The Liggins Institute, The University of Auckland, Auckland, New Zealand.
The Liggins Institute, The University of Auckland, Auckland, New Zealand.
J Autoimmun. 2023 Jul;138:103046. doi: 10.1016/j.jaut.2023.103046. Epub 2023 May 23.
Juvenile idiopathic arthritis (JIA) is an autoimmune, inflammatory joint disease with complex genetic etiology. Previous GWAS have found many genetic loci associated with JIA. However, the biological mechanism behind JIA remains unknown mainly because most risk loci are located in non-coding genetic regions. Interestingly, increasing evidence has found that regulatory elements in the non-coding regions can regulate the expression of distant target genes through spatial (physical) interactions. Here, we used information on the 3D genome organization (Hi-C data) to identify target genes that physically interact with SNPs within JIA risk loci. Subsequent analysis of these SNP-gene pairs using data from tissue and immune cell type-specific expression quantitative trait loci (eQTL) databases allowed the identification of risk loci that regulate the expression of their target genes. In total, we identified 59 JIA-risk loci that regulate the expression of 210 target genes across diverse tissues and immune cell types. Functional annotation of spatial eQTLs within JIA risk loci identified significant overlap with gene regulatory elements (i.e., enhancers and transcription factor binding sites). We found target genes involved in immune-related pathways such as antigen processing and presentation (e.g., ERAP2, HLA class I and II), the release of pro-inflammatory cytokines (e.g., LTBR, TYK2), proliferation and differentiation of specific immune cell types (e.g., AURKA in Th17 cells), and genes involved in physiological mechanisms related to pathological joint inflammation (e.g., LRG1 in arteries). Notably, many of the tissues where JIA-risk loci act as spatial eQTLs are not classically considered central to JIA pathology. Overall, our findings highlight the potential tissue and immune cell type-specific regulatory changes contributing to JIA pathogenesis. Future integration of our data with clinical studies can contribute to the development of improved JIA therapy.
幼年特发性关节炎（JIA）是一种自身免疫性、炎症性关节疾病，具有复杂的遗传病因。以前的 GWAS 发现了许多与 JIA 相关的遗传基因座。然而，JIA 的生物学机制仍然未知，主要是因为大多数风险基因座位于非编码遗传区域。有趣的是，越来越多的证据发现，非编码区域的调控元件可以通过空间（物理）相互作用来调节远处靶基因的表达。在这里，我们利用 3D 基因组组织（Hi-C 数据）的信息来识别与 JIA 风险基因座内的 SNP 物理相互作用的靶基因。随后，使用组织和免疫细胞类型特异性表达定量性状基因座（eQTL）数据库中的数据对这些 SNP-基因对进行分析，鉴定出调节其靶基因表达的风险基因座。总共，我们确定了 59 个 JIA 风险基因座，它们在不同的组织和免疫细胞类型中调节 210 个靶基因的表达。JIA 风险基因座内空间 eQTL 的功能注释与基因调控元件（即增强子和转录因子结合位点）有显著重叠。我们发现涉及免疫相关途径的靶基因，如抗原加工和呈递（例如，ERAP2、HLA Ⅰ类和Ⅱ类）、促炎细胞因子的释放（例如，LTBR、TYK2）、特定免疫细胞类型的增殖和分化（例如，Th17 细胞中的 AURKA）以及与病理性关节炎症相关的生理机制的基因（例如，动脉中的 LRG1）。值得注意的是，许多作为空间 eQTL 的 JIA 风险基因座作用的组织通常不被认为是 JIA 病理学的核心。总体而言，我们的研究结果强调了导致 JIA 发病机制的潜在组织和免疫细胞类型特异性调控变化。未来将我们的数据与临床研究相结合，可以为改善 JIA 治疗做出贡献。
