Zhang Zheng, Zhang Jiayi, Yan Xinyang, Wang Jiachen, Huang Haoxiang, Teng Menghao, Liu Qingguang, Han Shaoshan
Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China.
Department of Neurosurgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China.
J Transl Autoimmun. 2024 Nov 5;10:100260. doi: 10.1016/j.jtauto.2024.100260. eCollection 2025 Jun.
Autoimmune liver diseases (AILDs) encompass autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). The onset of these diseases is fundamentally influenced by genetic susceptibility. Although various extrahepatic factors are potentially linked to AILDs, the genetic underpinnings and mechanisms of these associations remain unclear.
Utilizing large-scale genome-wide association study (GWAS) data, this study systematically investigated the relationships between extrahepatic autoimmune diseases (EHAIDs), immune cells, and various triggering factors with AILDs. Mendelian randomization (MR) was employed to assess the causal effects of these extrahepatic factors on AILDs, complemented by linkage disequilibrium score (LDSC) regression to uncover shared genetic architecture and causal effects underlying the associations between autoimmune diseases. We employed colocalization, enrichment analysis, and protein-protein interaction (PPI) network to identify the functions of shared loci. Additionally, we proposed that activated immune cells in the circulation may contribute to liver and biliary tract inflammation via migration, mediating the impact of extrahepatic factors on AILDs. This hypothesis was tested using two mediation analysis methods: two-step MR (TSMR) and multivariable MR (MVMR).
Causal associations between multiple extrahepatic factors and AILDs were identified. Notably, CD27 B cells were found to be a risk factor for PBC, while PSC progression was associated with CD28 CD8 T cells exhaustion and increased levels of CD28 CD8 T cells. Mediation analyses revealed 64 pathways via TSMR and 15 pathways via MVMR, indicating that the effects of extrahepatic factors on AILDs may be mediated by circulating immune cells. The shared genetic architecture also contributed to these associations. Analysis of shared loci and gene functions identified ATXN2 as being shared between PBC and 9 EHAIDs, while SH2B3 and PSMG1 were shared with 6 and 5 EHAIDs, respectively, in PSC.
Our research compared three distinct AILDs, enhancing the understanding of their etiology and providing new evidence on risk factors, diagnostic markers, and potential therapeutic targets.
自身免疫性肝病（AILDs）包括自身免疫性肝炎（AIH）、原发性胆汁性胆管炎（PBC）和原发性硬化性胆管炎（PSC）。这些疾病的发病在根本上受遗传易感性影响。尽管各种肝外因素可能与AILDs相关，但这些关联的遗传基础和机制仍不清楚。
本研究利用大规模全基因组关联研究（GWAS）数据，系统地研究了肝外自身免疫性疾病（EHAIDs）、免疫细胞和各种触发因素与AILDs之间的关系。采用孟德尔随机化（MR）评估这些肝外因素对AILDs的因果效应，并辅以连锁不平衡评分（LDSC）回归，以揭示自身免疫性疾病之间关联的共享遗传结构和因果效应。我们采用共定位、富集分析和蛋白质-蛋白质相互作用（PPI）网络来确定共享位点的功能。此外，我们提出循环中活化的免疫细胞可能通过迁移导致肝脏和胆道炎症，介导肝外因素对AILDs的影响。使用两种中介分析方法对这一假设进行了检验：两步MR（TSMR）和多变量MR（MVMR）。
确定了多种肝外因素与AILDs之间的因果关联。值得注意的是，发现CD27 B细胞是PBC的一个危险因素，而PSC的进展与CD28 CD8 T细胞耗竭和CD28 CD8 T细胞水平升高有关。中介分析通过TSMR揭示了64条通路，通过MVMR揭示了15条通路，表明肝外因素对AILDs的影响可能由循环免疫细胞介导。共享遗传结构也促成了这些关联。对共享位点和基因功能的分析确定ATXN2在PBC和9种EHAIDs之间共享，而在PSC中，SH2B3和PSMG1分别与6种和5种EHAIDs共享。
我们的研究比较了三种不同的AILDs，加深了对其病因的理解，并为危险因素、诊断标志物和潜在治疗靶点提供了新证据。
