Department of Cell Biology, the Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Ann Rheum Dis. 2021 May;80(5):626-631. doi: 10.1136/annrheumdis-2020-218359. Epub 2021 Jan 6.
Juvenile idiopathic arthritis (JIA) is the most common type of arthritis among children, but a few studies have investigated the contribution of rare variants to JIA. In this study, we aimed to identify rare coding variants associated with JIA for the genome-wide landscape.
We established a rare variant calling and filtering pipeline and performed rare coding variant and gene-based association analyses on three RNA-seq datasets composed of 228 JIA patients in the Gene Expression Omnibus against different sets of controls, and further conducted replication in our whole-exome sequencing (WES) data of 56 JIA patients. Then we conducted differential gene expression analysis and assessed the impact of recurrent functional coding variants on gene expression and signalling pathway.
By the RNA-seq data, we identified variants in two genes reported in literature as JIA causal variants, as well as additional 63 recurrent rare coding variants seen only in JIA patients. Among the 44 recurrent rare variants found in polyarticular patients, 10 were replicated by our WES of patients with the same JIA subtype. Several genes with recurrent functional rare coding variants have also common variants associated with autoimmune diseases. We observed immune pathways enriched for the genes with rare coding variants and differentially expressed genes.
This study elucidated a novel landscape of recurrent rare coding variants in JIA patients and uncovered significant associations with JIA at the gene pathway level. The convergence of common variants and rare variants for autoimmune diseases is also highlighted in this study.
幼年特发性关节炎（JIA）是儿童中最常见的关节炎类型，但很少有研究探讨罕见变异对 JIA 的贡献。在这项研究中，我们旨在确定与 JIA 相关的全基因组罕见编码变异。
我们建立了一个罕见变异调用和过滤管道，并对三个由 228 名 JIA 患者组成的 RNA-seq 数据集进行了罕见编码变异和基于基因的关联分析，这些数据集来自 GEO 数据库，针对不同的对照组，并且进一步在我们的 56 名 JIA 患者的全外显子组测序（WES）数据中进行了复制。然后我们进行了差异基因表达分析，并评估了反复出现的功能性编码变异对基因表达和信号通路的影响。
通过 RNA-seq 数据，我们鉴定了两个在文献中被报道为 JIA 因果变异的基因中的变异，以及在 JIA 患者中仅发现的另外 63 个反复出现的罕见编码变异。在多关节炎患者中发现的 44 个反复出现的罕见变异中，有 10 个在我们对具有相同 JIA 亚型的患者的 WES 中得到了复制。具有反复出现的功能性罕见编码变异的几个基因也与自身免疫性疾病的常见变异有关。我们观察到免疫途径富集了具有罕见编码变异和差异表达基因的基因。
这项研究阐明了 JIA 患者中反复出现的罕见编码变异的新景观，并揭示了基因途径水平与 JIA 显著相关。本研究还强调了自身免疫性疾病常见变异和罕见变异的收敛性。
