Genetically distinct subsets within ANCA-associated vasculitis.
Genetically distinct subsets within ANCA-associated vasculitis.
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DOI：
10.1056/nejmoa1108735
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发表时间：
2012-07-19
期刊：
影响因子：
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通讯作者：
Smith KG
中科院分区：
文献类型：
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作者：
Lyons PA;Rayner TF;Trivedi S;Holle JU;Watts RA;Jayne DR;Baslund B;Brenchley P;Bruchfeld A;Chaudhry AN;Cohen Tervaert JW;Deloukas P;Feighery C;Gross WL;Guillevin L;Gunnarsson I;Harper L;Hrušková Z;Little MA;Martorana D;Neumann T;Ohlsson S;Padmanabhan S;Pusey CD;Salama AD;Sanders JS;Savage CO;Segelmark M;Stegeman CA;Tesař V;Vaglio A;Wieczorek S;Wilde B;Zwerina J;Rees AJ;Clayton DG;Smith KG
抗神经元胞质抗体（ANCA）相关性血管炎是一种严重的疾病，包括两个主要综合征：肉芽肿病伴多血管炎（以前称为韦格纳肉芽肿病）和显微镜下多血管炎。其原因尚不清楚，关于它是否是一个单一的疾病实体以及ANCA在其发病机制中起什么作用存在争议。我们研究了它的遗传基础。在1233名英国人的发现队列中进行了全基因组关联研究。ANCA相关性血管炎患者和5884名对照，并在1454名北方欧洲病例患者和1666名对照中重复。质量控制，人口分层，并根据标准进行统计分析。我们发现主要组织相容性复合体（MHC）和非MHC与ANCA相关性血管炎相关，肉芽肿性多血管炎和显微镜下多血管炎在遗传学上是不同的。最强的遗传关联与ANCA的抗原特异性有关，而与临床综合征无关。抗蛋白酶3 ANCA与HLA-DP和编码α1-抗胰蛋白酶（SERPINA 1）和蛋白酶3（PRTN 3）的基因相关（分别为P = 6.2×10−89、P = 5.6×10−12和P = 2.6×10−7）。抗髓过氧化物酶ANCA与HLA-DQ相关（P = 2.1×10−8）。本研究证实ANCA相关性血管炎的发病机制具有遗传成分，显示了肉芽肿性多血管炎和与ANCA特异性相关的显微镜下多血管炎之间的遗传差异，并表明对自身抗原蛋白酶3的反应是蛋白酶3 ANCA相关性血管炎的主要致病特征。这些数据为蛋白酶3 ANCA相关性血管炎和髓过氧化物酶ANCA相关性血管炎是不同的自身免疫综合征的概念提供了初步支持。（由英国心脏基金会和其他机构资助。
Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis is a severe condition encompassing two major syndromes: granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis) and microscopic polyangiitis. Its cause is unknown, and there is debate about whether it is a single disease entity and what role ANCA plays in its pathogenesis. We investigated its genetic basis. A genomewide association study was performed in a discovery cohort of 1233 U.K. patients with ANCA-associated vasculitis and 5884 controls and was replicated in 1454 Northern European case patients and 1666 controls. Quality control, population stratification, and statistical analyses were performed according to standard criteria. We found both major-histocompatibility-complex (MHC) and non-MHC associations with ANCA-associated vasculitis and also that granulomatosis with polyangiitis and microscopic polyangiitis were genetically distinct. The strongest genetic associations were with the antigenic specificity of ANCA, not with the clinical syndrome. Anti–proteinase 3 ANCA was associated with HLA-DP and the genes encoding α1-antitrypsin (SERPINA1) and proteinase 3 (PRTN3) (P = 6.2×10−89, P = 5.6×10−12, and P = 2.6×10−7, respectively). Anti–myeloperoxidase ANCA was associated with HLA-DQ (P = 2.1×10−8). This study confirms that the pathogenesis of ANCA-associated vasculitis has a genetic component, shows genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis that are associated with ANCA specificity, and suggests that the response against the autoantigen proteinase 3 is a central pathogenic feature of proteinase 3 ANCA–associated vasculitis. These data provide preliminary support for the concept that proteinase 3 ANCA–associated vasculitis and myeloperoxidase ANCA–associated vasculitis are distinct autoimmune syndromes. (Funded by the British Heart Foundation and others.)