Abstract

Post-ERCP pancreatitis (PEP) is an acute pancreatitis caused by endoscopic-retrograde-cholangiopancreatography (ERCP). About 10% of patients develop PEP after ERCP. Here we show that gamma-glutamyltransferase 1 (GGT1)-SNP rs5751901 is an eQTL in pancreatic cells associated with PEP and a positive regulator of the IL-6 amplifier. More PEP patients had the GGT1 SNP rs5751901 risk allele (C) than that of non-PEP patients at Hokkaido University Hospital. Additionally, GGT1 expression and IL-6 amplifier activation were increased in PEP pancreas samples with the risk allele. A mechanistic analysis showed that IL-6-mediated STAT3 nuclear translocation and STAT3 phosphorylation were suppressed in GGT1-deficient cells. Furthermore, GGT1 directly associated with gp130, the signal-transducer of IL-6. Importantly, GGT1-deficiency suppressed inflammation development in a STAT3/NF-κB-dependent disease model. Thus, the risk allele of GGT1-SNP rs5751901 is involved in the pathogenesis of PEP via IL-6 amplifier activation. Therefore, the GGT1-STAT3 axis in pancreas may be a prognosis marker and therapeutic target for PEP.

Details

Title
GGT1 is a SNP eQTL gene involved in STAT3 activation and associated with the development of Post-ERCP pancreatitis
Author
Furukawa, Ryutaro 1 ; Kuwatani, Masaki 2 ; Jiang, Jing-Jing 3 ; Tanaka, Yuki 4 ; Hasebe, Rie 5 ; Murakami, Kaoru 6 ; Tanaka, Kumiko 6 ; Hirata, Noriyuki 6 ; Ohki, Izuru 4 ; Takahashi, Ikuko 6 ; Yamasaki, Takeshi 5 ; Shinohara, Yuta 6 ; Nozawa, Shunichiro 1 ; Hojyo, Shintaro 7 ; Kubota, Shimpei I. 4 ; Hashimoto, Shigeru 8 ; Hirano, Satoshi 9 ; Sakamoto, Naoya 2 ; Murakami, Masaaki 10 

 Hokkaido University, Division of Molecular Psychoneuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Sapporo, Japan (GRID:grid.39158.36) (ISNI:0000 0001 2173 7691); Hokkaido University Faculty of Medicine and Graduate School of Medicine, Department of Gastroenterology and Hepatology, Sapporo, Japan (GRID:grid.39158.36) (ISNI:0000 0001 2173 7691) 
 Hokkaido University Faculty of Medicine and Graduate School of Medicine, Department of Gastroenterology and Hepatology, Sapporo, Japan (GRID:grid.39158.36) (ISNI:0000 0001 2173 7691) 
 Hokkaido University, Division of Molecular Psychoneuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Sapporo, Japan (GRID:grid.39158.36) (ISNI:0000 0001 2173 7691); Northwest University, Institute of Preventive Genomic Medicine, School of Life Sciences, Xian, China (GRID:grid.412262.1) (ISNI:0000 0004 1761 5538) 
 Hokkaido University, Division of Molecular Psychoneuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Sapporo, Japan (GRID:grid.39158.36) (ISNI:0000 0001 2173 7691); National Institutes for Quantum Science and Technology (QST), Quantum Immunology Team, Institute for Quantum Life Science, Chiba, Japan (GRID:grid.482503.8) (ISNI:0000 0004 5900 003X) 
 Hokkaido University, Division of Molecular Psychoneuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Sapporo, Japan (GRID:grid.39158.36) (ISNI:0000 0001 2173 7691); National Institute for Physiological Sciences, National Institutes of Natural Sciences, Division of Molecular Neuroimmunology, Okazaki, Japan (GRID:grid.467811.d) (ISNI:0000 0001 2272 1771) 
 Hokkaido University, Division of Molecular Psychoneuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Sapporo, Japan (GRID:grid.39158.36) (ISNI:0000 0001 2173 7691) 
 Hokkaido University, Division of Molecular Psychoneuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Sapporo, Japan (GRID:grid.39158.36) (ISNI:0000 0001 2173 7691); National Institutes for Quantum Science and Technology (QST), Quantum Immunology Team, Institute for Quantum Life Science, Chiba, Japan (GRID:grid.482503.8) (ISNI:0000 0004 5900 003X); Hokkaido University, Institute for Vaccine Research and Development (HU-IVReD), Sapporo, Japan (GRID:grid.39158.36) (ISNI:0000 0001 2173 7691) 
 Hokkaido University, Division of Molecular Psychoneuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Sapporo, Japan (GRID:grid.39158.36) (ISNI:0000 0001 2173 7691); Hokkaido University, Institute for Vaccine Research and Development (HU-IVReD), Sapporo, Japan (GRID:grid.39158.36) (ISNI:0000 0001 2173 7691) 
 Hokkaido University Faculty of Medicine, Department of Gastroenterological Surgery II, Sapporo, Japan (GRID:grid.39158.36) (ISNI:0000 0001 2173 7691) 
10  Hokkaido University, Division of Molecular Psychoneuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Sapporo, Japan (GRID:grid.39158.36) (ISNI:0000 0001 2173 7691); National Institutes for Quantum Science and Technology (QST), Quantum Immunology Team, Institute for Quantum Life Science, Chiba, Japan (GRID:grid.482503.8) (ISNI:0000 0004 5900 003X); National Institute for Physiological Sciences, National Institutes of Natural Sciences, Division of Molecular Neuroimmunology, Okazaki, Japan (GRID:grid.467811.d) (ISNI:0000 0001 2272 1771); Hokkaido University, Institute for Vaccine Research and Development (HU-IVReD), Sapporo, Japan (GRID:grid.39158.36) (ISNI:0000 0001 2173 7691) 
Pages
12224
Publication year
2024
Publication date
2024
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3060940520
Copyright
© The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.