Genetic variation at the IRF7/PHRF1 locus is associated with autoantibody profile and serum interferon-alpha activity in lupus patients.
Genetic variation at the IRF7/PHRF1 locus is associated with autoantibody profile and serum interferon-alpha activity in lupus patients.
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DOI：
10.1002/art.27182
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发表时间：
2010-02
影响因子：
--
通讯作者：
Niewold, Timothy B.
中科院分区：
文献类型：
--
作者：
Salloum, Rafah;Franek, Beverly S.;Kariuki, Silvia N.;Rhee, Lesley;Mikolaitis, Rachel A.;Jolly, Meenakshi;Utset, Tammy O.;Niewold, Timothy B.
干扰素-α（IFNα）是系统性红斑狼疮（SLE）的一种遗传危险因子。IRF 7附近的遗传变异与SLE易感性有关SLE相关自身抗体可通过Toll样受体/IRF 7途径刺激IFNα产生。本研究旨在确定IRF 7变体是否通过增加IFNα的产生而作为SLE的危险因素，以及自身抗体是否对这种现象很重要。我们研究了492例SLE患者（236例非洲裔美国人，162例欧洲裔美国人和94例西班牙裔美国人）。使用报告细胞测定法测定血清IFNα水平，并对IRF 7/PHRF 1位点的单核苷酸多态性（SNP）进行基因分型。在对欧洲裔美国人和西班牙裔美国人受试者的联合分析中，rs702966 C等位基因与抗双链DNA（抗dsDNA）抗体的存在相关（比值比[OR] 1.83，P = 0.0069）。rs702966 CC基因型仅与抗dsDNA抗体阳性的欧洲裔美国人和西班牙裔美国人患者的IFNα血清水平较高相关（抗dsDNA阳性患者的联合分析P = 4.1 × 10−5，抗dsDNA阴性患者的联合分析P = 0.99）。在非裔美国人受试者中，抗Sm抗体与IRF 7附近的rs 4963128 SNP相关（OR 1.95，P = 0.0017）。rs 4963128 CT和TT基因型仅在抗Sm抗体阳性的非裔美国人患者中与较高的IFNα血清水平相关（P = 0.0012）。在缺乏抗Sm抗体的非裔美国患者中，观察到抗dsDNA-rs702966 C等位基因相互作用对血清IFNα水平的影响，与其他患者组相似（总体联合分析P = 1.0 × 10 - 6）。在欧洲裔美国人和西班牙裔美国人患者中，IRF 5 SLE风险单倍型与rs702966 C等位基因对抗dsDNA阳性患者的IFNα水平显示出累加效应。我们的研究结果表明，IRF 7/PHRF 1变异体与SLE相关自身抗体联合导致更高的IFNα血清水平，在体内人类SLE中在蛋白水平上提供了该位点的生物学相关性。
Interferon-α (IFNα) is a heritable risk factor for systemic lupus erythematosus (SLE). Genetic variation near IRF7 is implicated in SLE susceptibility. SLE-associated autoantibodies can stimulate IFNα production through the Toll-like receptor/IRF7 pathway. This study was undertaken to determine whether variants of IRF7 act as risk factors for SLE by increasing IFNα production and whether autoantibodies are important to this phenomenon. We studied 492 patients with SLE (236 African American, 162 European American, and 94 Hispanic American subjects). Serum levels of IFNα were measured using a reporter cell assay, and single-nucleotide polymorphisms (SNPs) in the IRF7/PHRF1 locus were genotyped. In a joint analysis of European American and Hispanic American subjects, the rs702966 C allele was associated with the presence of anti–double-stranded DNA (anti-dsDNA) antibodies (odds ratio [OR] 1.83, P = 0.0069). The rs702966 CC genotype was only associated with higher serum levels of IFNα in European American and Hispanic American patients with anti-dsDNA antibodies (joint analysis P = 4.1 × 10−5 in anti-dsDNA–positive patients and P = 0.99 in anti-dsDNA–negative patients). In African American subjects, anti-Sm antibodies were associated with the rs4963128 SNP near IRF7 (OR 1.95, P = 0.0017). The rs4963128 CT and TT genotypes were associated with higher serum levels of IFNα only in African American patients with anti-Sm antibodies (P = 0.0012). In African American patients lacking anti-Sm antibodies, an effect of anti-dsDNA–rs702966 C allele interaction on serum levels of IFNα was observed, similar to the other patient groups (overall joint analysis P = 1.0 × 10−6). In European American and Hispanic American patients, the IRF5 SLE risk haplotype showed an additive effect with the rs702966 C allele on IFNα level in anti-dsDNA–positive patients. Our findings indicate that IRF7/PHRF1 variants in combination with SLE-associated autoantibodies result in higher serum levels of IFNα, providing a biologic relevance for this locus at the protein level in human SLE in vivo.
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DOI：
10.4049/jimmunol.182.1.34
发表时间：
2009-01-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Kariuki SN;Kirou KA;MacDermott EJ;Barillas-Arias L;Crow MK;Niewold TB
通讯作者：
Niewold TB
影响因子：
158.5
作者：
Arbuckle, MR;McClain, MT;Harley, JB
通讯作者：
Harley, JB
影响因子：
30.8
作者：
Skol, AD;Scott, LJ;Boehnke, M
通讯作者：
Boehnke, M
影响因子：
56.9
作者：
Blanco, P;Palucka, AK;Banchereau, J
通讯作者：
Banchereau, J
影响因子：
--
作者：
Kirou, KA;Lee, C;Crow, MK
通讯作者：
Crow, MK