Linkage to peroxisome proliferator-activated receptor-γ in SAMP1/YitFc mice and in human Crohn's disease

Kazuhiko Sugawara, Timothy S. Olson, Christopher A. Moskaluk, Brian K. Stevens, Sharon Hoang, Kosuke Kozaiwa, Fabio Cominelli, Klaus F. Ley, Marcia McDuffie

Research output: Contribution to journalArticlepeer-review

42 Scopus citations


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 × 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 γ (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 Pparγ expression in the parental mouse strains are found specifically in the crypts of the small intestine, and treatment of ileitis-prone mice with a Pparγ 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 PPARγ activity in the crypts of the small intestine.

Original languageEnglish (US)
Pages (from-to)351-360
Number of pages10
Issue number2
StatePublished - Feb 2005
Externally publishedYes

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology


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