IFNG rs1861494 Polymorphism Is Associated with IBD Disease Severity and Functional Changes in Both IFNG Methylation and Protein Secretion

Abstract

Background Mucosal expression of IFN-γ plays a pivotal role in IBD pathogenesis and IBD-risk regions flank IFNG. The conserved IFNG rs1861494 T/C, introduces a new CpG methylation site, and is associated with disease severity and lack of therapeutic response in other infectious and immune mediated disorders, and is in linkage-disequilibrium with a UC disease severity region. It seems likely that CpG-altering SNPs modify methylation and gene expression. This study evaluated the association between rs1861494 and clinical, serologic and methylation patterns in IBD patients. Methods Peripheral T cells of UC and CD patients were genotyped for rs1861494 and analyzed for allele-specific and IFNG promoter methylation. Serum ANCA and IFN-γ secretion were measured by ELISA and nucleo-protein complex formation by EMSA. Results IFNG rs1861494 T allele carriage in IBD patients was associated with enhanced secretion of IFN-γ. T allele carriage was associated in UC with high levels of ANCA 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, as well as serological markers associated with treatment resistance to anti-TNF therapy in IBD patients. These data may be useful prognostically as predictors of early response to anti-TNF therapy to identify IBD patients for improved personalized therapeutics.

Association Between <b><i>IFN-γ</i></b> Gene Polymorphisms and IgA Nephropathy in a Chinese Han Population

“…In the present study, we investigated the relationship between IFN-γ rs1861494 polymorphism and IgAN, and report that the IFN-γ rs1861494 polymorphism is associated with IFN-γ serum levels. This is in line with the results that T allele of rs1861494 in IFNG gene in patients with IBD correlated with elevated expression of IFN-γ [37]. …”

Loss of PTPN22 abrogates the beneficial effect of cohousing-mediated fecal microbiota transfer in murine colitis

“…43,44 Furthermore, genome-wide association studies linked SNPs around the IFNG locus and enhanced IFNG expression with IBD. 45,46 Certain bacteria promote specific T-cell responses, e.g., SFB drive the development of Th17 cells. 47 Likewise, specific bacteria in healthy mice might suppress the induction of Th1 cells.…”

Association of IFN‐γ polymorphisms with ankylosing spondylitis risk

“…Gao et al reported that although IFN‐γ rs1861494 polymorphism could influence serum IFN‐γ level, there was no obvious association between the SNP with immunoglobulin A nephropathy (IgAN) in Chinese Han population 27 . However, the study scheduled by Gonsky et al reported that IFN‐γ rs1861494 polymorphism could influence inflammatory bowel disease severity via its functional roles in IFN‐γ gene methylation and protein secretion among Caucasian population 19 . The divergences might be attributed to the relative small sample size, different study populations and geographic regions, as well as the diverse aetiologies of the study diseases.…”

“…A related case‐control study reported that IFN‐γ rs2430561 polymorphism may contribute to risk of AS via influencing IFN‐γ expression 20 . Rs2069727 and rs1861494 are two common polymorphisms in IFN‐γ gene, and both of them have the possibility to influence production of IFN‐γ protein 19,21 . According to the previous researches, we hypothesized that IFN‐γ r s2069727 and rs1861494 polymorphisms might be involved in AS.…”

“…In AS, a study carried out by Wang H et al reported that the protein expression level of IFN‐γ was significantly higher in AS patients than that in health individuals 18 . The transcription activity of IFN‐γ may be regulated by its genetic mutations 19 . A related case‐control study reported that IFN‐γ rs2430561 polymorphism may contribute to risk of AS via influencing IFN‐γ expression 20 .…”