title: The functional -374T/A polymorphism of the receptor for advanced glycation end products may modulate Crohn's disease.
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.
authors.affiliation: Dept. of General Pediatrics, Univ. Children's Hospital Muenster, Münster, Germany. jan.daebritz@ukmuenster.de
authors.forename: Jan
authors.initials: J
authors.lastname: Däbritz
authors.forename: Frauke
authors.initials: F
authors.lastname: Friedrichs
authors.forename: Toni
authors.initials: T
authors.lastname: Weinhage
authors.forename: Jochen
authors.initials: J
authors.lastname: Hampe
authors.forename: Torsten
authors.initials: T
authors.lastname: Kucharzik
authors.forename: Andreas
authors.initials: A
authors.lastname: Lügering
authors.forename: Ulrich
authors.initials: U
authors.lastname: Broeckel
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Tilmann
authors.initials: T
authors.lastname: Spieker
authors.forename: Monika
authors.initials: M
authors.lastname: Stoll
authors.forename: Dirk
authors.initials: D
authors.lastname: Foell
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D003092:Colitis / Q000139:chemically induced / Q000473:pathology; D003424:Crohn Disease / Q000235:genetics* / Q000473:pathology*; D016264:Dextran Sulfate; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000502:physiology*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics* / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D055815:Young Adult
chemical_list: D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha; D012313:RNA; D016264:Dextran Sulfate