Supplementary Tables 1-11.xlsx

<b>ABSTRACT</b><b>Objectives:</b><b> </b>To uncover the gene-regulatory mechanism linking juvenile idiopathic arthritis (JIA) to its comorbid conditions.<b>Methods</b>: A two-sample Mendelian Randomization (MR) analysis was conducted to identify genes causally linked to JIA. Integration of data from expression quantitative trait loci (eQTL), 3D genome organization, and protein-protein interaction network was performed to pinpoint sets of single-nucleotide polymorphisms (i.e., spatial eQTL SNPs) regulating the expression of these genes and their interaction partners. These SNPs were then cross-referenced against a public GWAS database to identify other traits that have been previously associated with these SNPs.<b>Results:</b><b> </b>MR analysis identified 54 blood-expressed genes causally linked to JIA. The spatial eQTLs regulating JIA causal genes and their interaction partners were enriched for the GWAS SNPs of 87 comorbid traits. Shared dysregulation of three HLA class II genes underpins the association between JIA and most comorbid traits. We highlighted a set of genes on chromosome 6p22.1 (<i>HLA-A, HCG4P5, HLA-T, MOG, TRIM26, HCG, IFITM4P</i>) involved in the association between JIA and specific autoimmune diseases, such as Crohn’s disease, type 1 diabetes, asthma, and rheumatoid arthritis. Unique associations between JIA and Hodgkin lymphoma was identified through genes in 6p21.3 (<i>FKBPL</i>, <i>PBX2</i>, <i>AGER</i>) and chronic lymphocytic leukaemia through the <i>BAK1</i> gene.<b>Conclusions:</b><b> </b>The JIA phenotype is partially determined by an individual's genetic susceptibility to specific co-occurring conditions. Our research enhances the understanding of disease origins by identifying regulatory mechanisms linking JIA with its comorbidities. This offers avenues for pinpointing shared therapeutic targets, thereby improving outcomes for patients with multimorbidity.

摘要
<b>研究目的：</b> 揭示幼年特发性关节炎（juvenile idiopathic arthritis, JIA）与其共病之间的基因调控机制。
<b>研究方法：</b> 本研究采用双样本孟德尔随机化（Mendelian Randomization, MR）分析，筛选与JIA存在因果关联的基因。整合表达数量性状位点（expression quantitative trait loci, eQTL）、三维基因组结构以及蛋白质相互作用网络的数据，精准定位调控这些基因及其互作伴侣表达的单核苷酸多态性（single-nucleotide polymorphisms, SNPs）集合（即空间eQTL SNPs）。随后将这些SNPs与公共全基因组关联分析（Genome-Wide Association Study, GWAS）数据库进行交叉比对，识别此前与这些SNPs相关联的其他性状。
<b>研究结果：</b> MR分析共筛选出54个与JIA存在因果关联的血液表达基因。调控JIA因果基因及其互作伴侣的空间eQTLs，在87种共病性状的GWAS SNPs中显著富集。3个HLA II类基因的共同失调，是JIA与大多数共病性状之间关联的基础。本研究重点关注6号染色体短臂2区2带1亚区（6p22.1）上的一组基因：<i>HLA-A、HCG4P5、HLA-T、MOG、TRIM26、HCG、IFITM4P</i>，这些基因参与了JIA与克罗恩病、1型糖尿病、哮喘及类风湿关节炎等特定自身免疫性疾病的关联。通过6p21.3区域的<i>FKBPL、PBX2、AGER</i>基因，本研究明确了JIA与霍奇金淋巴瘤之间的独特关联；通过<i>BAK1</i>基因，则明确了JIA与慢性淋巴细胞白血病之间的独特关联。
<b>研究结论：</b> JIA的表型部分由个体对特定共病的遗传易感性所决定。本研究通过揭示JIA与其共病之间的调控机制，加深了对疾病起源的理解，为确定共享治疗靶点提供了方向，从而有望改善多病共存患者的临床结局。