Association of functional polymorphisms in interferon regulatory factor 2 (IRF2) with susceptibility to systemic lupus erythematosus: a case-control association study

PLoS One. 2014 Oct 6;9(10):e109764. doi: 10.1371/journal.pone.0109764. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Case-Control Studies
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study*
  • Haplotypes
  • Humans
  • Interferon Regulatory Factor-2 / genetics*
  • Lupus Erythematosus, Systemic / genetics*
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Sequence Analysis
  • Transcriptional Activation

Substances

  • IRF2 protein, human
  • Interferon Regulatory Factor-2

Grants and funding

This work was supported by Japan Society for the Promotion of Science (JSPS; http://www.jsps.go.jp/) KAKENHI (Grants-in-Aid for Scientific Research) grant numbers 22390199 (NT), 23659495 (NT) and 23791101 (AK), Health and Labour Science Research Grants for the Research on intractable diseases from the Ministry of Health, Labour and Welfare of Japan (http://www.mhlw.go.jp/stf/seisakunitsuite/bunya/hokabunya/kenkyujigyou/) (NT), Japan Allergy Foundation (http://www.jaanet.org/) (NT), and Cooperative Research Grant of the Plant Transgenic Design Initiative, Gene Research Center, University of Tsukuba (http://ptrad.gene.tsukuba.ac.jp/)(for the facility). No individuals employed or contracted by the funders played any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.