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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:117.)
© 2003 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

In Silico Quantitative Trait Locus Map for Atherosclerosis Susceptibility in Apolipoprotein E–Deficient Mice

Jonathan D. Smith; Daylon James; Hayes M. Dansky; Knut M. Wittkowski; Karen J. Moore; Jan L. Breslow

From The Rockefeller University, New York, NY, and Millennium Pharmaceuticals, Inc (K.J.M.), Cambridge, Mass.

Correspondence to Jonathan D. Smith, The Cleveland Clinic Foundation, Department of Cell Biology, NC10, 9500 Euclid Ave, Cleveland, OH 44195. E-mail smithj{at}lerner.ccf.org

Objective— Atherosclerosis susceptibility is a genetic trait that varies between mouse strains. The goal of this study was to use a public mouse single nucleotide polymorphism (SNP) database to define the genetic loci that are associated with this trait, without the need to perform strain intercrosses that are normally required to obtain these loci.

Methods and Results— Apolipoprotein E (apoE)–deficient mice on 6 inbred genetic backgrounds were compared for atherosclerosis lesion size in the aortic root in 2 independent studies. After normalization to the C57BL/6 strain that was used in both studies, lesion areas were found in the following rank order: DBA/2J>C57BL/6>129/SV-ter>AKR/JBALB/cByJC3H/HeJ. The log lesion difference in phenotypes between each of the 15 heterologous strain pairs was determined. A mouse SNP database was then used to calculate the genetic differences between the 15 strain pairs in partially overlapping 30-cM bins across the mouse genome. Correlation analyses were preformed to analyze the genetic and phenotypic differences among the strain pairs for each genetic region. The genetic regions with the highest correlations define the in silico quantitative trait loci (QTL) associated with the atherosclerosis phenotype. Five in silico atherosclerosis QTL were identified on chromosomes 1, 10, 14, 15, and 18. The loci on chromosomes 1, 10, 14, and 18 overlap with suggestive atherosclerosis QTL identified through analyses of an F₂ cohort derived from apoE-deficient mice on the C57BL/6 and FVB/N strains.

Conclusions— The 5 identified in silico QTL are candidates for further study to confirm the presence and identity of atherosclerosis susceptibility genes within these loci.

Key Words: mouse genetics • SNP • complex disease • quantiative trait loci • atherosclerosis

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