Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK Vasculitis and Lupus Service, Addenbrooke's Hospital, Cambridge, UK Nephrology Unit, University Hospital of Parma, Parma, Italy.
Unit of Medical Genetics, University Hospital of Parma, Parma, Italy.
Nephrol Dial Transplant. 2015 Apr;30 Suppl 1:i37-45. doi: 10.1093/ndt/gfu386. Epub 2014 Dec 18.
The genetics of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a complex area of investigation because of the low frequency of AAVs, the rarity of familial cases and the complexity of disease phenotypes. However, recent studies have been able to gather significant numbers of patients, and multicentre collaborative efforts have allowed the performance of two genome-wide association studies (GWASs). Genetic association studies based on candidate gene approaches and the two GWASs have greatly contributed to our current understanding of the genetic basis of AAV. The central role of autoimmunity has been confirmed by the significant association with HLA polymorphisms; interestingly, the three main AAV subtypes are associated with distinct HLA variants, i.e. granulomatosis with polyangiitis (Wegener's GPA) with HLA-DP1, microscopic polyangiitis with HLA-DQ and eosinophilic GPA (Churg-Strauss) with HLA-DRB4. GWASs also revealed that polymorphic variants of genes encoding proteinase 3 (PR3), the predominant antigenic target of ANCA in GPA, and its main inhibitor, alpha-1 antitrypsin, are highly associated with GPA and, even more significantly, with PR3-ANCA positivity (regardless of the clinical diagnosis); this emphasizes the central pathogenic role of PR3 and humoral autoimmunity in PR3-ANCA positive vasculitis. Finally, candidate gene approach studies have shown associations with other variants involved in autoimmunity, such as those belonging to the CTLA-4 and PTPN22 genes, although these findings warrant replication in larger studies. Additional studies are underway to better characterize disease associations within the AAV spectrum, which could provide new pathogenetic clues and possibly new treatment targets.
抗中性粒细胞胞浆抗体 (ANCA)-相关性血管炎 (AAV) 的遗传学是一个复杂的研究领域，因为 AAV 的频率较低，家族病例罕见，疾病表型复杂。然而，最近的研究已经能够收集到大量的患者，并且多中心合作已经允许进行两项全基因组关联研究 (GWAS)。基于候选基因方法的遗传关联研究和两项 GWAS 极大地促进了我们目前对 AAV 遗传基础的理解。自身免疫的核心作用已通过与 HLA 多态性的显著关联得到证实；有趣的是，三种主要的 AAV 亚型与不同的 HLA 变体相关联，即肉芽肿性多血管炎（韦格纳 GPA）与 HLA-DP1、显微镜下多血管炎与 HLA-DQ 和嗜酸性粒细胞性 GPA（Churg-Strauss）与 HLA-DRB4。GWAS 还表明，编码蛋白酶 3 (PR3) 的基因多态性变体，PR3 是 GPA 中主要的 ANCA 抗原靶标，以及其主要抑制剂α-1 抗胰蛋白酶，与 GPA 高度相关，更重要的是与 PR3-ANCA 阳性（无论临床诊断如何）；这强调了 PR3 和体液自身免疫在 PR3-ANCA 阳性血管炎中的中心致病作用。最后，候选基因方法的研究表明与其他涉及自身免疫的变体相关联，例如属于 CTLA-4 和 PTPN22 基因的变体，尽管这些发现需要在更大的研究中进行复制。正在进行进一步的研究以更好地描述 AAV 谱内的疾病关联，这可能提供新的发病机制线索，并可能提供新的治疗靶点。
