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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:2180.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Athsq1 Is an Atherosclerosis Modifier Locus With Dramatic Effects on Lesion Area and Prominent Accumulation of Versican

Sara Bretschger Seidelmann; Chaoling Kuo; Nick Pleskac; Jennifer Molina; Scott Sayers; Rong Li; Jing Zhou; Pamela Johnson; Kathleen Braun; Christina Chan; Daniel Teupser; Jan L. Breslow; Thomas N. Wight; Alan R. Tall; Carrie L. Welch

From the Division of Molecular Medicine, Department of Medicine (S.B.S., C.K., N.P., J.M., S.S., R.L., J.Z., A.R.T., C.L.W.) and the Institute of Human Nutrition (S.B.S., C.K., J.M., S.S.), Columbia University, New York; Hope Heart Program (P.J., K.B., C.C., T.N.W.), Benaroya Research Institute at Virginia Mason, Seattle, Wash; the Laboratory of Biochemical Genetics and Metabolism (D.T., J.L.B.), The Rockefeller University, New York. Current address for S.B.S.: College of Medicine, University of Cincinnati, Ohio. Current address for J.M.: MD Anderson Cancer Center, University of Texas, Houston. Current address for D.T.: Institute of Laboratory Medicine, Clinical Chemistry, and Molecular Diagnostics, University of Leipzig, Germany.

Correspondence to Carrie L. Welch, Department of Medicine, P&S 8-401, 630 W. 168th St, New York, NY 10032. E-mail cbw13{at}columbia.edu

Objective— Susceptibility to atherosclerosis is genetically complex, and modifier genes that do not operate via traditional risk factors are largely unknown. A mouse genetics approach can simplify the genetic analysis and provide tools for mechanistic studies.

Methods and Results— We previously identified atherosclerosis susceptibility QTL (Athsq1) on chromosome 4 acting independently of systemic risk factors. We now report confirmation of this locus in congenic strains carrying the MOLF-derived susceptibility allele in the C57BL/6J-Ldlr^–/– genetic background. Homozygous congenic mice exhibited up to 4.5-fold greater lesion area compared to noncongenic littermates (P<0.0001). Analysis of extracellular matrix composition revealed prominent accumulation of versican, a presumed proatherogenic matrix component abundant in human lesions but almost absent in the widely-used C57BL/6 murine atherosclerosis model. The results of a bone marrow transplantation experiment suggested that both accelerated lesion development and versican accumulation are mediated, at least in part, by macrophages. Interestingly, comparative mapping revealed that the Athsq1 congenic interval contains the mouse region homologous to a widely-replicated CHD locus on human chromosome 9p21.

Conclusion— These studies confirm the proatherogenic activity of a novel gene(s) in the MOLF-derived Athsq1 locus and provide in vivo evidence for a causative role of versican in lesion development.

Key Words: atherosclerosis • congenic strain • genetics • extracellular matrix • mapping

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