227 (CAST/Ei x 129S1/SvImJ)F2 male animals were screened for 100 SSLP markers to detect QTLs associated with cholesterol gallstone formation. Male and female animals of parental strain CAST/Ei exhibit 40% incidence of cholesterol gallstones after 8 weekson a lithogenic diet whereas male and female animals of parental strain 129S1/SvImJ are completely resistant. Interestingly, male animals of (CAST/Ei x 129S1/SvImJ)F1 hybrids are gallstone susceptible. Parental strain CAST/Ei also exhibits greater bile cholesterol content and greater phospholipid and cholesterol secretion compared to 129S1/SvImJ.
Significant and suggestive linkages were detected on mouse Chromosome 5 around 30 cM - 40 cM. Linkage to gallstone solids peaked at 30 cM (LOD=4 at D5Mit183) and is named Lith13. The QTL interval of Lith13 spans 10 cM - 45 cM. Linkage to gallbladder volume peaked at 30 cM with LOD=3.7 at D5Mit255 and is named Gbvq1. The QTL interval of Gbvq1 spans 20 cM - 50 cM. Suggestive linkage to gallstone weight peaked at 44 cM with LOD=3 at D5Mit201 and was not named. The CAST/Ei-derived allele confers increased gallbladder volume in a recessive manner at Gbvq1 while the 129S1/SvImJ-derived allele confers recessively-inherited susceptibility to gallstone formation at Lith13. Possible candidate genes for Lith13 are Ppargc1, Lrpap1, and Cckar. Lrpap1 shows higher expression in the 129S1/SvImJ parental strain but does not show differential expression in the F2 population. Ppargc1 also does not show differential expression between CAST/Ei and 129S1/SvImJ. A possible candidate gene for Gbvq1 is Cckar.
Significant linkage to gallstone score was detected at 101 cM on mouse Chromosome 2 with LOD=3.6 at D2Mit113. This locus coincides with a previously identified QTL showing suggestive linkage for mucin glycoprotein accumulation and also coincides with a locus for gallstone score from a different cross. This QTL was designated Lith12. The QTL interval of Lith12 spans 90 cM - 110 cM. CAST/Ei-derived alleles confer recessively-inherited susceptibility to gallstone formation at Lith12. Possible candidate genes for Lith12 are Pltp, Cebpb, and Hnf4. Cebpb showed increased expression in the CAST/Ei parental strain.
On mouse Chromosome 6 a significant QTL associated with aggregated cholesterol monocrystals (AchMC) mapped to 66 cM with LOD=5.2 at D6Mit14.
Curator Note: The authors refer to this QTL as the previously identified Lith6 QTL, citing logic at the time of publication that colocalized QTL were assumed to be identical. However, because Lith6 was originally mapped using a (CAST/Ei x DBA/2J)F2 cross (J:85813), we consider the current study a separate mapping experiment and have named the QTL Lith25.
The QTL interval of Lith25 spans 46 cM - 80 cM. CAST/Ei-derived alleles confer dominantly-inherited susceptibility to gallstone formation at Lith25. Possible candidate genes for Lith25 are Slco1a1 and Pparg. Pparg showed decreased expression in both the parental and F2 population. Slco1a1 showed increased expression in CAST/Ei but isunlinked to the genotype at Lith25.
A QTL reaching suggestive linkage for gallstone score mapped to 42 cM on mouse Chromosome 16 with LOD=2.3 at D16Mit65. However, this QTL confirmed a previously identified suggestive QTL and was designated Lith14. The QTL interval of Lith14 spans 20 cM - 70 cM. CAST/Ei-derived alleles confer additively-inherited susceptibility to gallstone formation at Lith14. A possible candidate gene for Lith14 is Nr1i2but differential expression of this gene was not observed betweenCAST/Ei and 129S1/SvImJ.
Suggestive linkages to gallstone score were also detected at 24 cM on mouse Chromosome 1 (LOD=2.3 at D1Mit21) and at 10 cM on mouse Chromosome 14 (LOD=2.6 at D14Mit98). The CAST/Ei-derived allele appears to confer dominantly-inherited susceptibility to gallstone formation at chromosome 1 and confers recessively-inherited susceptibility to gallstone formation at chromosome 14. These loci await confirmation and remain unnamed.