title: IFNG rs1861494 polymorphism is associated with IBD disease severity and functional changes in both IFNG methylation and protein secretion.
abstract: BACKGROUND
  Mucosal expression of interferon (IFN)-γ plays a pivotal role in the pathogenesis of inflammatory bowel disease (IBD) and IBD risk regions flank IFNG. The conserved IFNG rs1861494 T/C introduces a new CpG methylation site, is associated with disease severity and lack of therapeutic response in other infectious and immune-mediated disorders, and is in linkage disequilibrium with a ulcerative colitis (UC) disease severity region. It seems likely that CpG-altering single nucleotide polymorphisms modify methylation and gene expression. This study evaluated the association between rs1861494 and clinical, serologic, and methylation patterns in patients with IBD.
  
  
  METHODS
  Peripheral T cells of UC and Crohn's disease (CD) patients were genotyped for rs1861494 and analyzed for allele-specific and IFNG promoter methylation. Serum antineutrophil cytoplasmic autoantibodies and IFN-γ secretion were measured by enzyme-linked immunosorbent assay and nucleoprotein complex formation by electrophoretic mobility shift assay.
  
  
  RESULTS
  IFNG rs1861494 T allele carriage in patients with IBD was associated with enhanced secretion of IFN-γ. T allele carriage was associated in UC with high levels of antineutrophil cytoplasmic autoantibodies and faster progression to colectomy. In CD, it was associated with complicated disease involving a stricturing/penetrating phenotype. Likewise, IFNG rs1861494 displayed genotype-specific modulation of DNA methylation and transcription factor complex formation.
  
  
  CONCLUSIONS
  This study reports the first association of IFNG rs1861494 T allele with enhanced IFN-γ secretion and known IBD clinical parameters indicative of more aggressive disease and serological markers associated with treatment resistance to anti-tumor necrosis factor therapy in patients with IBD. These data may be useful prognostically as predictors of early response to anti-tumor necrosis factor therapy to identify patients with IBD for improved personalized therapeutics.
authors.affiliation: F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Rivkah
authors.initials: R
authors.lastname: Gonsky
authors.forename: Richard L
authors.initials: RL
authors.lastname: Deem
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Landers
authors.forename: Talin
authors.initials: T
authors.lastname: Haritunians
authors.forename: Shaohong
authors.initials: S
authors.lastname: Yang
authors.forename: Stephan R
authors.initials: SR
authors.lastname: Targan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D003093:Colitis, Ulcerative / Q000097:blood / Q000235:genetics*; D003424:Crohn Disease / Q000097:blood / Q000235:genetics*; D019175:DNA Methylation; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: D007371:Interferon-gamma