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

Background-Diabetic patients have an increased risk of developing atherosclerosis and related complications compared with nondiabetic 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 2 phenotypes. Methods and Results-Female F-2 mice (n=266) 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 1 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 2 suggestive QTLs on Chr9 and Chr15 were identified for fasting glucose levels on the chow diet. Two significant QTLs, Bglu3 and Bglu13, and 1 suggestive locus on Chr8 were identified for fasting glucose on the Western diet. One significant locus on Chr1 and 2 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 2 diseases. (Circ Cardiovasc Genet. 2012;5:190-201.)