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

Henning Wittenburg,Malcolm A Lyons,Renhua Li,Ulrike Kurtz,Xiaosong Wang,Joachim Moässner,Gary A Churchill,Martin C Carey,Beverly Paigen

doi:10.1194/jlr.m500544-jlr200

Henning Wittenburg, Malcolm A Lyons + Show 7 more

Open Access

https://doi.org/10.1194/jlr.m500544-jlr200

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Abstract

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.

Highlights

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
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

Summary

Introduction

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. The analysis of combined data sets identified a QTL for HDL cholesterol on Chr 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. A number of genomewide linkage studies localized several genomic regions associated with variation in HDL and LDL cholesterol levels [6] This approach has not yet led to the identification of an underlying gene with different alleles influencing lipoprotein levels in humans.

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