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

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

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

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 tostudy the genetics of biliary bile acid composition. In parentalstrains, male C57BL/6J mice had significantly higher cholicacid (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 significantchromosome 9 loci in males but loci in females on chromosome9 for percentage CA (%CA) at 72 centimorgan (cM) [logarithmof the odds (LOD) 5.89] and %ßMC at 54 cM (LOD 4.09).Chromosome 9 congenic and subcongenic strains representing CASA/Rkintervals 38–73 cM (9KK) and 68–73 cM (9DKK) onthe C57BL/6J background were made. In 9KK and 9DKK males, %CAwas increased and %ßMC was unchanged, whereas in 9KKbut not 9DKK females, %CA was increased and %ßMC wasdecreased. Sterol 12 ${alpha}$ -hydroxylase (Cyp8b1) channels bile acidprecursors into CA and maps at chromosome 9 (73 cM). However,there was no significant difference in Cyp8b1 mRNA or enzymaticactivity between parental mice, parental-congenic-subcongenicmice, or high-low biliary %CA F2 mice. In summary, two chromosome9 loci control sexually dimorphic effects on biliary bile acidcomposition: a distal (68–73 cM) major determinant inmales, and a more proximal (38–68 cM) major determinantin 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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