title: PTGER4 expression-modulating polymorphisms in the 5p13.1 region predispose to Crohn's disease and affect NF-κB and XBP1 binding sites.
abstract: BACKGROUND
  Genome-wide association studies identified a PTGER4 expression-modulating region on chromosome 5p13.1 as Crohn's disease (CD) susceptibility region. The study aim was to test this association in a large cohort of patients with inflammatory bowel disease (IBD) and to elucidate genotypic and phenotypic interactions with other IBD genes.
  
  
  RESULTS
  A total of 7073 patients and controls were genotyped: 844 CD and 471 patients with ulcerative colitis and 1488 controls were analyzed for the single nucleotide polymorphisms (SNPs) rs4495224 and rs7720838 on chromosome 5p13.1. The study included two replication cohorts of North American (CD: n = 684; controls: n = 1440) and of German origin (CD: n = 1098; controls: n = 1048). Genotype-phenotype, epistasis and transcription factor binding analyses were performed. In the discovery cohort, an association of rs4495224 (p = 4.10×10⁻⁵; 0.76 [0.67-0.87]) and of rs7720838 (p = 6.91×10⁻⁴; 0.81 [0.71-0.91]) with susceptibility to CD was demonstrated. These associations were confirmed in both replication cohorts. In silico analysis predicted rs4495224 and rs7720838 as essential parts of binding sites for the transcription factors NF-κB and XBP1 with higher binding scores for carriers of the CD risk alleles, providing an explanation of how these SNPs might contribute to increased PTGER4 expression. There was no association of the PTGER4 SNPs with IBD phenotypes. Epistasis detected between 5p13.1 and ATG16L1 for CD susceptibility in the discovery cohort (p = 5.99×10⁻⁷ for rs7720838 and rs2241880) could not be replicated in both replication cohorts arguing against a major role of this gene-gene interaction in the susceptibility to CD.
  
  
  CONCLUSIONS
  We confirmed 5p13.1 as a major CD susceptibility locus and demonstrate by in silico analysis rs4495224 and rs7720838 as part of binding sites for NF-κB and XBP1. Further functional studies are necessary to confirm the results of our in silico analysis and to analyze if changes in PTGER4 expression modulate CD susceptibility.
authors.affiliation: Department of Medicine II-Grosshadern, University of Munich, Munich, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Glas
authors.forename: Julia
authors.initials: J
authors.lastname: Seiderer
authors.forename: Darina
authors.initials: D
authors.lastname: Czamara
authors.forename: Giulia
authors.initials: G
authors.lastname: Pasciuto
authors.forename: Julia
authors.initials: J
authors.lastname: Diegelmann
authors.forename: Martin
authors.initials: M
authors.lastname: Wetzke
authors.forename: Torsten
authors.initials: T
authors.lastname: Olszak
authors.forename: Christiane
authors.initials: C
authors.lastname: Wolf
authors.forename: Bertram
authors.initials: B
authors.lastname: Müller-Myhsok
authors.forename: Tobias
authors.initials: T
authors.lastname: Balschun
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Achkar
authors.forename: M Ilyas
authors.initials: MI
authors.lastname: Kamboh
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.forename: Richard H
authors.initials: RH
authors.lastname: Duerr
authors.forename: Stephan
authors.initials: S
authors.lastname: Brand
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001665:Binding Sites; D002648:Child; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D003424:Crohn Disease / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004843:Epistasis, Genetic; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000235:genetics* / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000378:metabolism*; D000071717:X-Box Binding Protein 1; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; D016328:NF-kappa B; C545650:PTGER4 protein, human; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human