期刊
ARTHRITIS AND RHEUMATISM
卷 62, 期 2, 页码 562-573出版社
WILEY
DOI: 10.1002/art.27223
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资金
- Swedish Research Council for Medicine
- Knut and Alice Wallenberg Foundation
- Alliance for Lupus Research
- Swedish Research Council
- Dana Foundation
- Swedish Rheumatism Association
- Gustafsson Foundation
- King Gustaf V's 80-Year Foundation
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH [5R03AR054070]
- Arthritis Foundation
Objective. Genetic variants of the interferon (IFN) regulatory factor 5 gene (IRF5) are associated with susceptibility to systemic lupus erythematosus (SLE). The contribution of these variants to IRF-5 expression in primary blood cells of SLE patients has not been addressed, nor has the role of type I IFNs. The aim of this study was to determine the association between increased IRF-5 expression and the IRF5 risk haplotype in SLE patients. Methods. IRF-5 transcript and protein levels in 44 Swedish patients with SLE and 16 healthy controls were measured by quantitative real-time polymerase chain reaction, minigene assay, and flow cytometry. Single-nucleotide polymorphisms rs2004640, rs10954213, and rs10488631 and the CGGGG insertion/deletion were genotyped in these patients. Genotypes of these polymorphisms defined both a common risk haplotype and a common protective haplotype. Results. IRF-5 expression and alternative splicing were significantly up- regulated in SLE patients compared with healthy donors. Enhanced transcript and protein levels were associated with the risk haplotype of IRF5; rs10488631 displayed the only significant independent association that correlated with increased transcription from the noncoding first exon 1C. Minigene experiments demonstrated an important role for rs2004640 and the CGGGG insertion/deletion, along with type I IFNs, in regulating IRF5 expression. Conclusion. This study provides the first formal proof that IRF-5 expression and alternative splicing are significantly up- regulated in primary blood cells of patients with SLE. Furthermore, the risk haplotype is associated with enhanced IRF-5 transcript and protein expression in patients with SLE.
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