Abstract 14107: Systems Genetics Analysis of Atherosclerosis Using a Hybrid Mouse Diversity Panel
Atherosclerosis is a multifactorial complex disease, making it unlikely that a single gene mutation will determine a significant portion of the observed phenotype. Rather, gene sets which act concordantly likely contribute to the disease. We developed an association analysis approach corrected for population structure to determine loci associated with atherosclerosis and performed a systems genetics approach to identify gene enrichment of relevant pathways. A panel of commercially available and fully genotyped mice, comprised of 21 common inbred and 57 recombinant inbred strains were crossed with dyslipidemic C57BL/6J mice expressing the apolipoprotein E Leiden and cholesteryl ester transfer protein human transgenes. This hybrid mouse diversity panel allows identification of common genetic variants contributing to atherosclerosis. The common inbred strains provide high mapping resolution whereas the recombinant inbred strains provide high mapping power. 544 F1 female mice were fed a Western diet for 16 weeks following which aortic root atherosclerotic lesions were stained with Oil-Red-O. A subset of 233 F1 female mice underwent transcriptome analysis of the thoracic aortas with Affymetrix microarray chips.
A wide range of atherosclerotic burden was observed between strains, which was largely independent from cholesterol levels (r2=0.14). No single locus reached genome-wide significance, however the peak SNP association for atherosclerosis burden occurred in a linkage disequilibrium block spanning from 47.99-48.88 Mb on chromosome 9. Candidate genes in that locus include nicotinamide N-methyltransferase which is involved in the production of homocysteine, a molecule previously implicated in atherosclerosis.
To understand the involvement of naturally occurring variation in gene expression in response to atherosclerosis, we developed co-expression networks analyzing aortic transcripts associated with lesion size. We identified 27 modules of which 10 were significantly correlated with lesion size. The most correlated module expressed 46 genes enriched for pathways involved in lipid metabolism (annexin 7, palmitoyl-protein thioesterase 1), extracellular matrix production (lysil oxidase) and coagulation (annexin 2).
- © 2013 by American Heart Association, Inc.