Objetive Systemic vasculitides represent a heterogeneous group of rare complex diseases of the blood vessels with a poorly understood aetiology. To investigate the shared genetic component underlying their predisposition, we performed the first cross-phenotype meta-analysis of genetic data from different clinically distinct patterns of vasculitis. Methods Immunochip genotyping data from 2465 patients diagnosed with giant cell arteritis, Takayasu’s arteritis, antineutrophil cytoplasmic antibody-associated vasculitis or IgA vasculitis as well as 4632 unaffected controls were analysed to identify common susceptibility loci for vasculitis development. The possible functional consequences of the associated variants were interrogated using publicly available annotation data. Results The strongest association signal corresponded with an intergenic polymorphism located between HLA-DQB1 and HLA-DQA2 (rs6932517, P=4.16E-14, OR=0.74). This single nucleotide polymorphism is in moderate linkage disequilibrium with the disease-specific human leucocyte antigen (HLA) class II associations of each type of vasculitis and could mark them. Outside the HLA region, we identified the KDM4C gene as a common risk locus for vasculitides (highest peak rs16925200, P=6.23E-07, OR=1.75). This gene encodes a histone demethylase involved in the epigenetic control of gene expression. Conclusions Through a combined analysis of Immunochip data, we have identified KDM4C as a new risk gene shared between systemic vasculitides, consistent with the increasing evidences of the crucial role that the epigenetic mechanisms have in the development of complex immune-mediated conditions.

中文翻译：

---

免疫芯片数据的交叉表型分析确定 KDM4Cas 是系统性血管炎发展的相关基因座

客观系统性血管炎代表一组异质性的罕见复杂血管疾病，其病因学知之甚少。为了研究其易感性的共同遗传成分，我们对来自不同临床不同血管炎模式的遗传数据进行了第一次交叉表型荟萃分析。方法分析来自 2465 名被诊断患有巨细胞动脉炎、Takayasu 动脉炎、抗中性粒细胞胞质抗体相关血管炎或 IgA 血管炎的患者以及 4632 名未受影响的对照的免疫芯片基因分型数据，以确定血管炎发展的常见易感位点。使用公开可用的注释数据询问相关变体的可能功能后果。结果最强的关联信号对应于位于HLA-DQB1和HLA-DQA2之间的基因间多态性（rs6932517，P=4.16E-14，OR=0.74）。这种单核苷酸多态性与每种血管炎的疾病特异性人类白细胞抗原 (HLA) II 类关联处于中度连锁不平衡状态，并且可以标记它们。在 HLA 区域之外，我们将 KDM4C 基因鉴定为血管炎的常见风险位点（最高峰 rs16925200，P=6.23E-07，OR=1.75）。该基因编码参与基因表达的表观遗传控制的组蛋白去甲基化酶。结论 通过对免疫芯片数据的综合分析，我们确定 KDM4C 是系统性血管炎之间共有的新风险基因，