Association of functional polymorphisms in interferon regulatory factor 2 (IRF2) with susceptibility to systemic lupus erythematosus: a case-control association study.
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); how...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4186848?pdf=render |
| _version_ | 1817995873652572160 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Aya Kawasaki |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-14T02:13:43Z |
| format | Article |
| id | doaj.art-e07e5f3a91cb4d4ba95ba8cd4556417a |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-14T02:13:43Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-e07e5f3a91cb4d4ba95ba8cd4556417a2022-12-22T02:18:19ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-01910e10976410.1371/journal.pone.0109764Association of functional polymorphisms in interferon regulatory factor 2 (IRF2) with susceptibility to systemic lupus erythematosus: a case-control association study.Aya KawasakiHiroshi FurukawaNao NishidaEiji WarabiYuya KondoSatoshi ItoIsao MatsumotoMakio KusaoiHirofumi AmanoAkiko SudaShouhei NagaokaKeigo SetoguchiTatsuo NagaiShunsei HirohataKota ShimadaShoji SugiiAkira OkamotoNoriyuki ChibaEiichi SuematsuShigeru OhnoMasao KatayamaAkiko OkamotoHajime KonoKatsushi TokunagaYoshinari TakasakiHiroshi HashimotoTakayuki SumidaShigeto TohmaNaoyuki TsuchiyaInterferon 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.http://europepmc.org/articles/PMC4186848?pdf=render |
| spellingShingle | 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 Association of functional polymorphisms in interferon regulatory factor 2 (IRF2) with susceptibility to systemic lupus erythematosus: a case-control association study. PLoS ONE |
| title | Association of functional polymorphisms in interferon regulatory factor 2 (IRF2) with susceptibility to systemic lupus erythematosus: a case-control association study. |
| title_full | Association of functional polymorphisms in interferon regulatory factor 2 (IRF2) with susceptibility to systemic lupus erythematosus: a case-control association study. |
| title_fullStr | Association of functional polymorphisms in interferon regulatory factor 2 (IRF2) with susceptibility to systemic lupus erythematosus: a case-control association study. |
| title_full_unstemmed | Association of functional polymorphisms in interferon regulatory factor 2 (IRF2) with susceptibility to systemic lupus erythematosus: a case-control association study. |
| title_short | Association of functional polymorphisms in interferon regulatory factor 2 (IRF2) with susceptibility to systemic lupus erythematosus: a case-control association study. |
| title_sort | association of functional polymorphisms in interferon regulatory factor 2 irf2 with susceptibility to systemic lupus erythematosus a case control association study |
| url | http://europepmc.org/articles/PMC4186848?pdf=render |
| work_keys_str_mv | AT ayakawasaki associationoffunctionalpolymorphismsininterferonregulatoryfactor2irf2withsusceptibilitytosystemiclupuserythematosusacasecontrolassociationstudy AT hiroshifurukawa associationoffunctionalpolymorphismsininterferonregulatoryfactor2irf2withsusceptibilitytosystemiclupuserythematosusacasecontrolassociationstudy AT naonishida associationoffunctionalpolymorphismsininterferonregulatoryfactor2irf2withsusceptibilitytosystemiclupuserythematosusacasecontrolassociationstudy AT eijiwarabi associationoffunctionalpolymorphismsininterferonregulatoryfactor2irf2withsusceptibilitytosystemiclupuserythematosusacasecontrolassociationstudy AT yuyakondo associationoffunctionalpolymorphismsininterferonregulatoryfactor2irf2withsusceptibilitytosystemiclupuserythematosusacasecontrolassociationstudy AT satoshiito