NEJM：ANCA相关性血管炎发病机制与遗传组分存在关联

根据一项于2012年7月19日发表在New England Journal of Medicine期刊上的一项研究，对ANCA(antineutrophil cytoplasmic antibody, ANCA, 即抗中性粒细胞胞质抗体)相关性血管炎的全基因组关联研究(genome-wide association study)表明遗传组分也促进疾病易感性产生，并且使得ANCA相关性血管炎(ANCA associated vasculitis, AAV)与肉芽肿病(granulomatosis)、多血管炎(polyangiitis)和显微镜下多血管炎(microscopic polyangiitis)相互区分开来。

为了研究ANCA相关性血管炎的遗传基础，英国剑桥大学Paul A. Lyons博士和同事们对1233名患有ANCA相关性血管炎的英国人和5884名健康人进行全基因关联研究。这种关联研究也在1454名北欧患者和1666名健康人中平行开展。

研究人员鉴定出主要组织相容性复合体(major histocompatibility complex, MHC)和非主要组织相溶性复合体(non-MHC)与ANCA相关性血管炎存在关联。此外，他们发现肉芽肿病、多血管炎和显微镜下多血管炎存在遗传差异。最为强烈的遗传关联并不与临床症状相对应，但是与ANCA的抗原特异性相对应。蛋白酶3 ANCA抗体与HLA-DP和编码α1-抗胰蛋白酶(α1-antitrypsin, SERPINA1)和蛋白酶3(proteinase 3, PRTN3)的基因存在显著性的关联。髓过氧物酶ANCA(anti-myeloperoxidase ANCA)抗体与HLA-DQ存在显著性的关联。

Lyons和同事们作出结论：这项研究证实ANCA相关性血管炎的发病机制与遗传组分存在关联，并表明肉芽肿病与多血管炎和显微镜下多血管炎存在遗传差异，其中后两者与ANCA抗原特异性相关联，这就提示着对自身抗原蛋白酶3产生的反应是蛋白酶3 ANCA相关性血管炎的一个最为重要的病理特征。

本文编译自ANCA-associated vasculitis has genetic component

doi: 10.1056/NEJMoa1108735
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Genetically Distinct Subsets within ANCA-Associated Vasculitis

Paul A. Lyons, Ph.D., Tim F. Rayner, Ph.D., Sapna Trivedi, M.R.C.P., M.Phil., Julia U. Holle, M.D., Ph.D., Richard A. Watts et al.

Background 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. Methods 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. Results 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). Conclusions 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.) Supported by grants from the British Heart Foundation (SP/09/001/27117, to Dr. Smith); the Wellcome Trust (083650/Z/07/Z, to Dr. Smith); the National Institute of Health Research Biomedical Research Centres of Cambridge, Imperial College, and Manchester; the Medical Research Council and Kidney Research UK (to Drs. Rees and Pusey); the West Anglia Comprehensive Local Research Network (to Drs. Smith and Jayne); the Norfolk and Suffolk Comprehensive Local Research Network (to Dr. Watts); and the German Research Foundation (KFO170, to Drs. Holle and Wieczorek); and by a contract from the European Union FP7 Infectious Triggers of Chronic Autoimmunity Consortium (CP-FP 261382, to Drs. Smith, Lyons, and Rees).