Linkage to peroxisome proliferator-activated receptor-gamma in SAMP1/YitFc mice and in human Crohn's disease.
OBJECTIVE
Genetic predisposition is implicated strongly in Crohn's disease. Disease-associated mutations in NOD2/CARD15 , the best-studied susceptibility gene in this disorder, explain only a small fraction of the heritability. The SAMP1/YitFc (SAMP1/Fc) mouse strain expresses many features of Crohn's disease in humans. We bred SAMP1/Fc to disease-resistant AKR mice to identify additional susceptibility genes that may play a role in human disease.


METHODS
Linkage disequilibrium mapping was performed in an (AKR x SAMP1/Fc) backcross to SAMP1/Fc, followed by sequencing, expression analysis using reverse transcription polymerase chain reaction (PCR) and immunohistochemistry, and functional testing in vivo of the regional candidate gene encoding the peroxisome proliferator-activated receptor gamma ( Pparg ). A cohort-based association study was performed in humans.


RESULTS
We show that ileitis is blocked in SAMP1/Fc mice by inheritance of AKR alleles on chromosome 6 in the region of Pparg . Major differences in Ppargamma expression in the parental mouse strains are found specifically in the crypts of the small intestine, and treatment of ileitis-prone mice with a Ppargamma agonist decreased disease severity in susceptible mice expressing low levels of the protein. Rare alleles of PPARG are associated significantly with Crohn's disease in humans.


CONCLUSIONS
We have identified Pparg as a susceptibility gene in both the SAMP/Yit mouse and in human Crohn's disease. Similarities between Crohn's disease and the SAMP1/Fc model suggest that the effect of this gene in humans may be mediated through regulation of PPARgamma activity in the crypts of the small intestine.
Sugawara
Kazuhiko
K
Department of Internal Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA.
Olson
Timothy S
TS
Moskaluk
Christopher A
CA
Stevens
Brian K
BK
Hoang
Sharon
S
Kozaiwa
Kosuke
K
Cominelli
Fabio
F
Ley
Klaus F
KF
McDuffie
Marcia
M
D000328:Adult; D000818:Animals; D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D015331:Cohort Studies; D003424:Crohn Disease / Q000235:genetics*; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics*; D051379:Mice; D008806:Mice, Inbred AKR; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D047495:PPAR gamma / Q000235:genetics*; D016133:Polymerase Chain Reaction; D040641:Quantitative Trait Loci
D007141:Immunoglobulin Fc Fragments; D047495:PPAR gamma