Comprehensive evaluation of the genetic variants of interferon regulatory factor 5 (IRF5) reveals a novel 5 bp length polymorphism as strong risk factor for systemic lupus erythematosus

Abstract

We analyzed a comprehensive set of single-nucleotide polymorphisms (SNPs) and length polymorphisms in the interferon regulatory factor 5 (IRF5) gene for their association with the autoimmune disease systemic lupus erythematosus (SLE) in 485 Swedish patients and 563 controls. We found 16 SNPs and two length polymorphisms that display association with SLE (P < 0.0005, OR > 1.4). Using a Bayesian model selection and averaging approach we identified parsimonious models with exactly two variants of IRF5 that are independently associated with SLE. The variants of IRF5 with the highest posterior probabilities (1.00 and 0.71, respectively) of being causal in SLE are a SNP (rs10488631) located 3' of IRF5, and a novel CGGGG insertion-deletion (indel) polymorphism located 64 bp upstream of the first untranslated exon (exon 1A) of IRF5. The CGGGG indel explains the association signal from multiple SNPs in the IRF5 gene, including rs2004640, rs10954213 and rs729302 previously considered to be causal variants in SLE. The CGGGG indel contains three or four repeats of the sequence CGGGG with the longer allele containing an additional SP1 binding site as the risk allele for SLE. Using electrophoretic mobility shift assays we show increased binding of protein to the risk allele of the CGGGG indel and using a minigene reporter assay we show increased expression of IRF5 mRNA from a promoter containing this allele. Increased expression of IRF5 protein was observed in peripheral blood mononuclear cells from SLE patients carrying the risk allele of the CGGGG indel. We have found that the same IRF5 allele also confers risk for inflammatory bowel diseases and multiple sclerosis, suggesting a general role for IRF5 in autoimmune diseases.

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

“…These three polymorphisms were selected for the study on primary SS based on our results from comprehensive association studies of IRF5 and STAT4, in which these polymorphisms account for most of the association signals with SLE. 13,16 Table 2 presents the results for the association between the three polymorphisms and primary SS obtained in this study in the cohorts from Sweden and Norway. It is notable that there was a slight difference in the risk allele frequencies for the IRF5 polymorphisms between Despite the low number of individuals in the Norwegian cohort, the CGGGG indel was significantly associated with primary SS and the IRF5 SNP rs10488631 showed a suggestive association with primary SS.…”

“…Both the SNP rs2004640 and the CGGGG indel are associated with SLE, and in a recent study we have shown that the CGGGG indel alone accounts for all the association signals from multiple linked SNPs in the 5 0 region, including the SNP rs2004640. 13 However, the current association data available for IRF5 in primary SS do not exclude the possibility that there could be differences between the association patterns in SLE and primary SS if a more comprehensive set of markers would be analyzed in a large set of primary SS samples. The longer (4 Â CGGGG) risk allele of the CGGGG indel, which is located 64 bp upstream of the alternative exon 1a of IRF5, creates an additional binding site for the transcription factor SP1.…”

“…13 According to a Bayesian model selection analysis of association data from Swedish SLE patients and controls, two polymorphisms in the IRF5 gene emerged as major, independent risk factors for SLE. One of them is a previously unknown 5-bp insertion-deletion (CGGGG indel) polymorphism located 64 kb upstream of the first untranslated exon 1a of IRF5, where the risk allele carries four copies of a repeated CGGGG unit.…”

“…The Bayesian model averaging approach takes into account all possible combinations of associated alleles, and according to this analysis the evidence for the CGGGG indel alone as causal allele was strong, compared with a model in which the risk alleles of the CGGGG indel and of the SNP rs2004640 or any other of the correlated alleles would act in concert. 13 The other independent risk factor is the SNP rs10488631 located 5 kb downstream of IRF5. This SNP is in high linkage disequilibrium (LD) with several other SNPs located in the 3 0 -untranslated region and downstream of IRF5.…”

Interferon regulatory factor-5 is genetically associated with systemic lupus erythematosus in African Americans

“…9 Interferon regulatory factor-5 (IRF5), a transcription factor, regulates the expression of IFN-a genes, 10,11 thus making it a good candidate gene for SLE susceptibility. Recent publications have reported a significant association between single nucleotide polymorphisms (SNPs) and haplotypes of IRF5 and SLE, both in familyand population-based studies of patients from multiple ethnicities [12][13][14][15][16][17][18][19][20][21] (including meta-analyses) 16 ; however, these studies have not examined African Americans.…”