期刊
ARTHRITIS AND RHEUMATISM
卷 58, 期 8, 页码 2481-2487出版社
WILEY-LISS
DOI: 10.1002/art.23613
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资金
- NIH [T32-AR-075117, AR-053646]
- National Institute of Allergy and Infectious Diseases) [AI-071651, AR-42460, AI-53747, AI-31584, DE-15223, RR-20143, AI-24717, AI-62629, AR-48940, AR-49084]
- Arthritis Foundation Postdoctoral Fellowship award
- Lupus Family Registry and Repository [AR-62277]
- US Department of Veterans Affairs
- Alliance for Lupus Research, and Rheuminations, Inc
- National Institute of Allergy and Infectious Diseases [R01-AI-059893]
Objective. A haplotype of the interferon regulatory factor 5 (IRF5) gene has been associated with the risk of developing systemic lupus erythematosus (SLE), and our previous studies have demonstrated that high levels of serum interferon-alpha (IFN alpha) activity are a heritable risk factor for SLE. The aim of this study was to determine whether the IRF5 SLE risk haplotype mediates the risk of SLE by predisposing patients to the development of high levels of serum IFNa activity. Methods. IFNa levels in 199 SLE patients of European and Hispanic ancestry were measured with a sensitive functional reporter cell assay. The rs2004640, rs3807306, rs10488631, and rs2280714 single-nucleotide polymorphisms (SNPs) in IRF5 were genotyped in these patients. Haplotypes were categorized as SLE risk, neutral, or protective based on published data. Results. SLE patients with risk/risk and risk/neutral IRF5 genotypes had higher serum IFNa activity than did those with protective/protective and neutral/protective genotypes (P = 0.025). This differential effect of IRF5 genotype on serum IFN alpha levels was driven largely by SLE patients who were positive for either anti-RNA binding protein (Anti-RBP) or anti-double-stranded DNA (anti-dsDNA) autoantibodies (P = 0.012 for risk/risk or risk/neutral versus protective/protective or neutral/protective). The rs3807306 genotype was independently associated with high serum IFNa in this autoantibody group. We found no difference in IFNa activity according to IRF5 genotype in patients lacking either type of autoantibody or in patients positive for both classes of autoantibody. Conclusion. The IRF5 SLE risk haplotype is associated with higher serum IFNa activity in SLE patients, and this effect is most prominent in patients positive for either anti-RBP or anti-dsDNA autoantibodies. This study demonstrates the biologic relevance of the SLE risk haplotype of IRF5 at the protein level.
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