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(Circulation Research. 2007;101:e11.)
© 2007 American Heart Association, Inc.

UltraRapid Communication

Identification of Pathways for Atherosclerosis in Mice

Integration of Quantitative Trait Locus Analysis and Global Gene Expression Data

Susanna S. Wang, Eric E. Schadt, Hui Wang, Xuping Wang, Leslie Ingram-Drake, Weibin Shi, Thomas A. Drake, Aldons J. Lusis

From the Departments of Human Genetics (S.S.W., L.I.-D., A.J.L.), Statistics (H.W.), Medicine (X.W., W.S., A.J.L.), and Pathology and Laboratory Medicine (L.I.-D., T.A.D.), University of California at Los Angeles; and Rosetta Inpharmatics LLC/Merck (E.E.S.), Seattle, Wash. Present address for W.S.: Department of Radiology, University of Virginia, Charlottesville.

Correspondence to Aldons J. Lusis, Department of Medicine, 675 Charles E Young Dr South, 3730 MRL, University of California, Los Angeles, CA 90095-1679. E-mail jlusis{at}mednet.ucla.edu

We report a combined genetic and genomic analysis of atherosclerosis in a cross between the strains C3H/HeJ and C57BL/6J on a hyperlipidemic apolipoprotein E–null background. We incorporated sex and sex-by-genotype interactions into our model selection procedure to identify 10 quantitative trait loci for lesion size, revealing a level of complexity greater than previously thought. Of the known risk factors for atherosclerosis, plasma triglyceride levels and plasma glucose to insulin ratios were particularly strongly, but negatively, associated with lesion size. We performed expression array analysis for 23 574 transcripts of the livers and adipose tissues of all 334 F2 mice and identified more than 10 000 expression quantitative trait loci that either mapped to the gene encoding the transcript, implying cis regulation, or to a separate locus, implying trans-regulation. The gene expression data allowed us to identify candidate genes that mapped to the atherosclerosis quantitative trait loci and for which the expression was regulated in cis. Genes highly correlated with lesions were enriched in certain known pathways involved in lesion development, including cholesterol metabolism, mitochondrial oxidative phosphorylation, and inflammation. Thus, global gene expression in peripheral tissues can reflect the systemic perturbations that contribute to atherosclerosis.

Key Words: atherosclerosis • quantitative trait locus • C3H/HeJ • expression arrays • sex

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