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To identify additional loci that influence lipoprotein cholesterol levels, we performed quantitative trait locus (QTL) mapping in offspring of PERA/EiJ3I/LnJ and PERA/EiJ3DBA/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. Increased serum LDL cholesterol and decreased HDL cholesterol levels are established risk factors for cardiovascular disease (1). In addition, data from large epidemiological studies support an independent association of low HDL cholesterol levels and gallstone prevalence rates (2).With the exception of rare monogenic disorders of LDL and HDL cholesterol metabolism (3, 4), individual lipoprotein cholesterol levels are determined by a combination of genetic and environmental factors, such as diet and body weight (5). Knowledge of the genes involved would lead to a better understanding of the physiology and pathophysiology of lipoprotein metabolism, and such insight will possibly enable targeted interventions to reduce the risk of cardiovascular disease and gallstone formation.In different human populations, a number of genomewide linkage studies localized several genomic regions associated with variation in HDL and LDL cholesterol levels (6). However, this approach has not yet led to the identification of an underlying gene with different alleles influencing lipoprotein levels in humans. Because of the challenges frequently encountered in the identification of genes that modify a quantitative phenotype in humans, we and others propose to ascertain the genetic determinants of lipoprotein levels in mice and to translate these results into directed studies in human populations. To localize genomic regions harboring genes that carry polymorphisms and account for variation of lipoprotein levels in offspring of inbred mouse crosses, quantitative trait locus (QTL) mapping is used (6). To date, using QTL map- Abbreviations: Chr, chromosome; ...

To examine further the genetic determinants of cholesterol gallstone susceptibility in inbred mice, we performed quantitative trait locus (QTL) analysis of an intercross of gallstone-susceptible PERA/EiJ and gallstone-resistant DBA/2J inbred mice. Three hundred twenty-four F2 offspring were phenotyped for cholelithiasis during consumption of a lithogenic diet and genotyped using microsatellite markers. Linkage analysis was performed by interval mapping. In addition, we analyzed the combined datasets from this cross and from an independent cross of strain PERA and gallstone-resistant I/Ln mice. QTL mapping detected one significant new gallstone susceptibility (Lith) locus on Chromosome 13 (Lith15). A second significant QTL on Chr 6 (Lith16) confirmed a previous QTL. Furthermore, suggestive QTLs confirmed Lith loci from previous crosses on Chromosomes 1, 2, 5, 16 and X. QTL analysis of the dataset derived from the combined crosses increased the detection power and narrowed confidence intervals of Lith loci on Chromosomes 2, 6, 13, and 16. Moreover, the analysis of combined datasets revealed a shared QTL between both crosses on Chromosome 17 (Lith9). Significantly higher mRNA expression of Abcg5 and Abcg8 in strain PERA compared with strains I/Ln and DBA/2 further substantiated that the PERA allele of Abcg5/Abcg8 was responsible for lithogenicity underlying Lith9.

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