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Originally published In Press as doi:10.1194/jlr.M600176-JLR200 on June 8, 2006

Papers In Press, published online ahead of print September 1, 2006
J. Lipid Res., doi:10.1194/jlr.M600176-JLR200
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Journal of Lipid Research, Vol. 47, 2020-2027, September 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Two loci on chromosome 9 control bile acid composition: evidence that a strong candidate gene, Cyp8b1, is not the culpritboxs

Ephraim Sehayek1,*, Lee R. Hagey{dagger}, Yee-Yan Fung*, Elizabeth M. Duncan*, Hannah J. Yu*, Gösta Eggertsen§, Ingemar Björkhem§, Alan F. Hofmann{dagger} and Jan L. Breslow*

* Laboratory of Biochemical Genetics and Metabolism, The Rockefeller University, New York, NY
{dagger} Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, CA
§ Division of Clinical Chemistry, Karolinska Institute, Huddinge, Sweden

boxs The online version of this article (available at http://www.jlr.org) contains an additional two tables.

Published, JLR Papers in Press, June 8, 2006.

1 To whom correspondence should be addressed. e-mail: sehayee{at}rockefeller.edu

An intercross between C57BL/6J and CASA/Rk mice was used to study the genetics of biliary bile acid composition. In parental strains, male C57BL/6J mice had significantly higher cholic acid (CA; 14%) and lower ß-muricholic acid (ßMC; 27%) than CASA/Rk mice, whereas females did not differ. However, quantitative trait locus analysis of F2 mice revealed no significant chromosome 9 loci in males but loci in females on chromosome 9 for percentage CA (%CA) at 72 centimorgan (cM) [logarithm of the odds (LOD) 5.89] and %ßMC at 54 cM (LOD 4.09). Chromosome 9 congenic and subcongenic strains representing CASA/Rk intervals 38–73 cM (9KK) and 68–73 cM (9DKK) on the C57BL/6J background were made. In 9KK and 9DKK males, %CA was increased and %ßMC was unchanged, whereas in 9KK but not 9DKK females, %CA was increased and %ßMC was decreased. Sterol 12{alpha}-hydroxylase (Cyp8b1) channels bile acid precursors into CA and maps at chromosome 9 (73 cM). However, there was no significant difference in Cyp8b1 mRNA or enzymatic activity between parental mice, parental-congenic-subcongenic mice, or high-low biliary %CA F2 mice. In summary, two chromosome 9 loci control sexually dimorphic effects on biliary bile acid composition: a distal (68–73 cM) major determinant in males, and a more proximal (38–68 cM) major determinant in females. In this intercross, Cyp8b1, a strong candidate, does not appear to be responsible.

Supplementary key words chenodeoxycholic acid • sterol 12{alpha}-hydroxylase • cholic acid

Abbreviations: CA, cholic acid; CDCA, chenodeoxycholic acid; cM, centimorgan; CYP8B1, sterol 12{alpha}-hydroxylase; LOD, logarithm of the odds; ßMC, ß-muricholic acid; QTL, quantitative trait locus


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