Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands.
Walaeus Library, Leiden University Medical Centre, Leiden, The Netherlands.
Ann Rheum Dis. 2016 Sep;75(9):1687-92. doi: 10.1136/annrheumdis-2015-207601. Epub 2015 Oct 6.
Genetic factors may influence the pathogenic pathways leading to antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We performed a meta-analysis to determine the genetic variants most likely associated with AAV and investigated whether diagnostic and serological subtypes within AAV have distinct genetic backgrounds.
Studies investigating the association between genetic variants and AAV in humans were searched in PubMed, EMBASE and Web of Science. All variants investigated in at least two studies were selected. Subsequently, all studies assessing these variants were included in this meta-analysis. Additionally, data on these variants from the largest genome-wide association studies in AAV were included to increase the validity of this meta-analysis.
The literature search yielded 5180 articles. 62 articles investigating 140 genetic variants were included, 33 of which were associated with AAV in a meta-analysis. These genetic variants were in or near the following genes: CD226, CTLA-4, FCGR2A, HLA-B, HLA-DP, HLA-DQ, HLA-DR, HSD17B8, IRF5, PTPN22, RING1/RXRB, RXRB, STAT4, SERPINA1 and TLR9. Moreover, we identified genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis and between proteinase 3 ANCA vasculitis and myeloperoxidase ANCA vasculitis. In 76% of the genetic variants, subdivision based on ANCA serotype resulted in higher ORs than subdivision based on clinical diagnosis.
This meta-analysis identified 33 genetic variants associated with AAV, supporting a role for alpha-1-antitrypsin, the major histocompatibility complex system, and several distinct inflammatory processes in AAV pathogenesis. Our results indicate that subdivision of AAV based on ANCA serotype has a stronger genetic basis than subdivision based on clinical diagnosis.
遗传因素可能影响导致抗中性粒细胞胞质抗体（ANCA）相关性血管炎（AAV）的致病途径。我们进行了一项荟萃分析，以确定与 AAV 最相关的遗传变异，并研究 AAV 中的诊断和血清学亚型是否具有不同的遗传背景。
在 PubMed、EMBASE 和 Web of Science 中搜索了研究遗传变异与人类 AAV 之间关联的研究。选择了至少有两项研究调查的所有变异。随后，将所有评估这些变异的研究纳入本荟萃分析。此外，还纳入了 AAV 最大的全基因组关联研究中这些变异的数据，以增加本荟萃分析的有效性。
文献检索产生了 5180 篇文章。纳入了 62 篇研究 140 个遗传变异的文章，其中 33 个在荟萃分析中与 AAV 相关。这些遗传变异位于或靠近以下基因：CD226、CTLA-4、FCGR2A、HLA-B、HLA-DP、HLA-DQ、HLA-DR、HSD17B8、IRF5、PTPN22、RING1/RXRB、RXRB、STAT4、SERPINA1 和 TLR9。此外，我们还发现了肉芽肿性多血管炎和显微镜下多血管炎以及蛋白酶 3-ANCA 血管炎和髓过氧化物酶-ANCA 血管炎之间的遗传差异。在 76%的遗传变异中，基于 ANCA 血清型的细分导致的 OR 高于基于临床诊断的细分。
本荟萃分析确定了 33 个与 AAV 相关的遗传变异，支持 α-1-抗胰蛋白酶、主要组织相容性复合体系统和几个不同的炎症过程在 AAV 发病机制中的作用。我们的结果表明，基于 ANCA 血清型的 AAV 细分比基于临床诊断的细分具有更强的遗传基础。
