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Papers In Press, published online ahead of print September 1, 2003
J. Lipid Res., doi:10.1194/jlr.M300149-JLR200

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Journal of Lipid Research, Vol. 44, 1763-1771, September 2003
Copyright © 2003 by American Society for Biochemistry and Molecular Biology

Lith6

: a new QTL for cholesterol gallstones from an intercross of CAST/Ei and DBA/2J inbred mouse strains¹,^,2,^,

Malcolm A. Lyons^3,*, Henning Wittenburg^4,*,, Renhua Li^*, Kenneth A. Walsh^*, Monika R. Leonard, Ron Korstanje^*, Gary A. Churchill^*, Martin C. Carey and Beverly Paigen^5,*

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

⁵ To whom correspondence should be addressed. e-mail: bjp{at}jax.org

A complex genetic basis determines the individual predisposition to develop cholesterol gallstones in response to environmental factors. We employed quantitative trait locus/loci (QTL) analyses of an intercross between inbred strains CAST/Ei (susceptible) and DBA/2J (resistant) to determine the subset of gallstone susceptibility (Lith) genes these strains possess. Parental and first filial generation mice of both genders and male intercross offspring were evaluated for gallstone formation after feeding a lithogenic diet. Linkage analysis was performed using a form of multiple interval mapping. One significant QTL colocalized with Lith1 [chromosome (chr) 2, 50 cM], a locus identified previously. Significantly, new QTL were detected and named Lith10 (chr 6, 4 cM), Lith6 (chr 6, 54 cM), and Lith11 (chr 8, 58 cM).

Statistical and genetic analyses suggest that Lith6 comprises two QTL in close proximity. Our molecular and genetic data support the candidacy of peroxisome proliferator-activated receptor (Pparg) and Slc21a1, encoding Pparg, and the basolateral bile acid transporter SLC21A1 (Slc21a1/Oatp1), respectively, as genes underlying Lith6.

Abbreviations: Abcb11, bile salt export pump (Bsep); Apobec1, apolipoprotein B mRNA editing complex 1; CAST, CAST/Ei; Cav, caveolin; Cav2, caveolin 2; Cftr, cystic fibrosis transmembrane conductance regulator; ChMC, cholesterol monohydrate crystal; chr, chromosome; CI, confidence interval; CSI, cholesterol saturation index; Cyp7a1/CYP7A1, cholesterol 7-hydroxylase; D2, DBA/2J; F₁, first filial generation; F₂, second filial generation or intercross; Lith, lithogenic locus; LOD, logarithm of the odds ratio; Lrp2/LRP2, low density lipoprotein receptor-related protein 2; Nr1h3/NR1H3, nuclear oxysterol receptor, (Lxra/LXR); Pparg/PPAR, peroxisome proliferator-activated receptor ; QTL, quantitative trait locus/loci; Rxra, retinoid X receptor ; Slc21a/ SLC21A, solute carrier family 21A, common name Oatp/OATP, organic anion transporting polypeptide

Supplementary key words quantitative trait locus • Castaneus • Lith genes • cholelithiasis • Pparg • Slc21a1 mice

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