Identification of a quantitative trait locus for ileitis in a spontaneous mouse model of Crohn's disease: SAMP1/YitFc.
OBJECTIVE
The SAMP1/Yit mouse strain develops spontaneous ileitis with histologic features of Crohn's disease. Disease expression in the SAMP1/YitFc subline (SAMP1/Fc) is partially inhibited by outcross to C57BL/6J (B6) mice, suggesting complex genetic control of disease susceptibility with both dominant and recessive determinants. We performed a genetic analysis of a (B6 x SAMP1/Fc)F(2) cross to localize the genes regulating intestinal inflammation in this model.


METHODS
A genome-wide scan was performed using a panel of microsatellite loci determined to be informative for this cross. Quantitative trait loci were identified with Map Manager QT using a serial regression approach. Positional candidate genes were selectively sequenced at the genomic level to identify potential susceptibility genes for functional screening.


RESULTS
A genome-wide scan of (B6 x SAMP1/Fc)F(2) mice identified a SAMP-derived quantitative trait loci with additive effects on chromosome 9 in a region likely to have been inherited from the AKR mouse strain. The candidate interval contains several genes of interest because of their potential role in either immune system function, intestinal epithelial function, or both. Suggestive evidence for additional loci was also observed on chromosomes 6 and X.


CONCLUSIONS
The SAMP1/Fc allele for a locus, designated Ibdq1, promotes inflammation-associated epithelial damage in these mice. Consistent with persistent mild ileitis in (B6 x SAMP1/Fc)F(1) mice, this locus appears to function in an additive fashion. Two genes in this interval, encoding the interleukin 10 receptor alpha chain and interleukin 18, are excellent candidates for Ibdq1.
Kozaiwa
Kosuke
K
Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
Sugawara
Kazuhiko
K
Smith
Michael F
MF
Carl
Virginia
V
Yamschikov
Vladimir
V
Belyea
Brian
B
McEwen
Sherri B
SB
Moskaluk
Christopher A
CA
Pizarro
Theresa T
TT
Cominelli
Fabio
F
McDuffie
Marcia
M
D000483:Alleles; D000818:Animals; D003424:Crohn Disease / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006183:H-2 Antigens / Q000235:genetics; D007079:Ileitis / Q000235:genetics*; D020382:Interleukin-18 / Q000235:genetics; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D008810:Mice, Inbred C57BL; D040641:Quantitative Trait Loci / Q000235:genetics*; D018123:Receptors, Interleukin / Q000235:genetics; D053701:Receptors, Interleukin-10; D014960:X Chromosome
D006183:H-2 Antigens; D020382:Interleukin-18; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10