Untangling HDL quantitative trait loci on mouse chromosome 5 and identifying Scarb1 and Acads as the underlying genes

Two high-density lipoprotein cholesterol quantitative trait loci (QTL), Hdlq1 at 125 Mb and Hdlq8 at 113 Mb, were previously identified on mouse distal chromosome 5. Our objective was to identify the underlying genes. We first used bioinformatics to narrow the Hdlq1 locus to 56 genes. The most likely candidate, Scarb1 (scavenger receptor B1), was supported by gene expression data consistent with knockout and transgenic mouse models. Then we confirmed Hdlq8 as an independent QTL by detecting it in an intercross between NZB and NZW (LOD = 12.7), two mouse strains that have identical genotypes for Scarb1. Haplotyping narrowed this QTL to 9 genes; the most likely candidate was Acads (acyl-coenzymeA dehydrogenase, short chain). Sequencing showed that Acads had an amino acid polymorphism, Gly94Asp, in a conserved region; Western blotting showed that protein levels were significantly different between parental strains. A previously known spontaneous deletion causes loss of ACADS activity in BALB/cBy mice. We showed that HDL levels were significantly elevated in BALB/cBy compared with BALB/c mice and that this HDL difference cosegregated with the Acads mutation. We confirmed that Hdlq1 and Hdlq8 are independent QTL on mouse chromosome 5 and demonstrated that Scarb1 and Acads are the underlying genes.