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

Abstract

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.

• Authors: Kazuhiko Sugawara, Timothy S Olson, Christopher A Moskaluk, Brian K Stevens, Sharon Hoang, Kosuke Kozaiwa, Fabio Cominelli, Klaus F Ley, Marcia McDuffie
• Journal: Gastroenterology (Gastroenterology) Vol. 128 Issue 2 Pg. 351-60 (Feb 2005) ISSN: 0016-5085 [Print] United States
• PMID: 15685547 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Immunoglobulin Fc Fragments
• PPAR gamma

Topics

• Adult
• Animals
• Chromosome Mapping
• Chromosomes, Human, Pair 6 (genetics)
• Cohort Studies
• Crohn Disease (genetics)
• Crosses, Genetic
• Disease Models, Animal
• Genetic Predisposition to Disease (genetics)
• Humans
• Immunoglobulin Fc Fragments (genetics)
• Mice
• Mice, Inbred AKR
• Mice, Inbred C57BL
• Mice, Mutant Strains
• PPAR gamma (genetics)
• Polymerase Chain Reaction
• Quantitative Trait Loci