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Journal of Lipid Research, Vol. 44, 953-967, May 2003
Copyright © 2003 by Lipid Research, Inc.

Quantitative trait loci that determine lipoprotein cholesterol levels in DBA/2J and CAST/Ei inbred mice^1,,2

Malcolm A. Lyons^*, Henning Wittenburg^*,, Renhua Li^*, Kenneth A. Walsh^*, Gary A. Churchill^*, Martin C. Carey and Beverly Paigen^3,*

^* The Jackson Laboratory, Bar Harbor, ME 04609
Department of Medicine, Harvard Medical School, Division of Gastroenterology, Brigham and Women's Hospital and Harvard Digestive Diseases Center, Boston, MA 02115

³ To whom correspondence should be addressed. e-mail: bjp{at}jax.org

To investigate genetic contributions to individual variations of lipoprotein cholesterol concentrations, we performed quantitative trait locus/loci (QTL) analyses of an intercross of CAST/Ei and DBA/2J inbred mouse strains after feeding a high-cholesterol cholic acid diet for 10 weeks. In total, we identified four QTL for HDL cholesterol. Three of these were novel and were named Hdlq10 [20 centimorgans (cM), chromosome 4], Hdlq11 (48 cM, chromosome 6), and Hdlq12 (68 cM, chromosome 6). The fourth QTL, Hdl1 (48 cM, chromosome 2), confirmed a locus discovered previously using a breeding cross that employed different inbred mouse strains. In addition, we identified one novel QTL for total and non-HDL cholesterol (8 cM, chromosome 9) that we named Chol6. Hdlq10, colocalized with a mutagenesis-induced point mutation (Lch), also affecting HDL.

We provide molecular evidence for Abca1 as the gene underlying Hdlq10 and Ldlr as the gene underlying Chol6 that, coupled with evidence generated by other researchers using knockout and transgenic models, causes us to postulate that polymorphisms of these genes, different from the mutations leading to Tangier's disease and familial hypercholesterolemia, respectively, are likely primary genetic determinants of quantitative variation of lipoprotein levels in mice and, by orthology, in the human population.

Abbreviations: CAST, CAST/Ei; D2, DBA/2J; LOD, logarithm of the odds ratio; QTL, quantitative trait locus/loci; SNP, single nucleotide polymorphism; SSLP, simple sequence-length polymorphism

Supplementary key words Castaneus • mouse • nuclear receptor • high density lipoprotein • low density lipoprotein • intercross • Abca1 • Ldlr • Pparg

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