NEJM：引发血管炎症的相关基因

近来，研究人员发现引发脉管炎，导致血管炎症的相关基因。相关研究论文发表在国际著名刊物New England Journal of Medicine杂志上。

血管炎可以影响所有包括只有借助显微镜才可见的微小血管在内的各类大小血管。当血管发炎时，组织损害会随之而来。这些症状可能很难诊断，因此导致血管炎一直是知之甚少。遗传因素是众所周知的参与其中的重要一部分，国际上一直在研究这些基因的细节。这项研究侧重于一种称为肉芽肿血管炎（GPA），是一种自体免疫疾病。

GPA是一个潜在的威胁生命的疾病，抗体测试技术已被彻底改变了此类疾病的诊断，这类抗体被称为C-ANCA抗体。该测试15年前就通过成立，结果测试后发现这种疾病比以前已知的更常见。这15年的时间后，有超过250部免疫学实验室分析样品来确诊病人。

使用C-ANCA测试可以非常明确诊断，其中对患者进行基因筛选研究是一个关键的细节。在这最近的一项研究，一种确定这些基因的单核苷酸多态性研究的方法被应用到GPA患者上。

在研究的第一部分，来自英国的1223例进行了调查，同时对1454北欧患者开展的相关也证实了结果，C-ANCA抗体的患者具有独特的免疫相关基因表达谱，这区别存在特有自身抗体P-ANCA的患者。这些结果不仅确定导致这种炎性疾病的遗传因素，这反过来又可以导致开发更具体的针对免疫系统的疗法。

编译自：Vasculitis related genes cause inflammation of blood vessels

doi:full/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

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.)