Atsushi Masamune1, Hiroshi Kotani2, Franziska Lena Sörgel3, Jian-Min Chen4, Shin Hamada5, Reiko Sakaguchi6, Emmanuelle Masson7, Eriko Nakano5, Yoichi Kakuta5, Tetsuya Niihori8, Ryo Funayama9, Matsuyuki Shirota9, Tatsuya Hirano2, Tetsuya Kawamoto2, Atsuki Hosokoshi2, Kiyoshi Kume5, Lara Unger3, Maren Ewers3, Helmut Laumen3, Peter Bugert10, Masayuki X Mori2, Volodymyr Tsvilovskyy11, Petra Weißgerber12, Ulrich Kriebs11, Claudia Fecher-Trost12, Marc Freichel11, Kalliope N Diakopoulos13, Alexandra Berninger13, Marina Lesina13, Kentaro Ishii14, Takao Itoi14, Tsukasa Ikeura15, Kazuichi Okazaki15, Tom Kaune16, Jonas Rosendahl16, Masao Nagasaki17, Yasuhito Uezono18, Hana Algül13, Keiko Nakayama9, Yoichi Matsubara19, Yoko Aoki8, Claude Férec7, Yasuo Mori2, Heiko Witt3, Tooru Shimosegawa5. 1. Division of Gastroenterology, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan. Electronic address: amasamune@med.tohoku.ac.jp. 2. Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan. 3. Else Kröner-Fresenius-Zentrum für Ernährungsmedizin, Paediatric Nutritional Medicine, Technische Universität München, Freising, Germany. 4. Inserm, Université de Brest, EFS, GGB, Brest, France. 5. Division of Gastroenterology, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan. 6. Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan; Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto, Japan. 7. Inserm, Université de Brest, EFS, GGB, Brest, France; CHU Brest, Service de Génétique, Brest, France. 8. Division of Medical Genetics, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan. 9. Division of Cell Proliferation, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan. 10. Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service of Baden-Württemberg- Hessen, Mannheim, Germany. 11. Pharmakologisches Institut, Universität Heidelberg, Heidelberg, Germany; German Center for Cardiovascular Research, partner site Heidelberg, Germany. 12. Experimentelle und Klinische Pharmakologie und Toxikologie, Universität des Saarlandes, Homburg, Germany. 13. Mildred Scheel Chair of Tumor Metabolism and Comprehensive Cancer Center Munich at the Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. 14. Department of Gastroenterology and Hepatology, Tokyo Medical University, Tokyo, Japan. 15. Department of Gastroenterology and Hepatology, Kansai Medical University, Hirakata, Japan. 16. Department of Internal Medicine I, Martin Luther University, Halle (Saale), Germany. 17. Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan. 18. Cancer Pathophysiology Division, National Cancer Center Research Institute, Tokyo, Japan. 19. National Center for Child Health and Development, Tokyo, Japan.
Abstract
BACKGROUND & AIMS: Changes in pancreatic calcium levels affect secretion and might be involved in development of chronic pancreatitis (CP). We investigated the association of CP with the transient receptor potential cation channel subfamily V member 6 gene (TRPV6), which encodes a Ca2+-selective ion channel, in an international cohort of patients and in mice. METHODS: We performed whole-exome DNA sequencing from a patient with idiopathic CP and from his parents, who did not have CP. We validated our findings by sequencing DNA from 300 patients with CP (not associated with alcohol consumption) and 1070 persons from the general population in Japan (control individuals). In replication studies, we sequenced DNA from patients with early-onset CP (20 years or younger) not associated with alcohol consumption from France (n = 470) and Germany (n = 410). We expressed TRPV6 variants in HEK293 cells and measured their activity using Ca2+ imaging assays. CP was induced by repeated injections of cerulein in TRPV6mut/mut mice. RESULTS: We identified the variants c.629C>T (p.A210V) and c.970G>A (p.D324N) in TRPV6 in the index patient. Variants that affected function of the TRPV6 product were found in 13 of 300 patients (4.3%) and 1 of 1070 control individuals (0.1%) from Japan (odds ratio [OR], 48.4; 95% confidence interval [CI], 6.3-371.7; P = 2.4 × 10-8). Twelve of 124 patients (9.7%) with early-onset CP had such variants. In the replication set from Europe, 18 patients with CP (2.0%) carried variants that affected the function of the TRPV6 product compared with 0 control individuals (P = 6.2 × 10-8). Variants that did not affect the function of the TRPV6 product (p.I223T and p.D324N) were overrepresented in Japanese patients vs control individuals (OR, 10.9; 95% CI, 4.5-25.9; P = 7.4 × 10-9 for p.I223T and P = .01 for p.D324N), whereas the p.L299Q was overrepresented in European patients vs control individuals (OR, 3.0; 95% CI, 1.9-4.8; P = 1.2 × 10-5). TRPV6mut/mut mice given cerulein developed more severe pancreatitis than control mice, as shown by increased levels of pancreatic enzymes, histologic alterations, and pancreatic fibrosis. CONCLUSIONS: We found that patients with early-onset CP not associated with alcohol consumption carry variants in TRPV6 that affect the function of its product, perhaps by altering Ca2+ balance in pancreatic cells. TRPV6 regulates Ca2+ homeostasis and pancreatic inflammation.
BACKGROUND & AIMS: Changes in pancreatic calcium levels affect secretion and might be involved in development of chronic pancreatitis (CP). We investigated the association of CP with the transient receptor potential cation channel subfamily V member 6 gene (TRPV6), which encodes a Ca2+-selective ion channel, in an international cohort of patients and in mice. METHODS: We performed whole-exome DNA sequencing from a patient with idiopathic CP and from his parents, who did not have CP. We validated our findings by sequencing DNA from 300 patients with CP (not associated with alcohol consumption) and 1070 persons from the general population in Japan (control individuals). In replication studies, we sequenced DNA from patients with early-onset CP (20 years or younger) not associated with alcohol consumption from France (n = 470) and Germany (n = 410). We expressed TRPV6 variants in HEK293 cells and measured their activity using Ca2+ imaging assays. CP was induced by repeated injections of cerulein in TRPV6mut/mut mice. RESULTS: We identified the variants c.629C>T (p.A210V) and c.970G>A (p.D324N) in TRPV6 in the index patient. Variants that affected function of the TRPV6 product were found in 13 of 300 patients (4.3%) and 1 of 1070 control individuals (0.1%) from Japan (odds ratio [OR], 48.4; 95% confidence interval [CI], 6.3-371.7; P = 2.4 × 10-8). