association of functional polymorphisms in interferon regulatory factor 2 (irf2) with susceptibility to systemic lupus erythematosus: a case-control association study.
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ID: 156521
2014
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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.
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kawasaki2014plosassociation
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| Authors | ;Aya Kawasaki;Hiroshi Furukawa;Nao Nishida;Eiji Warabi;Yuya Kondo;Satoshi Ito;Isao Matsumoto;Makio Kusaoi;Hirofumi Amano;Akiko Suda;Shouhei Nagaoka;Keigo Setoguchi;Tatsuo Nagai;Shunsei Hirohata;Kota Shimada;Shoji Sugii;Akira Okamoto;Noriyuki Chiba;Eiichi Suematsu;Shigeru Ohno;Masao Katayama;Akiko Okamoto;Hajime Kono;Katsushi Tokunaga;Yoshinari Takasaki;Hiroshi Hashimoto;Takayuki Sumida;Shigeto Tohma;Naoyuki Tsuchiya |
| Journal | ensaio pesquisa em educação em ciências |
| Year | 2014 |
| DOI |
10.1371/journal.pone.0109764
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