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Original Articles

Quantitative Trait Locus Analysis of Neointimal Formation in an Intercross Between C57BL/6 and C3H/HeJ Apolipoprotein E–Deficient Mice

Zuobiao Yuan, MD, PhD; Hong Pei, MD; Drew J. Roberts, BS; Zhimin Zhang, MD; Jessica S. Rowlan, BS; Alan H. Matsumoto, MD and Weibin Shi, MD, PhD

From the Departments of Radiology and of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Va.

Correspondence to Weibin Shi, MD, PhD, University of Virginia, Box 801339, Snyder 266, 480 Ray Hunt Dr, Charlottesville, VA 22908. E-mail ws4v{at}virginia.edu

Received May 15, 2008; accepted April 16, 2009.

Background— Inbred mouse strains C57BL/6J (B6) and C3H/HeJ (C3H) exhibit marked differences in neointimal formation after arterial injury when deficient in apolipoprotein E (apoE^–/–) and fed a Western diet. Quantitative trait locus analysis was performed on an intercross between B6.apoE^–/– and C3H.apoE^–/– mice to determine genetic factors contributing to the phenotype.

Methods and Results— Female B6.apoE^–/– mice were crossed with male C3H.apoE^–/– mice to generate F₁s, which were intercrossed to generate 204 male F₂ progeny. At 10 weeks of age, F₂s underwent endothelium denudation injury to the left common carotid artery. Mice were fed a Western diet for 1 week before and 4 weeks after injury and analyzed for neointimal lesion size, plasma lipid, and membrane cofactor protein (MCP)-1 levels. One significant quantitative trait locus, named Nih1 (61 cM; LOD score, 5.02), on chromosome 12 and a suggestive locus on chromosome 13 (35 cM; LOD score, 2.67) were identified to influence lesion size. One significant quantitative trait locus on distal chromosome 1 accounted for major variations in plasma non–high-density lipoprotein cholesterol and triglyceride levels. Four suggestive quantitative trait locis on chromosomes 1, 2, and 3 were detected for circulating MCP-1 levels. No correlations were observed between neointimal lesion size and plasma lipid levels or between lesion size and plasma MCP-1 levels.

Conclusions— Neointimal formation is controlled by genetic factors independent of those affecting plasma lipid levels and circulating MCP-1 levels in the B6 and C3H mouse model.

Key Words: atherosclerosis • hypercholesterolemia • neointimal hyperplasia • quantitative trait locus • restenosis • mice

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