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Papers In Press, published online ahead of print August 1, 2006
J. Lipid Res., doi:10.1194/jlr.M500544-JLR200

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Journal of Lipid Research, Vol. 47, 1780-1790, August 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

QTL mapping for genetic determinants of lipoprotein cholesterol levels in combined crosses of inbred mouse strains^1,,

Henning Wittenburg^2,*,,, Malcolm A. Lyons^3,*, Renhua Li^*, Ulrike Kurtz, Xiaosong Wang^*, Joachim Mössner, Gary A. Churchill^*, Martin C. Carey and Beverly Paigen^*

^* The Jackson Laboratory, Bar Harbor, ME
Brigham and Women's Hospital and Harvard Medical School, Boston, MA
Department of Medicine II, University of Leipzig, Leipzig, Germany

¹ This paper was presented in part at the annual meeting of the American Gastroenterology Association, 2004, in New Orleans, and published as an abstract (Gastroenterology 2004; 126: A748). Data from the current study were used in part to exemplify novel statistical means to improve QTL mapping strategies in inbred mice and published in a statistical methods paper (Genetics 2005; 169: 1699–1709).

The online version of this article (available at http://www.jlr.org) contains an additional three tables and two figures.

Published, JLR Papers in Press, May 9, 2006.

³ Present address of M. A. Lyons: Centre for Medical Research, University of Western Australia, and Western Australian Institute for Medical Research, Perth WA, Australia.

² To whom correspondence should be addressed. e-mail: henning.wittenburg{at}medizin.uni-leipzig.de

To identify additional loci that influence lipoprotein cholesterol levels, we performed quantitative trait locus (QTL) mapping in offspring of PERA/EiJxI/LnJ and PERA/EiJxDBA/2J intercrosses and in a combined data set from both crosses after 8 weeks of consumption of a high fat-diet. Most QTLs identified were concordant with homologous chromosomal regions that were associated with lipoprotein levels in human studies. We detected significant new loci for HDL cholesterol levels on chromosome (Chr) 5 (Hdlq34) and for non-HDL cholesterol levels on Chrs 15 (Nhdlq9) and 16 (Nhdlq10). In addition, the analysis of combined data sets identified a QTL for HDL cholesterol on Chr 17 that was shared between both crosses; lower HDL cholesterol levels were conferred by strain PERA. This QTL colocalized with a shared QTL for cholesterol gallstone formation detected in the same crosses. Haplotype analysis narrowed this QTL, and sequencing of the candidate genes Abcg5 and Abcg8 confirmed shared alleles in strains I/LnJ and DBA/2J that differed from the alleles in strain PERA/EiJ. In conclusion, our analysis furthers the knowledge of genetic determinants of lipoprotein cholesterol levels in inbred mice and substantiates the hypothesis that polymorphisms of Abcg5/Abcg8 contribute to individual variation in both plasma HDL cholesterol levels and susceptibility to cholesterol gallstone formation.

Supplementary key words quantitative trait locus • high density lipoprotein • low density lipoprotein • Abca1 • Abcg5 • Abcg8

Abbreviations: Chr, chromosome; cM, centimorgan; D, inbred mouse strain DBA/2J; I, inbred mouse strain I/LnJ; IBS, identical by state; LOD, logarithm of the odds; P, inbred mouse strain PERA/EiJ; QTL, quantitative trait locus; SNP, single nucleotide polymorphism; SSLP, simple sequence length polymorphism

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