Abstract
Interferon regulatory factor 2 (IRF2) negatively regulates type I interferon (IFN) responses, while it plays a role in induction of Th1 differentiation. Previous linkage and association studies in European-American populations suggested genetic role of IRF2 in systemic lupus erythematosus (SLE); however, this observation has not yet been confirmed. No studies have been reported in the Asian populations. Here we investigated whether IRF2 polymorphisms contribute to susceptibility to SLE in a Japanese population. Association study of 46 IRF2 tag single nucleotide polymorphisms (SNPs) detected association of an intronic SNP, rs13146124, with SLE. When the association was analyzed in 834 Japanese patients with SLE and 817 healthy controls, rs13146124 T was significantly increased in SLE compared with healthy controls (dominant model, P = 5.4×10−4, Bonferroni-corrected P [Pc] = 0.026, odds ratio [OR] 1.48, 95% confidence interval [CI] 1.18–1.85). To find causal SNPs, resequencing was performed by next-generation sequencing. Twelve polymorphisms in linkage disequilibrium with rs13146124 (r2: 0.30–1.00) were identified, among which significant association was observed for rs66801661 (allele model, P = 7.7×10−4, Pc = 0.037, OR 1.53, 95%CI 1.19–1.96) and rs62339994 (dominant model, P = 9.0×10−4, Pc = 0.043, OR 1.46, 95%CI 1.17–1.82). The haplotype carrying both of the risk alleles (rs66801661A–rs62339994A) was significantly increased in SLE (P = 9.9×10−4), while the haplotype constituted by both of the non-risk alleles (rs66801661G–rs62339994G) was decreased (P = 0.0020). A reporter assay was carried out to examine the effect of the IRF2 haplotypes on the transcriptional activity, and association of the IRF2 risk haplotype with higher transcriptional activity was detected in Jurkat T cells under IFNγ stimulation (Tukey's test, P = 1.2×10−4). In conclusion, our observations supported the association of IRF2 with susceptibility to SLE, and the risk haplotype was suggested to be associated with transcriptional activation of IRF2.
Highlights
Genome-wide association studies (GWAS) as well as candidate gene studies of systemic lupus erythematosus (SLE) have identified more than 70 susceptibility loci
Our observations suggested that Interferon regulatory factor 2 (IRF2) is associated with SLE, and the risk haplotype is associated with transcriptional activation of IRF2
Forty six tag single nucleotide polymorphisms (SNPs) which capture 100 SNPs in the IRF2 region with r2$0.8 were selected, and a casecontrol study for the tag SNPs was conducted on the discovery set which consists of 501 Japanese patients with SLE and 551 healthy Japanese controls
Summary
Genome-wide association studies (GWAS) as well as candidate gene studies of systemic lupus erythematosus (SLE) have identified more than 70 susceptibility loci. They account for a small fraction of heritability of SLE; it appears that many susceptibility genes remain to be identified [1,2,3,4,5,6,7,8,9,10,11]. IRF family comprises of nine members, IRF1 to IRF9. IRFs have a conserved DNA binding domain with five tryptophan residues in the N-terminal region, and an IRF association domain (IAD) 1 or IAD2 in the C-terminal region, which mediates interactions with IRF members or other transcription factors [12]. IRF5 has already been established as an SLE susceptibility gene in various populations, including Japanese [17]
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