Association Of Functional Polymorphisms In IRF2 With Systemic Lupus Erythematosus In a Japanese Population

Aya Kawasaki¹, Hiroshi Furukawa², Nao Nishida³, Eiji Warabi⁴, Yuya Kondo⁵, Satoshi Ito⁶, Isao Matsumoto⁷, Makio Kusaoi⁸, Akiko Suda⁹, Shouhei Nagaoka¹⁰, Keigo Setoguchi¹¹, Tatsuo Nagai¹², Shunsei Hirohata¹³, Katsushi Tokunaga¹⁴, Yoshinari Takasaki¹⁵, Hiroshi Hashimoto¹⁶, Takayuki Sumida⁵, Shigeto Tohma² and Naoyuki Tsuchiya¹, ¹Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan, ²Clinical Research Center for Allergy and Rheumatology, Sagamihara Hospital, National Hospital Organization, Sagamihara, Japan, ³Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan, ⁴Environmental Molecular Biology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan, ⁵Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan, ⁶Niigata Rheumatic Center, Shibata, Japan, ⁷Department of Internal Medicine, Faculty of Medicine,, University of Tsukuba, Tsukuba, Japan, ⁸Department of Internal Medicine and Rheumatology, Juntendo University, Tokyo, Japan, ⁹Center for Rheumatic Diseases, Yokohama City University Medical Center, Yokohama, Japan, ¹⁰Department of Rheumatology, Yokohama Minami Kyousai Hospital, Yokohama, Japan, ¹¹Allergy and Immunological Diseases, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan, ¹²Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Sagamihara, Japan, ¹³Int Med/Rheumatol & Infec Dis, Kitasato University School of Medicine, Sagamihara, Japan, ¹⁴Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan, ¹⁵Department of Rheumatology, Juntendo University School of Medicine, Tokyo, Japan, ¹⁶Juntendo University School of Medicine, Tokyo, Japan

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Disease susceptibility, interferons, polymorphism and systemic lupus erythematosus (SLE)

Session Information

Title: Genetics and Genomics of Rheumatic Disease I

Session Type: Abstract Submissions (ACR)

Background/Purpose:

Interferon regulatory factor (IRF) families are transcription factors involved in type I interferon (IFN) pathway. Recent genetic studies identified association of IRF family genes, IRF5, IRF7, and IRF8, with systemic lupus erythematosus (SLE). IRF2 is thought to negatively regulate the type I IFN signals. In addition, IRF2 has a role in induction of Th1 differentiation and NK cell development. So far, association of IRF2 with SLE has not been published. In this study, we conducted an association study to examine whether IRF2 contributes to susceptibility to SLE in a Japanese population.

Methods:

A case-control association study was performed in 501 Japanese patients with SLE and 551 healthy controls on 46 tag SNPs in the IRF2 gene, selected based on linkage disequilibrium (LD) and minor allele frequencies (r²≥0.8, minor allele frequency≥0.05), using the DigiTag2 and the TaqMan allele discrimination assays. To identify functional SNPs, resequencing of the IRF2 region was performed using the next-generation sequencing. Effect of IRF2 SNPs on transcriptional activity was analyzed using a luciferase assay.

Results:

Among the IRF2 tag SNPs, rs13146124T in intron 1 was most significantly associated with SLE (dominant model, P=7.4X10^-4, odds ratio [OR] 1.60, 95% confidence interval [CI] 1.22-2.11). Resequencing identified SNPs in LD with rs13146124. Eight SNPs including rs62339994 were in almost absolute LD with rs13146124 (r²: 0.98-1), whereas rs66801661 showed moderate LD (r²: 0.52).

We next examined association of rs66801661 with SLE. rs66801661A allele was significantly increased in SLE (allelic model, P=3.7X10^-4, OR 1.75, 95%CI 1.29-2.39). Haplotype analysis identified three haplotypes constituted by rs66801661 and rs13146124, and the haplotype carrying both of the risk alleles, rs66801661A – rs13146124T, was significantly increased in SLE (SLE: 10.8%, control: 6.4%, permutation P=2.0X10^-4). On the other hand, the haplotype formed by the non-risk alleles, rs66801661G – rs13146124C, was decreased in SLE (SLE: 83.1%, control: 87.9%, permutation P=0.0014).

To examine the functional significance of the risk haplotype, IRF2 region containing the promoter region, exon 1 and the 5’ part of intron 1 encompassing rs66801661 and rs62339994, which was in tight LD with rs13146124, were inserted upstream of the luciferase gene. Three constructs corresponding to the naturally-occurring haplotypes were transfected, and the luciferase activities were compared. The construct carrying both of the risk alleles, rs66801661A and rs62339994A (in LD with rs13146124T), was associated with the highest transcriptional activity in Jurkat cells under IFNγ stimulation (ANOVA, P=1.3X10^-4).

Conclusion:

IRF2 polymorphisms are associated with susceptibility to SLE in a Japanese population. The SLE risk haplotype appeared to be associated with transcriptional activation of IRF2.

Disclosure:

A. Kawasaki,
None;

H. Furukawa,
None;

N. Nishida,
None;

E. Warabi,
None;

Y. Kondo,
None;

S. Ito,
None;

I. Matsumoto,
None;

M. Kusaoi,
None;

A. Suda,
None;

S. Nagaoka,
None;

K. Setoguchi,
None;

T. Nagai,
None;

S. Hirohata,
None;

K. Tokunaga,
None;

Y. Takasaki,
None;

H. Hashimoto,
None;

T. Sumida,
None;

S. Tohma,
None;

N. Tsuchiya,
None.

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