title: Analysis of IL12B gene variants in inflammatory bowel disease.
abstract: BACKGROUND
  IL12B encodes the p40 subunit of IL-12, which is also part of IL-23. Recent genome-wide association studies identified IL12B and IL23R as susceptibility genes for inflammatory bowel disease (IBD). However, the phenotypic effects and potential gene-gene interactions of IL12B variants are largely unknown.
  
  
  RESULTS
  We analyzed IL12B gene variants regarding association with Crohn's disease (CD) and ulcerative colitis (UC). Genomic DNA from 2196 individuals including 913 CD patients, 318 UC patients and 965 healthy, unrelated controls was analyzed for four SNPs in the IL12B gene region (rs3212227, rs17860508, rs10045431, rs6887695). Our analysis revealed an association of the IL12B SNP rs6887695 with susceptibility to IBD (p = 0.035; OR 1.15 [95% CI 1.01-1.31] including a trend for rs6887695 for association with CD (OR 1.41; [0.99-1.31], p = 0.066) and UC (OR 1.18 [0.97-1.43], p = 0.092). CD patients, who were homozygous C/C carriers of this SNP, had significantly more often non-stricturing, non-penetrating disease than carriers of the G allele (p = 6.8×10(-5); OR = 2.84, 95% CI 1.66-4.84), while C/C homozygous UC patients had less often extensive colitis than G allele carriers (p = 0.029; OR = 0.36, 95% CI 0.14-0.92). In silico analysis predicted stronger binding of the minor C allele of rs6887695 to the transcription factor RORα which is involved in Th17 differentiation. Differences regarding the binding to the major and minor allele sequence of rs6887695 were also predicted for the transcription factors HSF1, HSF2, MZF1 and Oct-1. Epistasis analysis revealed weak epistasis of the IL12B SNP rs6887695 with several SNPs (rs11889341, rs7574865, rs7568275, rs8179673, rs10181656, rs7582694) in the STAT4 gene which encodes the major IL-12 downstream transcription factor STAT4 (p<0.05) but there was no epistasis between IL23R and IL12B variants.
  
  
  CONCLUSIONS
  The IL12B SNP rs6887695 modulates the susceptibility and the phenotype of IBD, although the effect on IBD susceptibilty is less pronounced than that of IL23R gene variants.
authors.affiliation: Department of Medicine II-Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Glas
authors.forename: Julia
authors.initials: J
authors.lastname: Seiderer
authors.forename: Johanna
authors.initials: J
authors.lastname: Wagner
authors.forename: Torsten
authors.initials: T
authors.lastname: Olszak
authors.forename: Christoph
authors.initials: C
authors.lastname: Fries
authors.forename: Cornelia
authors.initials: C
authors.lastname: Tillack
authors.forename: Matthias
authors.initials: M
authors.lastname: Friedrich
authors.forename: Florian
authors.initials: F
authors.lastname: Beigel
authors.forename: Johannes
authors.initials: J
authors.lastname: Stallhofer
authors.forename: Christian
authors.initials: C
authors.lastname: Steib
authors.forename: Martin
authors.initials: M
authors.lastname: Wetzke
authors.forename: Burkhard
authors.initials: B
authors.lastname: Göke
authors.forename: Thomas
authors.initials: T
authors.lastname: Ochsenkühn
authors.forename: Julia
authors.initials: J
authors.lastname: Diegelmann
authors.forename: Darina
authors.initials: D
authors.lastname: Czamara
authors.forename: Stephan
authors.initials: S
authors.lastname: Brand
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003093:Colitis, Ulcerative / Q000235:genetics; D003424:Crohn Disease / Q000235:genetics; D005260:Female; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics*; D053762:Interleukin-12 Subunit p40 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: C500879:IL12B protein, human; D053762:Interleukin-12 Subunit p40