■幼年特发性关节炎(JIA)是一种自身免疫性关节疾病,经常与其他复杂表型同时发生,包括癌症和其他自身免疫性疾病。尽管通过全基因组关联研究(GWAS)鉴定了许多风险变异,受影响的基因,它们与JIA发病机制的联系,它们在相关性状发展中的作用尚不清楚。这项研究旨在通过阐明JIA发病机理的基因调控机制并探索其在相关性状出现中的潜在作用来解决这些差距。
■进行了双样本孟德尔随机化(MR)分析,以鉴定与JIA有因果关系的血液表达基因。随后使用经过策划的蛋白质相互作用网络来鉴定单核苷酸多态性的集合(即,空间eQTLSNP),调节JIA因果基因及其蛋白质相互作用伴侣的表达。将这些SNP与GWAS目录交叉引用以鉴定与JIA相关的统计学上富集的性状。
■双样本MR分析确定了52个基因,其在血液中的表达变化被认为是JIA的因果关系。这些基因(例如,HLA,LTA,LTB,IL6ST)参与一系列免疫相关途径(例如,抗原呈递,细胞因子信号),并展示不同免疫细胞类型之间的细胞类型特异性调节模式(例如,CD4+T细胞中的PPP1R11)。调节JIA因果基因及其相互作用伙伴的空间eQTL在统计上丰富了与95个其他性状相关的GWASSNP,包括已知和新颖的JIA相关特征。这种综合分析确定了其失调的基因可以解释JIA和相关性状之间的联系。如自身免疫性/炎性疾病(6p22.1位点的基因),霍奇金淋巴瘤(6p21.3基因[FKBPL,PBX2,AGER]),慢性淋巴细胞白血病(BAK1)。
■我们的方法为理解JIA的遗传结构和相关性状提供了重大进展。结果表明,JIA患者的相关性状负担可能不同,受它们在不同性状簇之间的综合遗传风险的影响。未来对已识别的连接的实验验证可以为精细的患者分层铺平道路,新生物标志物的发现,和共同的治疗目标。
UNASSIGNED: Juvenile idiopathic arthritis (JIA) is an autoimmune joint disease that frequently co-occurs with other complex phenotypes, including cancers and other autoimmune diseases. Despite the identification of numerous risk variants through genome-wide association studies (GWAS), the affected genes, their connection to JIA pathogenesis, and their role in the development of associated traits remain unclear. This study aims to address these gaps by elucidating the gene-regulatory mechanisms underlying JIA pathogenesis and exploring its potential role in the emergence of associated traits.
UNASSIGNED: A two-sample Mendelian Randomization (MR) analysis was conducted to identify blood-expressed genes causally linked to JIA. A curated protein interaction network was subsequently used to identify sets of single-nucleotide polymorphisms (i.e., spatial eQTL SNPs) that regulate the expression of JIA causal genes and their protein interaction partners. These SNPs were cross-referenced against the GWAS catalog to identify statistically enriched traits associated with JIA.
UNASSIGNED: The two-sample MR analysis identified 52 genes whose expression changes in the blood are putatively causal for JIA. These genes (e.g., HLA, LTA, LTB, IL6ST) participate in a range of immune-related pathways (e.g., antigen presentation, cytokine signalling) and demonstrate cell type-specific regulatory patterns across different immune cell types (e.g., PPP1R11 in CD4+ T cells). The spatial eQTLs that regulate JIA causal genes and their interaction partners were statistically enriched for GWAS SNPs linked with 95 other traits, including both known and novel JIA-associated traits. This integrative analysis identified genes whose dysregulation may explain the links between JIA and associated traits, such as autoimmune/inflammatory diseases (genes at 6p22.1 locus), Hodgkin lymphoma (genes at 6p21.3 [FKBPL, PBX2, AGER]), and chronic lymphocytic leukemia (BAK1).
UNASSIGNED: Our approach provides a significant advance in understanding the genetic architecture of JIA and associated traits. The results suggest that the burden of associated traits may differ among JIA patients, influenced by their combined genetic risk across different clusters of traits. Future experimental validation of the identified connections could pave the way for refined patient stratification, the discovery of new biomarkers, and shared therapeutic targets.