Journal
INFLAMMATORY BOWEL DISEASES
Volume 20, Issue 10, Pages 1794-1801Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/MIB.0000000000000172
Keywords
human; T Lymphocytes; methylation; interferon; Crohn's disease; ulcerative colitis; serological antibodies
Categories
Funding
- National Center for Research Resources [UL1RR033176]
- National Center for Advancing Translational Sciences [UL1TR000124]
- United States Public Health Service [DK043211, DK046763, U01DK062413]
- European Union [IBD-BIOM 305479]
- Leona M. and Harry. B. Helmsley Charitable Trust
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute
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Background: Mucosal expression of interferon (IFN)-gamma 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-gamma 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-gamma. 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-gamma 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.
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