Association of the IRF5 risk haplotype with high serum interferon-alpha activity in systemic lupus erythematosus patients.
Association of the IRF5 risk haplotype with high serum interferon-alpha activity in systemic lupus erythematosus patients.
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DOI：
10.1002/art.23613
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发表时间：
2008-08
影响因子：
--
通讯作者：
Crow, Mary K.
中科院分区：
文献类型：
--
作者：
Niewold, Timothy B.;Kelly, Jennifer A.;Flesch, Marie. H.;Espinoza, Luis R.;Harley, John B.;Crow, Mary K.
干扰素调节因子5（interferon regulatory factor 5，IRF 5）基因的单倍型与系统性红斑狼疮（systemic lupus erythematosus，SLE）的发生有关，我们的前期研究表明高水平的血清干扰素-α（interferon-α，IFNα）活性是SLE的一个遗传危险因素。本研究的目的是确定IRF 5 SLE风险单倍型是否通过诱发患者发展为高水平的血清IFNα活性来介导SLE的风险。用灵敏的功能性报告细胞法测定了199例欧洲和西班牙血统的SLE患者的IFNα水平。在这些患者中对IRF 5的rs 2004640、rs3807306、rs 10488631和rs 2280714单核苷酸多态性（SNP）进行基因分型。根据已发表的数据，将单倍型分为SLE风险型、中性型或保护型。SLE患者IRF 5基因型为危险/危险型和危险/中性型者血清IFNα活性高于保护/保护型和中性/保护型者（P = 0.025）。IRF 5基因型对血清IFNα水平的差异性影响主要由抗RNA结合蛋白（抗RBP）或抗双链DNA（抗dsDNA）自身抗体阳性的SLE患者驱动（风险/风险或风险/中性vs保护性/保护性或中性/保护性P = 0.012）。rs3807306基因型与该自身抗体组的高血清IFNα独立相关。我们发现，在缺乏任一类型自身抗体或两种类型自身抗体阳性的患者中，根据IRF 5基因型，IFNα活性无差异。SLE患者中IRF 5 SLE风险单倍型与较高的血清IFNα活性相关，并且这种效应在抗RBP或抗dsDNA自身抗体阳性的患者中最为突出。本研究证实了SLE风险单倍型IRF 5在蛋白水平上的生物学相关性。
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-α (IFNα) 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 IFNα activity. IFNα 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. SLE patients with risk/risk and risk/neutral IRF5 genotypes had higher serum IFNα activity than did those with protective/protective and neutral/protective genotypes (P = 0.025). This differential effect of IRF5 genotype on serum IFNα 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 IFNα in this autoantibody group. We found no difference in IFNα activity according to IRF5 genotype in patients lacking either type of autoantibody or in patients positive for both classes of autoantibody. The IRF5 SLE risk haplotype is associated with higher serum IFNα 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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影响因子：
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通讯作者：
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