title: Runt-related transcription factor 3 is associated with ulcerative colitis and shows epistasis with solute carrier family 22, members 4 and 5.
abstract: BACKGROUND
  Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), are intestinal inflammatory disorders with a complex genetic background. Mice deficient for the runt-domain-transcription-factor3 (Runx3) develop spontaneous colitis. Human RUNX3 resides in an IBD-susceptibility locus. We studied the association of RUNX3 in a cohort of IBD patients and analyzed the interaction with SLC22A4/5. RUNX3 and OCTN1 mRNA expression was assessed in inflamed and noninflamed mucosa from patients and controls.
  
  
  METHODS
  543 IBD patients (309 CD / 234 UC) and 296 controls were included. Four single nucleotide polymorphisms (SNPs) and 4 microsatellite markers were studied for RUNX3. Five SNPs (including SNP-207G-->C and SNP1672C-->T) were analyzed for SLC22A4/5. RUNX3, and OCTN1 expression in mucosal tissue from 30 patients (14 UC / 16 CD) and 6 controls were determined by quantitative polymerase chain reaction.
  
  
  RESULTS
  A significant association between RUNX3-SNP rs2236851 and UC (OR 1.61; 95% confidence interval [CI] 1.11-2.32, P = 0.020) was found. Carriership is associated with pancolitis (odds ratio [OR] 1.86; 95% CI 1.08-3.21). SLC22A4/5-SNPs rs272893 and rs273900 are associated with CD (OR 2.16; 95% CI 1.21-3.59 and OR 2.40; 95% CI 1.43-4.05). We found epistasis for carriership of a risk-associated allele in RUNX3 and SLC22A4/5 for UC patients versus CD patients (OR 3.83; 95% CI 1.26-11.67). RUNX3 mRNA expression is increased (P = 0.01) in inflamed colonic mucosa of UC patients compared to noninflamed mucosa and controls.
  
  
  CONCLUSIONS
  We provide evidence for the genetic association of RUNX3 with UC and for CD with the IBD5 locus including SLC22A4/5. An epistatic effect of RUNX3 and SLC22A4 was associated with an increased risk for UC. Our data suggest a role for RUNX3 in UC susceptibility.
authors.affiliation: Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. R.K.Weersma@int.umcg.nl
authors.forename: Rinse K
authors.initials: RK
authors.lastname: Weersma
authors.forename: Lu
authors.initials: L
authors.lastname: Zhou
authors.forename: Ilja M
authors.initials: IM
authors.lastname: Nolte
authors.forename: Gerrit
authors.initials: G
authors.lastname: van der Steege
authors.forename: Hendrik M
authors.initials: HM
authors.lastname: van Dullemen
authors.forename: Elvira
authors.initials: E
authors.lastname: Oosterom
authors.forename: Lisette
authors.initials: L
authors.lastname: Bok
authors.forename: Maikel P
authors.initials: MP
authors.lastname: Peppelenbosch
authors.forename: Klaas N
authors.initials: KN
authors.lastname: Faber
authors.forename: Jan H
authors.initials: JH
authors.lastname: Kleibeuker
authors.forename: Gerard
authors.initials: G
authors.lastname: Dijkstra
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002648:Child; D002895:Chromosomes, Human, Pair 5; D003093:Colitis, Ulcerative / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000378:metabolism / Q000473:pathology; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics* / Q000378:metabolism; D003424:Crohn Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004843:Epistasis, Genetic / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007124:Immunoenzyme Techniques; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D027701:Organic Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000074058:Solute Carrier Family 22 Member 5; D027981:Symporters; D055815:Young Adult
chemical_list: D050677:Core Binding Factor Alpha 3 Subunit; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D027701:Organic Cation Transport Proteins; D012333:RNA, Messenger; C493729:Runx3 protein, human; C109807:SLC22A4 protein, human; C492020:SLC22A5 protein, human; D000074058:Solute Carrier Family 22 Member 5; D027981:Symporters