Atherosclerosis susceptibility in the collaborative cross

Authors: RINDY, ALEXA - University Of California, Davis; YAM, PHOEBE - University Of California, Davis; ALBRIGHT, JODY - University Of North Carolina; VERHAUGE, MELISSA - University Of North Carolina; Bennett, Brian

Submitted to: Arteriosclerosis Thrombosis and Vascular Biology
Publication Type: Abstract Only
Publication Acceptance Date: 2/20/2019
Publication Date: 3/12/2019
Citation: Rindy, A., Yam, P., Albright, J., Verhauge, M., Bennett, B.J. 2019. Atherosclerosis susceptibility in the collaborative cross. Arteriosclerosis Thrombosis and Vascular Biology. 38(1). https://doi.org/10.1161/atvb.38.suppl_1.643.
DOI: https://doi.org/10.1161/atvb.38.suppl_1.643

Interpretive Summary: Inbred mice exhibit strain-specific variation in susceptibility to atherosclerosis and dyslipidemia that renders them useful in dissecting the genetic and dietary architecture of these complex diseases. Traditional genetic mapping studies using inbred strains often identify large genomic regions, containing many genes, due to limited recombination and/or sample size. This hampers candidate gene identification and translation of these results into possible risk factors and therapeutic targets. An alternative approach is the use of multi-parental recombinant inbred strains for genetic mapping, such as the Collaborative Cross mouse panel, which can be more informative than traditional two-parent crosses and can aid in the identification of causal genes and dietary factors associated with disease. The current abstract describes our initial studies characterizing atherosclerosis susceptibility in the Collaborative Cross.

Technical Abstract: Objective—The Collaborative Cross (CC) is a large recombinant inbred mouse population, generated from elaborate intercrosses of C57BL6/J, A/J, NOD/ShiLtJ, NZO/HiLtJ, WSB/EiJ, CAST/EiJ, PWK/PhJ, and 129S1/SvImJ mouse strains, useful for complex trait mapping and systems genetics. The CC population has tremendous genetic diversity, containing approximately 45 million segregating single-nucleotide polymorphisms (SNPs). The purpose of this study was to characterize atherosclerosis susceptibility in the Collaborative Cross. Methods and Results—We obtained 5 females from 20 CC lines available at the University of North Carolina and placed them on a synthetic control (AIN-76) diet for 2 weeks. Following 2 weeks of diet, all mice were assessed for plasma cardio-metabolic risk factors. The mice were then randomly assigned to cages and placed on a synthetic high-fat, cholic acid (HFCA) diet that contained 20% fat, 1.25% cholesterol, and 0.5% cholic acid. Aortic root atherosclerosis and cardio-metabolic risk factors were quantitated following 16 weeks of HFCA diet. Atherosclerotic lesion size ranged from completely resistant (strains C004/TauUnc and CC037/TauUnc) to moderate lesion development in a majority of several strains. Notably all mice from strain CC063/Unc died prior to 20 weeks of age while strain CC028/GeniUnc was highly susceptible to lesion development with an average lesion size of 105,781 ' 17,370 um2. As expected, strain is a significant contributor to atherosclerosis susceptibility (one way Anova analysis, p<8.23x10-08). Similar effects were observed for circulating cholesterol with strains C004/TauUnc and CC037/TauUnc having relatively low circulating total cholesterol after HFCA feeding (187 and 198 mg/dl respectively) to > 500 mg/dl in strains CC006/UNC, CC011/Unc and CC036/Unc. Circulating cholesterol and atherosclerosis were significantly correlated (Spearman rho>0.30, p< 0.007). Conclusion—These results suggest that selective crosses between various CC strains should yield loci associated with atherosclerosis. High-resolution genome-wide association analysis for atherosclerosis may be feasible when more Collaborative Cross strains become available.