An insertion deletion polymorphism in the Interferon Regulatory Factor 5 (IRF5) gene confers risk of inflammatory bowel diseases

Abstract

The interferon regulatory factor 5 (IRF5) gene encodes a transcription factor that plays an important role in the innate as well as in the cell-mediated immune responses. The IRF5 gene has been shown to be associated with systemic lupus erythematosus and rheumatoid arthritis. We studied whether the IRF5 gene is also associated with inflammatory bowel diseases (IBD), Crohn disease (CD) and ulcerative colitis (UC). Twelve polymorphisms in the IRF5 gene were genotyped in a cohort of 1007 IBD patients (748 CD and 254 UC) and 241 controls from Wallonia, Belgium. The same polymorphisms were genotyped in a confirmatory cohort of 311 controls and 687 IBD patients (488 CD and 192 UC) from Leuven, Belgium. A strong signal of association [P = 1.9 x 10(-5), odds ratio (OR) 1.81 (1.37-2.39)] with IBD was observed for a 5 bp indel (CGGGG) polymorphism in the promoter region of the IRF5 gene. The association was detectable also in CD patients (P = 6.8 x 10(-4)) and was particularly strong among the UC patients [P = 5.3 x 10(-8), OR = 2.42 (1.76-3.34)]. The association of the CGGGG indel was confirmed in the second cohort [P = 3.2 x 10(-5), OR = 1.59 (1.28-1.98)]. The insertion of one CGGGG unit is predicted to create an additional binding site for the transcription factor SP1. Using an electrophoretic mobility shift assay, we show allele-specific differences in protein binding to this repetitive DNA-stretch, which suggest a potential function role for the CGGGG indel.

The CGGGG insertion/deletion polymorphism of the IRF5 promoter is a strong risk factor for primary Sjögren's syndrome

“…Patients carrying the IRF5 is a gene implicated in type I IFN secretion after stimulation of innate immunity and in type I IFN signal transduction. A polymorphism located in the splicing sequence of exon 1B of IRF5 (rs2004640) has been found to be associated with several autoimmune diseases (5,6,8), including SS (7). The CGGGG insertion/deletion polymorphism, located in the promoter region of the IRF5 transcript containing exon 1A, is in linkage disequilibrium with rs2004640.…”

“…Recently, a 5-bp insertion/ deletion polymorphism (CGGGG insertion/deletion) located in the promoter region of the IRF5 transcript containing exon 1A was described, which may resolve this question. The IRF5 CGGGG insertion/deletion has been associated with ulcerative colitis, Crohn's disease (8), and lupus (6). Two alleles of the IRF5 CGGGG insertion/deletion polymorphism, consisting of 3 repeats or 4 repeats of the CGGGG sequence, have been identified.…”

Additive effects of the major risk alleles of IRF5 and STAT4 in primary Sjögren's syndrome

“…It is interesting to note that when IRF5 polymorphisms from both groups have been investigated for their association with inflammatory bowel diseases and multiple sclerosis, association from only the group of polymorphisms defined by the CGGGG indel has been observed, 28,29 whereas no association has been reported for the SNP rs10488631 or other perfectly linked SNPs (Table 4). These findings provide evidence for a more similar genetic background in the rheumatic diseases primary SS, SLE and the subset of RA patients who are anti-CCP negative, which differs from that in inflammatory bowel diseases and multiple sclerosis.…”

Progress and Promise of Genome-Wide Association Studies for Human Complex Trait Genetics

“…The IRF5 locus includes variants that disrupt intron splicing, decrease mRNA transcript stability, and delete part of the interferon regulating factor (IRF) protein , explaining independent associations with systemic lupus erythmatosis (Sigurdsson et al 2005;Graham et al 2006), inflammatory bowel disease (Dideberg et al 2007), and RA (Stahl et al 2010). Allele-specific chromatin remodeling affecting the expression of several genes in the ORMDL3 locus region (Verlaan et al 2009) explains its association with asthma ), Crohn's disease (Barrett et al 2008), and T1D (Barrett et al 2009a).…”