contribute to the regional development and progression of atherosclerosis. 1 Because vessel geometry, which affects hemodynamic parameters, varies widely across human populations, the risk of developing atherosclerotic lesions might be higher in some individuals by virtue of their particular vascular geometry. 2 However, the complexity of the relationships between vascular geometry, hemodynamics, and atherosclerosis combined with the genetic heterogeneity of human populations makes it extremely difficult to search for relevant genetic factors using human patients. Here, we reduce the genetic complexity by using inbred mice, and increase the incidence of lesions by using suitable mutants.Apolipoprotein (apo)E-null mice spontaneously develop atherosclerotic plaques in the aortic root and aortic arch, 3 but our recent report demonstrates that apoE-null mice on a 129S6/SvEvTac (129-apoE) and those on a C57BL/6J (B6-apoE) show several strain-specific differences in the patterns of plaque distributions in their aortas. 4 For example, atherosclerotic lesions at the aortic arch develop more rapidly in 129-apoE mice than in B6-apoE mice. In contrast, lesions at the aortic root develop more slowly in 129-apoE mice than in B6-apoE mice. In addition, no significant male/female differences in the development of plaques are recognizable at either the aortic root or the aortic arch in 129-apoE mice, whereas there is a well-known gender effect in B6-apoE mice in which females develop more extensive plaques at the aortic root than males. The 2 strains also show distinct and easily recognizable differences in the geometry of the aortic arch. Additionally, computer simulations based on the differences in aortic arch geometry and hemodynamics of wild-type 129 and B6 mice support an interaction between these factors in determining the differences in plaque patterns in t...

Apolipoprotein E-null mice on a DBA/2J genetic background (DBA-apoE) are highly susceptible to atherosclerosis in the aortic root area compared with those on a 129S6 background (129-apoE). To explore atherosclerosis-responsible genetic regions, we performed a quantitative trait locus (QTL) analysis using 172 male and 137 female F2 derived from an intercross between DBA-apoE and 129-apoE mice. A genome-wide scan identified two significant QTL for the size of lesions at the root: one is Ath44 on Chromosome (Chr) 1 at 158 Mb, and the other Ath45 on Chr 2 at 162 Mb. Ath44 co-localizes with but appears to be independent of a previously reported QTL, Ath1, while Ath45 is a novel QTL. DBA alleles of both Ath44 and Ath45 confer atherosclerosis-susceptibility. In addition, a QTL on Chr 14 at 73 Mb was found significant only in males, and 129 allele conferring susceptibility. Further analysis detected female-specific interactions between a second QTL on Chr 1 at 73 Mb and a QTL on Chr 3 at 21 Mb, and between Chr 7 at 84 Mb and Chr 12 at 77 Mb. These loci for the root atherosclerosis were independent of QTLs for plasma total cholesterol and QTLs for triglycerides, but a QTL for HDL (Chr 1 at 126 Mb) overlapped with the Ath44. Notably, haplotype analysis among 129S6, DBA/2J and C57BL/6 genomes and their gene expression data narrowed the candidate regions for Ath44 and Ath45 to less than 5 Mb intervals where multiple genome wide associations with cardiovascular phenotypes have also been reported in humans. SNPs in or near Fmo3, Sele and Selp for Ath44, and Lbp and Pkig for Ath45 were suggested for further investigation as potential candidates underlying the atherosclerosis susceptibility.

Quantitative trait locus (QTL) analyses of intercross populations between widely used mouse inbred strains provide a powerful approach for uncovering genetic factors that influence susceptibility to atherosclerosis. Epistatic interactions are common in complex phenotypes and depend on genetic backgrounds. To dissect genetic architecture of atherosclerosis, we analyzed F2 progeny from a cross between apolipoprotein E-null mice on DBA/2J (DBA-apoE) and C57BL/6J (B6-apoE) genetic backgrounds and compared the results with those from two previous F2 crosses of apolipoprotein E-null mice on 129S6/SvEvTac (129-apoE) and DBA-apoE backgrounds, and B6-apoE and 129-apoE backgrounds. In these round-robin crosses, in which each parental strain was crossed with two others, large-effect QTLs are expected to be detectable at least in two crosses. On the other hand, observation of QTLs in one cross only may indicate epistasis and/or absence of statistical power. For atherosclerosis at the aortic arch, Aath4 on chromosome (Chr)2:66 cM follows the first pattern, with significant QTL peaks in (DBAx129)F2 and (B6xDBA)F2 mice but not in (B6x129)F2 mice. We conclude that genetic variants unique to DBA/2J at Aath4 confer susceptibility to atherosclerosis at the aortic arch. A similar pattern was observed for Aath5 on chr10:35 cM, verifying that the variants unique to DBA/2J at this locus protect against arch plaque development. However, multiple loci, including Aath1 (Chr1:49 cM), and Aath2 (Chr1:70 cM) follow the second type of pattern, showing significant peaks in only one of the three crosses (B6-apoE x 129-apoE). As for atherosclerosis at aortic root, the majority of QTLs, including Ath29 (Chr9:33 cM), Ath44 (Chr1:68 cM) and Ath45 (Chr2:83 cM), was also inconsistent, being significant in only one of the three crosses. Only the QTL on Chr7:37 cM was consistently suggestive in two of the three crosses. Thus QTL analysis of round-robin crosses revealed the genetic architecture of atherosclerosis.

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