Genetic Analysis of Atherosclerosis and Glucose Homeostasis in an Intercross Between C57BL/6 and BALB/cJ Apolipoprotein E–Deficient Mice

Abstract

Background Diabetic patients have an increased risk of developing atherosclerosis and related complications compared to non-diabetic individuals. The increased cardiovascular risk associated with diabetes is due in part to genetic variations that influence both glucose homeostasis and atherosclerotic lesion growth. Mouse strains C57BL/6J (B6) and BALB/cJ (BALB) exhibit distinct differences in fasting plasma glucose and atherosclerotic lesion size when deficient in apolipoprotein E (Apoe−/− . Quantitative trait locus (QTL) analysis was performed to determine genetic factors influencing the two phenotypes. Methods and Results 266 female F2 mice were generated from an intercross between B6.Apoe−/− and BALB.Apoe−/− mice and fed a Western diet for 12 weeks. Atherosclerotic lesions in the aortic root, fasting plasma glucose, and body weight were measured. 130 microsatellite markers across the entire genome were genotyped. Four significant QTLs, Ath1 on chromosome (Chr) 1, Ath41 on Chr2, Ath42 on Chr5, and Ath29 on Chr9, and one suggestive QTL on Chr4, were identified for atherosclerotic lesion size. Four significant QTLs, Bglu3 and Bglu12 on Chr1, Bglu13 on Chr5, Bglu15 on Chr12, and two suggestive QTLs on Chr9 and Chr15 were identified for fasting glucose levels on the chow diet. Two significant QTLs, Bglu3 and Bglu13, and one suggestive locus on Chr8 were identified for fasting glucose on the Western diet. One significant locus on Chr1 and two suggestive loci on Chr9 and Chr19 were identified for body weight. Ath1 and Ath42 coincided with Bglu3 and Bglu13, respectively, in the confidence interval. Conclusions We have identified novel QTLs that have major influences on atherosclerotic lesion size and glucose homeostasis. The colocalization of QTLs for atherosclerosis and diabetes suggests possible genetic connections between the two diseases.

Quantitative Trait Loci Affecting Atherosclerosis at the Aortic Root Identified in an Intercross between DBA2J and 129S6 Apolipoprotein E-Null Mice

“…At this locus DBA and 129 show additive effects. This QTL also appears to be distinct from any of QTL previously mapped on mouse Chr 2: Athla1 [18], Ath28 [6], Ath39 [19] and Ath41 [8]. We name this novel QTL locus Ath45 .…”

“…By utilizing the strain-specific variations in atherosclerosis susceptibility, quantitative trait locus (QTL) analyses on different sets of intercross have identified more than 40 chromosomal loci that affect atherosclerotic plaque sizes [3], [5], [6], [7], [8]. Genetic studies in mice primarily focus on the very early stages of atherosclerosis, such as plaque initiation and growth at the aortic root, which complement GWAS where loci are primarily associated with advanced atherosclerosis or clinical vascular events.…”

Genetic analysis of atherosclerosis identifies a major susceptibility locus in the major histocompatibility complex of mice

“…The LOD score plots for chromosome 5 revealed two distinct peaks, suggesting the existence of two QTLs for atherosclerosis. The distal QTL was overlapping with Ath42 mapped in a B6 × BALB Apoe –/– intercross [19]. The proximal QTL replicated a suggestive QTL mapped in a B6 × C3H Apoe –/– intercross [20] and was named Ath50 .…”

“…2 and 3C). The distal QTL replicated Ath42, mapped in a B6- Apoe –/– × BALB- Apoe –/– intercross [19]. The proximal QTL replicated a suggestive one mapped in a B6- Apoe –/– × C3H- Apoe –/– intercross [20] and was named Ath50 .…”

New quantitative trait loci for carotid atherosclerosis identified in an intercross derived from apolipoprotein E-deficient mouse strains

“…Apoe −/− mice at the N10 generation were generated in our laboratory. The creation of a female F 2 population from the two Apoe −/− mouse strains was as reported (59). Mice were started on a Western diet containing 21% fat, 34.1% sucrose, 0.15% cholesterol, and 19.5% casein (Harlan Laboratories, TD 88137) at 6 wk of age and maintained on the diet for 12 wk.…”