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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1928.)
© 2004 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Hyplip2, a New Gene for Combined Hyperlipidemia and Increased Atherosclerosis

Xuping Wang; Peter Gargalovic; Jack Wong; Jennifer L. Gu; Xiaohui Wu; Hongxiu Qi; Pingzi Wen; Li Xi; Bing Tan; Rocky Gogliotti; Lawrence W. Castellani; Aurobindo Chatterjee; Aldons J. Lusis

From the Departments of Medicine, Microbiology, Immunology, and Molecular Genetics, and Human Genetics (X.Wang, P.G., J.W., X.Wu, H.Q., P.W., L.W.C., A.J.L.), University of California, Los Angeles; the Division of Biology (J.L.G.), California Institute of Technology, Pasadena; and the Department of Cardiovascular Molecular Sciences and Technologies (L.X., B.T., R.G., A.C.), Pfizer Global Research & Development, Ann Arbor, Mich.

Correspondence to Aldons J. Lusis, Department of Medicine/Division of Cardiology, 47-123 CHS, UCLA, Los Angeles, CA 90095-1679. E-mail jlusis{at}mednet.ucla.edu

Objective— We previously reported the mapping of a quantitative trait locus (QTL) on chromosome 15 contributing to hyperlipidemia in a cross between inbred strains MRL/MpJ (MRL) and BALB/cJ (BALB). Using marker-assisted breeding, we constructed a congenic strain in which chromosome 15 interval from MRL is placed on the genetic background of BALB. The congenic allowed us to confirm the QTL result and to further characterize the properties and location of the underlying gene.

Methods and Results— On chow and high-fat (atherogenic) diets, the congenic mice exhibited higher levels of plasma triglycerides and cholesterol than BALB mice. In response to the atherogenic diet, the congenic mice but not BALB mice exhibited a dramatic 30-fold increase in atherogenic lesions accompanied by 2-fold decrease in high-density lipoprotein cholesterol levels. With respect to atherosclerotic lesions and some lipid parameters, this chromosome 15 gene, designated Hyplip2, exhibited dominant inheritance. Expression array analyses suggested that Hyplip2 may influence inflammatory and bile acid synthesis pathways. Finally, we demonstrated the usefulness of subcongenic strains to narrow the locus (50 Mbp) with the goal of positionally cloning Hyplip2.

Conclusions— Our data demonstrate that the Hyplip2 gene significantly contributes to combined hyperlipidemia and increased atherosclerosis in mice.

We have investigated the vasorelaxant properties of CRP using commercial preparations of CRP, CRP purified from ascites, and our in-house recombinant CRP. We conclude that CRP has no vasorelaxant properties, and previous studies reporting such responses are artifacts caused by sodium azide present in commercial preparations of CRP.

Key Words: hyperlipidemia • atherosclerosis • QTL • chromosome 15 • FCHL

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