Ueno Kazuko, Aiba Yoshihiro, Hitomi Yuki, Shimoda Shinji, Nakamura Hitomi, Gervais Olivier, Kawai Yosuke, Kawashima Minae, Nishida Nao, Kohn Seik-Soon, Kojima Kaname, Katsushima Shinji, Naganuma Atsushi, Sugi Kazuhiro, Komatsu Tatsuji, Mannami Tomohiko, Matsushita Kouki, Yoshizawa Kaname, Makita Fujio, Nikami Toshiki, Nishimura Hideo, Kouno Hiroshi, Kouno Hirotaka, Ohta Hajime, Komura Takuya, Tsuruta Satoru, Yamauchi Kazuhiko, Kobata Tatsuro, Kitasato Amane, Kuroki Tamotsu, Abiru Seigo, Nagaoka Shinya, Komori Atsumasa, Yatsuhashi Hiroshi, Migita Kiyoshi, Ohira Hiromasa, Tanaka Atsushi, Takikawa Hajime, Nagasaki Masao, Tokunaga Katsushi, Nakamura Minoru
Genome Medical Science Project National Center for Global Health and Medicine Tokyo Japan.
Department of Human Genetics Graduate School of Medicine University of Tokyo Tokyo Japan.
Hepatol Commun. 2020 Mar 15;4(5):724-738. doi: 10.1002/hep4.1497. eCollection 2020 May.
Genome-wide association studies (GWASs) in European and East Asian populations have identified more than 40 disease-susceptibility genes in primary biliary cholangitis (PBC). The aim of this study is to computationally identify disease pathways, upstream regulators, and therapeutic targets in PBC through integrated GWAS and messenger RNA (mRNA) microarray analysis. Disease pathways and upstream regulators were analyzed with ingenuity pathway analysis in data set 1 for GWASs (1,920 patients with PBC and 1,770 controls), which included 261 annotated genes derived from 6,760 single-nucleotide polymorphisms ( < 0.00001), and data set 2 for mRNA microarray analysis of liver biopsy specimens (36 patients with PBC and 5 normal controls), which included 1,574 genes with fold change >2 versus controls ( < 0.05). Hierarchical cluster analysis and categorization of cell type-specific genes were performed for data set 2. There were 27 genes, 10 pathways, and 149 upstream regulators that overlapped between data sets 1 and 2. All 10 pathways were immune-related. The most significant common upstream regulators associated with PBC disease susceptibility identified were interferon-gamma (IFNG) and CD40 ligand (CD40L). Hierarchical cluster analysis of data set 2 revealed two distinct groups of patients with PBC by disease activity. The most significant upstream regulators associated with disease activity were IFNG and CD40L. Several molecules expressed in B cells, T cells, Kupffer cells, and natural killer-like cells were identified as potential therapeutic targets in PBC with reference to a recently reported list of cell type-specific gene expression in the liver. : Our integrated analysis using GWAS and mRNA microarray data sets predicted that IFNG and CD40L are the central upstream regulators in both disease susceptibility and activity of PBC and identified potential downstream therapeutic targets.
欧洲和东亚人群的全基因组关联研究（GWAS）已在原发性胆汁性胆管炎（PBC）中鉴定出40多个疾病易感基因。本研究的目的是通过整合GWAS和信使核糖核酸（mRNA）微阵列分析，以计算方式确定PBC中的疾病通路、上游调节因子和治疗靶点。在GWAS的数据集1（1920例PBC患者和1770例对照）中，使用 Ingenuity 通路分析对疾病通路和上游调节因子进行分析，该数据集包括来自6760个单核苷酸多态性（<0.00001）的261个注释基因；在肝脏活检标本的mRNA微阵列分析数据集2（36例PBC患者和5例正常对照）中进行分析，该数据集包括1574个与对照相比变化倍数>2（<0.05）的基因。对数据集2进行了层次聚类分析和细胞类型特异性基因分类。数据集1和2之间有27个基因、10条通路和149个上游调节因子重叠。所有10条通路均与免疫相关。鉴定出的与PBC疾病易感性相关的最显著常见上游调节因子是干扰素-γ（IFNG）和CD40配体（CD40L）。数据集2的层次聚类分析按疾病活动度揭示了两组不同的PBC患者。与疾病活动度相关的最显著上游调节因子是IFNG和CD40L。参照最近报道的肝脏中细胞类型特异性基因表达列表，在B细胞、T细胞、库普弗细胞和自然杀伤样细胞中表达的几种分子被确定为PBC的潜在治疗靶点。我们使用GWAS和mRNA微阵列数据集的综合分析预测，IFNG和CD40L是PBC疾病易感性和活动度的核心上游调节因子，并确定了潜在的下游治疗靶点。
