| First Author | Sugawara K | Year | 2005 |
| Journal | Gastroenterology | Volume | 128 |
| Issue | 2 | Pages | 351-60 |
| PubMed ID | 15685547 | Mgi Jnum | J:105411 |
| Mgi Id | MGI:3615050 | Doi | 10.1053/j.gastro.2004.11.001 |
| Citation | Sugawara K, et al. (2005) Linkage to peroxisome proliferator-activated receptor-gamma in SAMP1/YitFc mice and in human Crohn's disease. Gastroenterology 128(2):351-60 |
| abstractText | BACKGROUND AND 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. |
