Quantitative Trait Locus Analysis of Atherosclerosis in an Intercross Between C57BL/6 and C3H Mice Carrying the Mutant Apolipoprotein E Gene

Abstract

Inbred mouse strains C57BL/6J (B6) and C3H/HeJ (C3H) differ significantly in atherosclerosis susceptibility and plasma lipid levels on the apolipoprotein E-deficient (apoE ÿ/ÿ ) background when fed a Western diet. To determine genetic factors contributing to the variations in these phenotypes, we performed quantitative trait locus (QTL) analysis using an intercross between the two strains carrying the apoE ÿ/ÿ gene. Atherosclerotic lesions at the aortic root and plasma lipid levels of 234 female F 2 mice were analyzed after being fed a Western diet for 12 weeks. QTL analysis revealed one significant QTL, named Ath22 (42 cM, LOD 4.1), on chromosome 9 and a suggestive QTL near D11mit236 (20 cM, LOD 2.4) on chromosome 11 that influenced atherosclerotic lesion size. One significant QTL on distal chromosome 1, which accounted for major variations in plasma LDL/VLDL cholesterol and triglyceride levels, coincided with a QTL having strong effects on body weight. Plasma LDL/VLDL cholesterol or triglyceride levels of F 2 mice were significantly correlated with body weight, but they were not correlated with atherosclerotic lesion sizes. These data indicate that atherosclerosis susceptibility and plasma cholesterol levels are controlled by separate genetic factors in the B6 and C3H mouse model and that genetic linkages exist between body weight and lipoprotein metabolism.

Apolipoprotein E knockout mice have accentuated malnutrition with mucosal disruption and blunted insulin-like growth factor I responses to refeeding

“…ApoE knock-out (ko) mice were purchased from Jackson laboratories after being generated from B6.apoE −/− at the N10 backcross and constructed from B6.129 apoE −/− mice [20]. C57BL/6J wild types were purchased from Charles River Laboratories (Wilmington, MA).…”

Association of a Vcam1 mutation with atherosclerosis susceptibility in diet-induced models of atherosclerosis

“…Mice were fed a Western diet containing 42% fat, 0.15% cholesterol and 19.5% casein for 12 weeks. The phenotypic measurements, including atherosclerotic lesion size, of F2 mice were previously reported [13]. Vcam1 genotypes of F2 mice were determined by the PCR-RFLP method.…”

“…In contrast, in the F2 population derived from B6.apoE −/− and C3H.apoE −/− mice, the association between Vcam1 genotypes and atherosclerotic lesion size was not detected. The confounding influence of atherosclerosis susceptibility loci on chromosomes 9 and 11 [13] may have diminished the power to detect associations between Vcam1 and atherosclerotic lesions using the cross. Another explanation is that VCAM-1 contributed less significantly to the development of atherosclerosis in the apoE −/− model than in the diet-induced model.…”

Candidate genes for plasma triglyceride, FFA, and glucose revealed from an intercross between inbred mouse strains NZB/B1NJ and NZW/LacJ*

“…FFA concentrations were affected by a significant locus on Chr 4, a suggestive locus on Chr 16, and two interacting loci on Chr 2 and 15. Plasma glucose concentrations were affected by QTL on Chr 2,4,7,8,10,15,17,and 18. Comparative genomics narrowed the QTL by 31% to 86%; haplotype analysis was usually able to further narrow it by 80%.…”

“…Because of inherent difficulties in carrying out linkage analyses for complex traits in humans, inbred strains of mice have been used as a powerful tool for identifying quantitative trait loci (QTL) that contribute to variations in circulating levels of lipids and glucose (7)(8)(9). Studies in mice not only have revealed a large number of QTL that regulate lipid levels but also have shown that there is a high degree of concordance with human QTL that regulate the same traits (7).…”