Association of a functional IRF7 variant with systemic lupus erythematosus - PubMed (original) (raw)

Jian Zhao, Xiaoxia Qian, Jonathan L H Wong, Kenneth M Kaufman, C Yung Yu; Hwee Siew Howe; Tan Tock Seng Hospital Lupus Study Group; Mo Yin Mok, John B Harley, Joel M Guthridge, Yeong Wook Song, Soo-Kyung Cho, Sang-Cheol Bae, Jennifer M Grossman, Bevra H Hahn, Frank C Arnett, Nan Shen, Betty P Tsao

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Association of a functional IRF7 variant with systemic lupus erythematosus

Qiong Fu et al. Arthritis Rheum. 2011 Mar.

Abstract

Objective: A previous genome-wide association study conducted in a population of European ancestry identified rs4963128, a KIAA1542 single-nucleotide polymorphism (SNP) 23 kb telomeric to IRF7 (the gene for interferon regulatory factor 7 [IRF-7]), to be strongly associated with systemic lupus erythematosus (SLE). This study was undertaken to investigate whether genetic polymorphism within IRF7 is a risk factor for the development of SLE.

Methods: We genotyped one KIAA1542 SNP (rs4963128) and one IRF7 SNP (rs1131665 [Q412R]) in an Asian population (1,302 cases, 1,479 controls), to assess their association with SLE. Subsequently, rs1131665 was further genotyped in independent panels of Chinese subjects (528 cases, 527 controls), European American subjects (446 cases, 461 controls), and African American subjects (159 cases, 115 controls) by TaqMan genotyping assay, to seek confirmation of association in various ethnic groups. A luciferase reporter assay was used to assess the effect of Q412R polymorphism on the activation of IRF-7.

Results: Consistent association of rs1131665 (Q412R) with SLE was identified in Asian, European American, and African American populations (total 2,435 cases and 2,582 controls) (P(meta) = 6.18 × 10(-6) , odds ratio 1.42 [95% confidence interval 1.22-1.65]). Expression of the IRF7 412Q risk allele resulted in a 2-fold increase in interferon-stimulated response element transcriptional activity compared with expression of IRF7 412R (P = 0.0003), suggesting that IRF7 412Q confers elevated IRF-7 activity and may therefore affect a downstream interferon pathway.

Conclusion: These findings show that the major allele of a nonsynonymous SNP, rs1131665 (412Q) in IRF7, confers elevated activation of IRF-7 and predisposes to the development of SLE in multiple ethnic groups. This result provides direct genetic evidence that IRF7 may be a risk gene for human SLE.

Copyright © 2011 by the American College of Rheumatology.

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Figures

Figure 1

Figure 1

Schematic structure of IRF7. A, Genomic structure of KIAA1542-IRF7 locus. Two KIAA1542 SNPs, rs4963128 and rs702966, are 23kb and 0.6kb telomeric to IRF7, respectively. In HapMap datasets (CEU, YRI, CHB and JPT), rs702966 is in strong LD (r2=1) with multiple SNPs in IRF7. B, Transcript structure of IRF7 isoform a. rs1131665 (Q412R) is highlighted. C, Conservative domain in IRF7 protein. DBD: DNA binding domain; CAD: constitutive activation domain; VAD: virus-activated domain; ID: inhibitory domain; SRD: signal response domain.

Figure 2

Figure 2

Functional analysis of Q412R polymorphism. A, Protein sequence alignment of IRF7. The multiple sequence alignment of the IRF7 protein homologs was performed using MUSCLE. Q412R is highlighted. B, 3D structure prediction of IRF7 protein. Left panel: 412Q; right panel: 412R. The Q412R is depicted in blue and the nearby amino acids 459R, 407F and 429Y in plum. The contacts between Q412R and other amino acids are represented by red lines. R shows much more contacts with these amino acids as compared to Q. C, Q412R regulates IRF7 activity in vitro. ISRE reporter plasmid was co-transfected with either IRF7 412Q or 412R vector to HEK293 cells, and relative ISRE luciferase activity was measured after 24 hours. Expression of IRF7 412Q resulted in a 2-fold increase in ISRE transcriptional activity compared with that of IRF7 412R.

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