Department of Medical Genetics, University of British Columbia, and BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada.
Department of Pediatric Rheumatology and Immunology, University Hospital Muenster, Muenster, Germany.
Arthritis Rheumatol. 2023 Jun;75(6):1048-1057. doi: 10.1002/art.42423. Epub 2023 Mar 30.
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare, life-threatening inflammation of blood vessels that can affect both adults and children. Compared to adult-onset disease, AAV is especially rare in children, with an annual prevalence of 0.5-6.4 cases per million children. The etiology of AAV remains largely unknown, and both environmental and genetic factors are likely involved. The present study was undertaken to explore the genetic susceptibility factors recently identified in adult patients, including HLA-DP and HLA-DQ, in pediatric patients.
We performed a genome-wide association study of pediatric AAV in patients of European ancestry (n = 63 AAV cases, n = 315 population-matched controls).
We identified a significant genetic association between pediatric AAV and the HLA-DPB104:01 allele (P = 1.5 × 10 , odds ratio [OR] 3.5), with a stronger association observed in children with proteinase 3-ANCA positivity than in children with myeloperoxidase-ANCA positivity. Among the HLA alleles, the HLA-DPB104:01 allele was the most highly associated with AAV, although not significantly, in a follow-up adult AAV cohort (P = 2.6 × 10 , OR 0.4). T cell receptor and interferon signaling pathways were also shown to be enriched in the pediatric AAV cohort.
The HLA-DPB1 locus showed an association with pediatric AAV, as similarly shown previously in adult AAV. Despite the difference in the age of onset, these findings suggest that childhood- and adult-onset vasculitis share a common genetic predisposition. The identification of genetic variants contributing to AAV is an important step to improved classification tools and treatment strategies.
抗中性粒细胞胞浆抗体（ANCA）相关性血管炎（AAV）是一种罕见的、危及生命的血管炎症，可影响成人和儿童。与成人发病相比，AAV 在儿童中尤其罕见，每百万儿童中每年的患病率为 0.5-6.4 例。AAV 的病因仍在很大程度上未知，环境和遗传因素都可能参与其中。本研究旨在探讨最近在成人患者中发现的遗传易感性因素，包括 HLA-DP 和 HLA-DQ，在儿科患者中的作用。
我们对欧洲血统的儿科 AAV 患者（n=63 例 AAV 病例，n=315 例人群匹配对照）进行了全基因组关联研究。
我们发现儿科 AAV 与 HLA-DPB104:01 等位基因之间存在显著的遗传关联（P=1.5×10 ，优势比[OR]3.5），在蛋白酶 3-ANCA 阳性的儿童中比在髓过氧化物酶-ANCA 阳性的儿童中观察到更强的关联。在 HLA 等位基因中，尽管在随后的成人 AAV 队列中没有显著意义（P=2.6×10 ，OR 0.4），但 HLA-DPB104:01 等位基因与 AAV 的关联最密切。T 细胞受体和干扰素信号通路也在儿科 AAV 队列中富集。
HLA-DPB1 基因座与儿科 AAV 相关，如先前在成人 AAV 中所示。尽管发病年龄不同，但这些发现表明儿童和成人发病的血管炎具有共同的遗传易感性。确定导致 AAV 的遗传变异是改善分类工具和治疗策略的重要步骤。
