IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus.
IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus.
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DOI：
10.1136/annrheumdis-2011-200463
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发表时间：
2012-03
影响因子：
27.4
通讯作者：
Harley JB
中科院分区：
文献类型：
--
作者：
Niewold TB;Kelly JA;Kariuki SN;Franek BS;Kumar AA;Kaufman KM;Thomas K;Walker D;Kamp S;Frost JM;Wong AK;Merrill JT;Alarcón-Riquelme ME;Tikly M;Ramsey-Goldman R;Reveille JD;Petri MA;Edberg JC;Kimberly RP;Alarcón GS;Kamen DL;Gilkeson GS;Vyse TJ;James JA;Gaffney PM;Moser KL;Crow MK;Harley JB
高血清干扰素α（IFNα）活性是系统性红斑狼疮（SLE）的一个可遗传的危险因素。SLE中发现的自身抗体形成免疫复合物，可通过激活内体Toll样受体和干扰素调节因子（IRF）（包括IRF 5）刺激IFNα产生。IRF 5的遗传变异与SLE易感性相关;然而，目前尚不清楚IRF 5功能性遗传元件如何促进人类疾病。1034例SLE患者和989名欧洲血统的对照，555例SLE患者和679名非洲裔美国人血统的对照，以及73例南非血统的SLE患者在IRF 5多态性进行基因分型，这定义了主要的单倍型。使用功能测定法测定血清IFNα活性。在欧洲血统的受试者中，抗双链DNA（dsDNA）和抗Ro抗体各自与不同的单倍型相关，其特征在于功能遗传元件的不同组合（OR > 2.56，p > 003 C;两者均为1.9×10−14）。这些IRF 5单倍型-自身抗体关联强烈预测SLE患者血清IFNα水平升高，并解释了> 70%的IRF 5所致SLE遗传风险。在非裔美国SLE患者中，观察到血清学和IFNα之间的类似关系，尽管先前描述的欧洲血统风险单倍型在非裔美国受试者中以混合比例存在，而在非洲SLE患者中不存在。作者定义了一种与抗dsDNA抗体相关的IRF 5的新风险单倍型，并表明由于IRF 5基因型导致的SLE风险在很大程度上取决于特定的自身抗体。这表明自身抗体在人SLE中是直接致病的，导致IFNα与IRF 5功能遗传元件的特定组合协同作用而增加。SLE是一种全身性自身免疫性疾病，影响多个器官系统，包括皮肤，肌肉骨骼，肾脏和造血系统。体液性自身免疫是SLE的标志，患者经常有针对dsDNA的循环自身抗体，以及RNA结合蛋白（RBP）。抗RBP自身抗体包括识别Ro、La、Smith（抗Sm）和核糖核蛋白（抗nRNP）的抗体，统称为抗视黄醇结合蛋白。抗视黄醇结合蛋白和抗双链DNA自身抗体在健康人群中很少见。这些自身抗体可在临床SLE疾病发作前数年存在于血清中，并且在SLE中可能是致病性的。
High serum interferon α (IFNα) activity is a heritable risk factor for systemic lupus erythematosus (SLE). Auto-antibodies found in SLE form immune complexes which can stimulate IFNα production by activating endosomal Toll-like receptors and interferon regulatory factors (IRFs), including IRF5. Genetic variation in IRF5 is associated with SLE susceptibility; however, it is unclear how IRF5 functional genetic elements contribute to human disease. 1034 patients with SLE and 989 controls of European ancestry, 555 patients with SLE and 679 controls of African–American ancestry, and 73 patients with SLE of South African ancestry were genotyped at IRF5 polymorphisms, which define major haplotypes. Serum IFNα activity was measured using a functional assay. In European ancestry subjects, anti-double-stranded DNA (dsDNA) and anti-Ro antibodies were each associated with different haplotypes characterised by a different combination of functional genetic elements (OR > 2.56, p >003C; 1.9×10−14 for both). These IRF5 haplotype-auto-antibody associations strongly predicted higher serum IFNα in patients with SLE and explained > 70% of the genetic risk of SLE due to IRF5. In African–American patients with SLE a similar relationship between serology and IFNα was observed, although the previously described European ancestry-risk haplotype was present at admixture proportions in African–American subjects and absent in African patients with SLE. The authors define a novel risk haplotype of IRF5 that is associated with anti-dsDNA antibodies and show that risk of SLE due to IRF5 genotype is largely dependent upon particular auto-antibodies. This suggests that auto-antibodies are directly pathogenic in human SLE, resulting in increased IFNα in cooperation with particular combinations of IRF5 functional genetic elements. SLE is a systemic autoimmune disorder affecting multiple organ systems including the skin, musculoskeletal, renal and haematopoietic systems. Humoral autoimmunity is a hallmark of SLE, and patients frequently have circulating auto-antibodies directed against dsDNA, as well as RNA binding proteins (RBP). Anti-RBP autoantibodies include antibodies which recognize Ro, La, Smith (anti-Sm), and ribonucleoprotein (anti-nRNP), collectively referred to as anti-retinol-binding protein). Anti-retinol-binding protein and anti-dsDNA auto-antibodies are rare in the healthy population. These auto-antibodies can be present in sera for years preceding the onset of clinical SLE illness and are likely pathogenic in SLE.