associationoffunctionalpolymorphismsininterferonregulatoryfactor2irf2withsusceptibilitytosystemiclupuserythematosusacasecontrolassociationstudy AT isaomatsumoto associationoffunctionalpolymorphismsininterferonregulatoryfactor2irf2withsusceptibilitytosystemiclupuserythematosusacasecontrolassociationstudy AT makiokusaoi associationoffunctionalpolymorphismsininterferonregulatoryfactor2irf2withsusceptibilitytosystemiclupuserythematosusacasecontrolassociationstudy AT hirofumiamano associationoffunctionalpolymorphismsininterferonregulatoryfactor2irf2withsusceptibilitytosystemiclupuserythematosusacasecontrolassociationstudy AT akikosuda associationoffunctionalpolymorphismsininterferonregulatoryfactor2irf2withsusceptibilitytosystemiclupuserythematosusacasecontrolassociationstudy AT shouheinagaoka associationoffunctionalpolymorphismsininterferonregulatoryfactor2irf2withsusceptibilitytosystemiclupuserythematosusacasecontrolassociationstudy AT keigosetoguchi associationoffunctionalpolymorphismsininterferonregulatoryfactor2irf2withsusceptibilitytosystemiclupuserythematosusacasecontrolassociationstudy AT tatsuonagai associationoffunctionalpolymorphismsininterferonregulatoryfactor2irf2withsusceptibilitytosystemiclupuserythematosusacasecontrolassociationstudy AT shunseihirohata associationoffunctionalpolymorphismsininterferonregulatoryfactor2irf2withsusceptibilitytosystemiclupuserythematosusacasecontrolassociationstudy AT kotashimada associationoffunctionalpolymorphismsininterferonregulatoryfactor2irf2withsusceptibilitytosystemiclupuserythematosusacasecontrolassociationstudy AT shojisugii associationoffunctionalpolymorphismsininterferonregulatoryfactor2irf2withsusceptibilitytosystemiclupuserythematosusacasecontrolassociationstudy AT akiraokamoto associationoffunctionalpolymorphismsininterferonregulatoryfactor2irf2withsusceptibilitytosystemiclupuserythematosusacasecontrolassociationstudy AT noriyukichiba associationoffunctionalpolymorphismsininterferonregulatoryfactor2irf2withsusceptibilitytosystemiclupuserythematosusacasecontrolassociationstudy AT eiichisuematsu associationoffunctionalpolymorphismsininterferonregulatoryfactor2irf2withsusceptibilitytosystemiclupuserythematosusacasecontrolassociationstudy AT shigeruohno associationoffunctionalpolymorphismsininterferonregulatoryfactor2irf2withsusceptibilitytosystemiclupuserythematosusacasecontrolassociationstudy AT masaokatayama associationoffunctionalpolymorphismsininterferonregulatoryfactor2irf2withsusceptibilitytosystemiclupuserythematosusacasecontrolassociationstudy AT akikookamoto associationoffunctionalpolymorphismsininterferonregulatoryfactor2irf2withsusceptibilitytosystemiclupuserythematosusacasecontrolassociationstudy AT hajimekono associationoffunctionalpolymorphismsininterferonregulatoryfactor2irf2withsusceptibilitytosystemiclupuserythematosusacasecontrolassociationstudy AT katsushitokunaga associationoffunctionalpolymorphismsininterferonregulatoryfactor2irf2withsusceptibilitytosystemiclupuserythematosusacasecontrolassociationstudy AT yoshinaritakasaki associationoffunctionalpolymorphismsininterferonregulatoryfactor2irf2withsusceptibilitytosystemiclupuserythematosusacasecontrolassociationstudy AT hiroshihashimoto associationoffunctionalpolymorphismsininterferonregulatoryfactor2irf2withsusceptibilitytosystemiclupuserythematosusacasecontrolassociationstudy AT takayukisumida associationoffunctionalpolymorphismsininterferonregulatoryfactor2irf2withsusceptibilitytosystemiclupuserythematosusacasecontrolassociationstudy AT shigetotohma associationoffunctionalpolymorphismsininterferonregulatoryfactor2irf2withsusceptibilitytosystemiclupuserythematosusacasecontrolassociationstudy AT naoyukitsuchiya associationoffunctionalpolymorphismsininterferonregulatoryfactor2irf2withsusceptibilitytosystemiclupuserythematosusacasecontrolassociationstudy |