Genetic architecture of atherosclerosis dissected by QTL analyses in three F2 intercrosses of apolipoprotein E-null mice on C57BL6/J, DBA/2J and 129S6/SvEvTac backgrounds.

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.

Quantitative trait loci affecting atherosclerosis at the aortic root identified in an intercross between DBA2J and 129S6 apolipoprotein E-null mice.

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.

Aortic arch curvature and atherosclerosis have overlapping quantitative trait loci in a cross between 129S6/SvEvTac and C57BL/6J apolipoprotein E-null mice.

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=0.34, P<0.0001) and weakly with the arch diameter (r=0.20, P=0.02). Quantitative trait locus (QTL) analysis identified 2 significant peaks for aortic arch lesion size on chromosome 1 (105 Mb, LOD=5.0, and 163 Mb, LOD=6.8), and a suggestive QTL on chromosome 15 (96 Mb, LOD=4.7). A significant QTL for aortic root lesion size was on chromosome 9 (61 Mb, LOD=6.9), but it was distinct from the QTLs for arch lesion size. Remarkably, the QTLs for susceptibility to atherosclerosis in the arch overlapped with a significant QTL that affects curvature of the arch on chromosome 1 (121 Mb, LOD=5.6) and a suggestive QTL on chromosome 15 (76 Mb, LOD=3.5). CONCLUSIONS: The overlapping QTLs for curvature of the aortic arch and atherosclerosis support that the ontogeny of the aortic arch formation is a potential risk factor for atherosclerosis.