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Papers In Press, published online ahead of print January 1, 2009
J. Lipid Res., doi:10.1194/jlr.M800411-JLR200

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Journal of Lipid Research, Vol. 50, 116-125, January 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Genetic basis of HDL variation in 129/SvImJ and C57BL/6J mice: importance of testing candidate genes in targeted mutant mice^*,

Zhiguang Su^*, Xiaosong Wang, Shirng-Wern Tsaih^*, Aihong Zhang, Allison Cox^*, Susan Sheehan^* and Beverly Paigen^1,*

^* The Jackson Laboratory, Bar Harbor, ME 04609
Novartis Institutes for BioMedical Research, Cambridge, MA 02139

^* This work was funded by the US National Institutes of Health grants to BP (HL 81162, HL74086, and HL77796), the American Heart Association grant 0725905T to ZS and by the Novartis Institutes for Biomedical Research.

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of three tables.

Published, JLR Papers in Press, September 4, 2008.

¹ To whom correspondence should be addressed. e-mail: bev.paigen{at}jax.org

To evaluate the effect of genetic background on high-density lipoprotein cholesterol (HDL) levels in Soat1^–/– mice, we backcrossed sterol O-acyltransferase 1 (Soat1)^–/– mice, originally reported to have elevated HDL levels, to C57BL/6 mice and constructed a congenic strain with only a small region (3.3Mb) of 129 alleles, specifically excluding the nearby apolipoprotein A-II (Apoa2) gene from 129. HDL levels in these Soat1^–/– mice were no different from C57BL/6, indicating that the passenger gene Apoa2 caused the previously reported elevation of HDL in these Soat1^–/– mice. Because many knockouts are made in strain 129 and then subsequently backcrossed into C57BL/6, it is important to identify quantitative trait loci (QTL) that differ between 129 and C57BL/6 so that one can guard against effects ascribed to a knockout but really caused by a passenger gene from 129. To provide such data, we generated 528 F₂ progeny from an intercross of 129S1/SvImJ and C57BL/6 and measured HDL concentrations in F₂ animals first fed chow and then atherogenic diet. A genome wide scan using 508 single-nucleotide polymorphisms (SNPs) identified 19 QTL, 2 of which were male specific and 2 were female specific. Using comparative genomics and haplotype analysis, we narrowed QTL on chromosomes 3, 5, 8, 17, and 18 to 0.5, 6.3, 2.6, 1.1, and 0.6 Mb, respectively. These data will serve as a reference for any effort to test the impact of candidate genes on HDL using a knockout strategy.

Supplementary key words Soat1 • QTL • comparative genomics • haplotype

Abbreviations: Apoa2, apolipoprotein A-II; HDL, high-density lipoprotein cholesterol; IBD, identical by descent; KO, knockout; LOD, logarithm of the odds ratio; QTL, quantitative trait loci; Soat1, sterol O-acyltransferase 1; SNP, single-nucleotide polymorphism

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