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

• Published in: Scientific reports Vol. 14; no. 1; pp. 12224 - 10
• Main Authors: Furukawa, Ryutaro, Kuwatani, Masaki, Jiang, Jing-Jing, Tanaka, Yuki, Hasebe, Rie, Murakami, Kaoru, Tanaka, Kumiko, Hirata, Noriyuki, Ohki, Izuru, Takahashi, Ikuko, Yamasaki, Takeshi, Shinohara, Yuta, Nozawa, Shunichiro, Hojyo, Shintaro, Kubota, Shimpei I., Hashimoto, Shigeru, Hirano, Satoshi, Sakamoto, Naoya, Murakami, Masaaki
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.05.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 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; Mice; Middle Aged; multidisciplinary; NF-kappa B - metabolism; NF-κB protein; Nuclear transport; Pancreas; Pancreatitis; Pancreatitis - etiology; Pancreatitis - genetics; Phosphorylation; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Science; Science (multidisciplinary); Signal Transduction; Single-nucleotide polymorphism; Stat3 protein; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Therapeutic targets; Translocation; γ-Glutamyltransferase
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-60312-2

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.