Journal Article

GGT1 is a SNP eQTL gene involved in STAT3 activation and associated with the development of Post-ERCP pancreatitis

Takeshi Yamasaki, Ikuko Takahashi, Jing-Jing Jiang, Shintaro Hojyo, Naoya Sakamoto, Yuta Shinohara, Kaoru Murakami, Shigeru Hashimoto, Yuki Tanaka, Masaaki Murakami, Noriyuki Hirata, Ryutaro Furukawa, Kumiko Tanaka, Shunichiro Nozawa, Shimpei I. Kubota, Masaki Kuwatani, Satoshi Hirano, Izuru Ohki, Rie Hasebe

2024

Overview

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.

• Publisher: Springer Science and Business Media LLC,Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/250 / 631/250/127 / 631/250/256 / Alleles / Animals / Cholangiopancreatography, Endoscopic Retrograde / Cytokine Receptor gp130 - genetics / Cytokine Receptor gp130 - metabolism / Female / gamma-Glutamyltransferase - genetics / gamma-Glutamyltransferase - metabolism / Genetic Predisposition to Disease / Glycoprotein gp130 / Humanities and Social Sciences / Humans / Interleukin 6 / Interleukin-6 - genetics / Interleukin-6 - metabolism / Male / Medicine / Mice / Middle Aged / multidisciplinary / NF-kappa B - metabolism / NF-κB protein / Nuclear transport / Pancreas / Pancreatitis / Pancreatitis - etiology / Pancreatitis - genetics / Phosphorylation / Polymorphism, Single Nucleotide / Q / Quantitative Trait Loci / R / Science / Science (multidisciplinary) / Signal Transduction / Single-nucleotide polymorphism / Stat3 protein / STAT3 Transcription Factor - genetics / STAT3 Transcription Factor - metabolism / Therapeutic targets / Translocation / γ-Glutamyltransferase