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

• Published in: Journal of lipid research 2006-08, Vol.47 (8), p.1780-1790
• Main Authors: Wittenburg, Henning, Lyons, Malcolm A., Li, Renhua, Kurtz, Ulrike, Wang, Xiaosong, Moässner, Joachim, Churchill, Gary A., Carey, Martin C., Paigen, Beverly
• Format: Article
• Language: English
• Subjects: Abca1; Abcg5; Abcg8; Alleles; Animals; Cholesterol - blood; Cholesterol - metabolism; Cholesterol, HDL - blood; Cholesterol, HDL - metabolism; Chromosome Mapping - methods; Chromosomes, Mammalian - genetics; Crosses, Genetic; Female; Genetic Linkage - genetics; Genotype; Haplotypes - genetics; high density lipoprotein; Lipoproteins - blood; Lipoproteins - metabolism; low density lipoprotein; Male; Mice; Mice, Inbred DBA; Mice, Inbred Strains; Phenotype; Quantitative Trait Loci - genetics; quantitative trait locus; Regression Analysis; Sequence Analysis, DNA
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M500544-JLR200

To identify additional loci that influence lipoprotein cholesterol levels, we performed quantitative trait locus (QTL) mapping in offspring of PERA/EiJ×I/LnJ and PERA/EiJ×DBA/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.