TY - JOUR
T1 - Integrated GWAS and mRNA Microarray Analysis Identified IFNG and CD40L as the Central Upstream Regulators in Primary Biliary Cholangitis
AU - PBC-GWAS Consortium in Japan
AU - Ueno, Kazuko
AU - Aiba, Yoshihiro
AU - Hitomi, Yuki
AU - Shimoda, Shinji
AU - Nakamura, Hitomi
AU - Gervais, Olivier
AU - Kawai, Yosuke
AU - Kawashima, Minae
AU - Nishida, Nao
AU - Kohn, Seik Soon
AU - Kojima, Kaname
AU - Katsushima, Shinji
AU - Naganuma, Atsushi
AU - Sugi, Kazuhiro
AU - Komatsu, Tatsuji
AU - Mannami, Tomohiko
AU - Matsushita, Kouki
AU - Yoshizawa, Kaname
AU - Makita, Fujio
AU - Nikami, Toshiki
AU - Nishimura, Hideo
AU - Kouno, Hiroshi
AU - Kouno, Hirotaka
AU - Ohta, Hajime
AU - Komura, Takuya
AU - Tsuruta, Satoru
AU - Yamauchi, Kazuhiko
AU - Kobata, Tatsuro
AU - Kitasato, Amane
AU - Kuroki, Tamotsu
AU - Abiru, Seigo
AU - Nagaoka, Shinya
AU - Komori, Atsumasa
AU - Yatsuhashi, Hiroshi
AU - Migita, Kiyoshi
AU - Ohira, Hiromasa
AU - Tanaka, Atsushi
AU - Takikawa, Hajime
AU - Nagasaki, Masao
AU - Tokunaga, Katsushi
AU - Nakamura, Minoru
N1 - Funding Information:
We thank all the patients and volunteers who enrolled in the study and all clinical staffs who participated in collection of samples (serum, DNA, and liver biopsy samples) and clinical information and obtaining informed consents from PBC patients. We also thank Ms. Mayumi Ishii and Takayo Tsuchiura (National Center for Global Health and Medicine) and Ms. Natsumi Baba, Ms. Yoshimi Shigemori, and Ms. Tomoko Suzuki (University of Tokyo) for their technical and administrative assistance.
Publisher Copyright:
© 2020 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.
PY - 2020/5/1
Y1 - 2020/5/1
N2 - 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 (P ' 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 (P ' 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. Conclusion: 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.
AB - 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 (P ' 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 (P ' 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. Conclusion: 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.
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U2 - 10.1002/hep4.1497
DO - 10.1002/hep4.1497
M3 - Article
AN - SCOPUS:85102291120
SN - 2471-254X
VL - 4
SP - 724
EP - 738
JO - Hepatology Communications
JF - Hepatology Communications
IS - 5
ER -