Faculty Collaboration Database

The functional -374T/A polymorphism of the receptor for advanced glycation end products may modulate Crohn's disease. Am J Physiol Gastrointest Liver Physiol 2011 May;300(5):G823-32

Date

02/12/2011

Pubmed ID

21311028

DOI

10.1152/ajpgi.00115.2010

Scopus ID

2-s2.0-79955568373 (requires institutional sign-in at Scopus site)   39 Citations

Abstract

The receptor for advanced glycation end products (RAGE) is involved in innate immune mechanisms. Polymorphisms of the RAGE gene have been described as a factor amplifying inflammation in susceptible patients, but the association with Crohn's disease (CD) is not known. The coding RAGE polymorphism G82S (rs2070600) and two promoter polymorphisms, -374T/A (rs1800624) and -429T/C (rs1800625), were studied in two samples from Germany and the United States consisting of 421 and 317 CD patients and 549 and 218 controls, respectively. To test the functional relevance, additional data on serum soluble RAGE (sRAGE), tissue RNA, and protein levels were collected and immunohistochemical stainings of bowel tissue of CD patients and healthy controls as well as models of experimental (dextran sodium sulfate-induced) colitis in RAGE knockout and wild-type mice were performed. The -374T/A RAGE promotor single nucleotide polymorphism (SNP) was negatively associated with CD (odds ratio = 0.708, 95% confidence interval = 0.535-0.938, P = 0.016) and with stenosis (OR = 0.627, P = 0.04) in the German sample. Transmission disequilibrium testing confirmed an undertransmission of the -374A allele. Serum sRAGE levels were higher in patients in complete remission of the -374AA/TA group (1,975 ± 299 pg/ml; -374TT group: 1,310 ± 153 pg/ml SE, P < 0.05) and showed a trend toward decreased levels in CD patients with active disease compared with CD patients in remission. Further in vitro and in vivo studies indicated that an increase of sRAGE ameliorates inflammation. The -429T/C and the G82S polymorphism were not associated with CD. The -374T/A RAGE polymorphism leading to facilitated RAGE gene transcription may to some degree protect from developing a stricturing subphenotype of CD, most likely by increasing levels of sRAGE, which neutralizes proinflammatory mediators.

Author List

Däbritz J, Friedrichs F, Weinhage T, Hampe J, Kucharzik T, Lügering A, Broeckel U, Schreiber S, Spieker T, Stoll M, Foell D

Author

Ulrich Broeckel MD Chief, Center Associate Director, Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Animals
Case-Control Studies
Colitis
Crohn Disease
Dextran Sulfate
Enzyme-Linked Immunosorbent Assay
Female
Genotype
Humans
Immunohistochemistry
Male
Mice
Mice, Knockout
Middle Aged
Monocytes
Phenotype
Polymorphism, Genetic
RNA
Receptor for Advanced Glycation End Products
Receptors, Immunologic
Tumor Necrosis Factor-alpha
Young Adult