title: Association of functional polymorphisms in interferon regulatory factor 2 (IRF2) with susceptibility to systemic lupus erythematosus: a case-control association study.
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.
authors.affiliation: Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Kawasaki
authors.affiliation: Clinical Research Center for Allergy and Rheumatology, Sagamihara Hospital, National Hospital Organization, Sagamihara, Kanagawa, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Furukawa
authors.affiliation: Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan.
authors.forename: Nao
authors.initials: N
authors.lastname: Nishida
authors.affiliation: Environmental Molecular Biology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Warabi
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Kondo
authors.affiliation: Department of Rheumatology, Niigata Rheumatic Center, Shibata, Niigata, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ito
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Matsumoto
authors.affiliation: Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Makio
authors.initials: M
authors.lastname: Kusaoi
authors.affiliation: Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Amano
authors.affiliation: Department of Rheumatology, Yokohama Minami Kyosai Hospital, Yokohama, Kanagawa, Japan; Center for Rheumatic Diseases, Yokohama City University Medical Center, Yokohama, Kanagawa, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Suda
authors.affiliation: Department of Rheumatology, Yokohama Minami Kyosai Hospital, Yokohama, Kanagawa, Japan.
authors.forename: Shouhei
authors.initials: S
authors.lastname: Nagaoka
authors.affiliation: Allergy and Immunological Diseases, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.
authors.forename: Keigo
authors.initials: K
authors.lastname: Setoguchi
authors.affiliation: Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Nagai
authors.affiliation: Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
authors.forename: Shunsei
authors.initials: S
authors.lastname: Hirohata
authors.affiliation: Department of Rheumatology, Tokyo Metropolitan Tama Medical Center, Fuchu, Tokyo, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Shimada
authors.affiliation: Department of Rheumatology, Tokyo Metropolitan Tama Medical Center, Fuchu, Tokyo, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Sugii
authors.affiliation: Department of Rheumatology, Himeji Medical Center, National Hospital Organization, Himeji, Hyogo, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Okamoto
authors.affiliation: Department of Rheumatology, Morioka Hospital, National Hospital Organization, Morioka, Iwate, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Chiba
authors.affiliation: Department of Internal Medicine and Rheumatology, Clinical Research Institute, Kyushu Medical Center, National Hospital Organization, Fukuoka, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Suematsu
authors.affiliation: Center for Rheumatic Diseases, Yokohama City University Medical Center, Yokohama, Kanagawa, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ohno
authors.affiliation: Department of Internal Medicine, Nagoya Medical Center, National Hospital Organization, Nagoya, Aichi, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Katayama
authors.affiliation: Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Okamoto
authors.affiliation: Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Kono
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Katsushi
authors.initials: K
authors.lastname: Tokunaga
authors.affiliation: Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Takasaki
authors.affiliation: Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hashimoto
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sumida
authors.affiliation: Clinical Research Center for Allergy and Rheumatology, Sagamihara Hospital, National Hospital Organization, Sagamihara, Kanagawa, Japan.
authors.forename: Shigeto
authors.initials: S
authors.lastname: Tohma
authors.affiliation: Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Tsuchiya
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D050836:Interferon Regulatory Factor-2 / Q000235:genetics*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017421:Sequence Analysis; D015533:Transcriptional Activation
chemical_list: C494229:IRF2 protein, human; D050836:Interferon Regulatory Factor-2