Salloum Rafah, Franek Beverly S, Kariuki Silvia N, Rhee Lesley, Mikolaitis Rachel A, Jolly Meenakshi, Utset Tammy O, Niewold Timothy B
University of Chicago, Chicago, IL, USA.
Arthritis Rheum. 2010 Feb;62(2):553-61. doi: 10.1002/art.27182.
Interferon-alpha (IFNalpha) is a heritable risk factor for systemic lupus erythematosus (SLE). Genetic variation near IRF7 is implicated in SLE susceptibility. SLE-associated autoantibodies can stimulate IFNalpha 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 IFNalpha 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 IFNalpha 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 IFNalpha in European American and Hispanic American patients with anti-dsDNA antibodies (joint analysis P = 4.1 x 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 IFNalpha 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 IFNalpha was observed, similar to the other patient groups (overall joint analysis P = 1.0 x 10(-6)). In European American and Hispanic American patients, the IRF5 SLE risk haplotype showed an additive effect with the rs702966 C allele on IFNalpha 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 IFNalpha, providing a biologic relevance for this locus at the protein level in human SLE in vivo.
α干扰素（IFNα）是系统性红斑狼疮（SLE）的一种遗传风险因素。IRF7附近的基因变异与SLE易感性有关。SLE相关自身抗体可通过Toll样受体/IRF7途径刺激IFNα产生。本研究旨在确定IRF7变异是否通过增加IFNα产生而成为SLE的风险因素，以及自身抗体对这一现象是否重要。
我们研究了492例SLE患者（236例非裔美国人、162例欧洲裔美国人、94例西班牙裔美国人）。使用报告细胞分析法测量血清IFNα水平，并对IRF7/PHRF1基因座中的单核苷酸多态性（SNP）进行基因分型。
在欧洲裔美国人和西班牙裔美国人的联合分析中，rs702966 C等位基因与抗双链DNA（抗dsDNA）抗体的存在相关（优势比[OR]1.83，P = 0.0069）。rs702966 CC基因型仅在有抗dsDNA抗体的欧洲裔美国人和西班牙裔美国人患者中与较高的血清IFNα水平相关（抗dsDNA阳性患者联合分析P = 4.1×10⁻⁵，抗dsDNA阴性患者P = 0.99）。在非裔美国人中，抗Sm抗体与IRF7附近的rs4963128 SNP相关（OR 1.95，P = 0.0017）。rs4963128 CT和TT基因型仅在有抗Sm抗体的非裔美国人患者中与较高的血清IFNα水平相关（P = 0.0012）。在缺乏抗Sm抗体的非裔美国人患者中，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，IRF5 SLE风险单倍型在抗dsDNA阳性患者中与rs702966 C等位基因对IFNα水平有累加效应。
我们的研究结果表明，IRF7/PHRF1变异与SLE相关自身抗体共同作用导致血清IFNα水平升高，为该基因座在人类SLE体内蛋白质水平上提供了生物学相关性。
