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

Abstract

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.

Figure 1

A. Representative images of excised aortas from 9-month-old 129-apoE and B6-apoE male mice. B. Schema representing angle of the aortic arch (angle BAC), and diametersof ascending aorta (DA1), transverse aorta (DA2), and descending aorta (DA3). C. Representative cross-sectional histological preparations of the aortic arch in 9-month-old 129-apoE and B6-apoE male mice stained with Sudan IV and counterstained with hematoxylin. D. Relationship between arch lesion sizes measured by captured image and by cross-sectional preparations in F2 males (n=111).

Figure 2

Genome-wide QTL analyses on atherosclerosis, vascular geometry, and plasma lipids in F2 males (left panels), females (middle panels), and combined (right panels). Atherosclerotic lesion sizes and plasma lipids were logarithmically transformed. Horizontal dashed lines and alternate long and short dash lines represent significant (p=0.05) and suggestive (p=0.63) levels, respectively, as determined by 1000 permutationtests.

Figure 3

Allelic effects of the SNP marker closest to the peak LOD positions on root lesion size (A and B), arch lesion size (C, D, and E), angle (F and G), and mean diameter ofaortic arch (mean DA1–3) (H). 129/129, 129/B6, and B6/B6 represent homozygous 129, heterozygous, and homozygousB6 alleles, respectively. Atherosclerotic lesion sizes were logarithmically transformed. Values are means±SEM. *p<0.05 and **p<0.01.

Figure 4

Detailed LOD score plots for the overlapping QTLs on chromosome1 (A), 15 (B), and 9 (C), using the data from F2 males and females with sex treated as an interactive covariate. Solid lines represent atherosclerotic lesion sizes in aortic arch (black) and root (green), angle (red), and mean diameter of aortic arch (blue). Dashed lines represent plasma levels of cholesterol (red), triglyceride (blue), and HDL-C (green). Horizontal dashed lines and alternate long and short dash lines represent significant (p=0.05) and suggestive (p=0.63) levels for arch lesion size (A and B) or root lesion size (C).