Novel identification of the IRF7 region as an anticentromere autoantibody propensity locus in systemic sclerosis

Abstract

Objective Systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are related chronic autoimmune diseases of complex aetiology in which the interferon (IFN) pathway plays a key role. Recent studies have reported an association between IRF7 and SLE which confers a risk to autoantibody production. A study was undertaken to investigate whether the IRF7 genomic region is also involved in susceptibility to SSc and the main clinical features. Methods Two case-control sets of Caucasian origin from the USA and Spain, comprising a total of 2316 cases of SSc and 2347 healthy controls, were included in the study. Five single nucleotide polymorphisms (SNPs) in the PHRF1-IRF7-CDHR5 locus were genotyped using TaqMan allelic discrimination technology. A meta-analysis was performed to test the overall effect of these genetic variants on SSc. Results Four out of five analysed SNPs were Significantly associated with the presence of anticentromere autoantibodies (ACA) in the patients with SSc in the combined analysis (rs1131665: pFDR=6.14 × 10−4, OR=0.78; rs4963128: pFDR=6.14 × 10−4, OR=0.79; rs702966: pFDR=3.83 × 10−3, OR=0.82; and rs2246614: pFDR=3.83 × 10−3, OR=0.83). Significant p values were also obtained when the disease was tested globally; however, the statistical significance was lost when the ACA-positive patients were excluded from the study, suggesting that these associations rely on ACA positivity. Conditional logistic regression and allelic combination analyses suggested that the functional IRF7 SNP rs1131665 is the most likely causal variant. Conclusions The results show that variation in the IRF7 genomic region is associated with the presence of ACA in patients with SSc, supporting other evidence that this locus represents a common risk factor for autoantibody production in autoimmune diseases.

The Role of Type 1 Interferon in Systemic Sclerosis

“…Furthermore, recent genetic studies have established IRF7 as a susceptibility locus in SLE (77–80). Similarly, our group recently reported that a functional variant in the IRF7 exonic region, rs1131665 was associated with SSc (35). These findings support that IRF7 may represent a common risk factor for systemic autoimmune disease processes, including SSc.…”

“…These studies independently replicated genetic risk factors such as STAT4 (24–26), BLK (27–30), BANK1 (31, 32), Interferon regulatory factor ( IRF ) -5 (33, 34), IRF-7 , and -8 (35–38), and the T cell receptor zeta-chain ( CD247 ) (26) which are involved in innate and adaptive immune system.…”

Immunogenetics of systemic sclerosis: Defining heritability, functional variants and shared-autoimmunity pathways

“…Carmona et al, found an additional association of another IRF gene, IRF7, with the presence of ACA in SSc patients [41]. Interestingly, IRF7 also represents a risk factor for SLE autoantibody production [42,43].…”

“…However, the real implication of IRF7 in the modulation, the reproducibility of these eQTL findings in SSc patients and the functional mechanisms that connect all the previously mentioned processes require experimental confirmation. Furthermore, Carmona et al suggested that the association in IRF7 may be due to a different variant, a non-synonymous SNP (rs1131665), although the dependence between both signals is not clear [41]. Thus, additional efforts and research may shed light on the actual relevance of this locus and its structure in SSc.…”

“…This fact confirms that using the 'closest gene' criterion to explore the impact of genetic variants might not be correct in the majority of the loci. Interestingly, the IRF7 rs4963128 variant [41], which is a cis-eQTL for IRF7 and other loci, was also found to be the only significant trans-eQTL among the selected variants [80]. The IRF7 rs4963128 SNP acts as a trans-eQTL for the PRDM2 locus (which has been proposed as specific estrogen activator), ZNF512 (involved in lipid and glucose metabolism), ITGA7 (metalloproteinase inhibition) and some regions with unknown function [119e121].…”