Submitted on December 16, 2005
Revised on April 21, 2006
Accepted on May 9, 2006
QTL mapping for genetic determinants of lipoprotein cholesterol levels in independent and combined crosses of inbred mouse strains
Henning Wittenburg, Malcolm A. Lyons, Renhua Li, Ulrike Kurtz, Xiaosong Wang, Joachim Mössner, Gary A. Churchill, Martin C. Carey, and Beverly Paigen
Department of Medicine II, University of Leipzig, Leipzig 04103
Corresponding Author: henning.wittenburg{at}medizin.uni-leipzig.de
To identify additional loci that influence lipoprotein cholesterol levels, we performed QTL mapping in offspring of PERA/EiJ x I/LnJ and PERA/EiJ x DBA/2J intercrosses and in a combined dataset from both crosses after 8 weeks’ 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 5 (Hdlq34) and for non-HDL cholesterol levels on chromosomes 15 (Nhdlq9) and 16 (Nhdlq10). In addition, the analysis of combined datasets identified a QTL for HDL cholesterol on chromosome 17 that was shared between both crosses; lower HDL cholesterol levels were conferred by strain PERA. This QTL co-localized 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/Ln and DBA/2 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.
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