Journal
GASTROENTEROLOGY
Volume 128, Issue 2, Pages 351-360Publisher
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2004.11.001
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- NIDDK NIH HHS [P01 DK57880] Funding Source: Medline
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Background & Aims: 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.
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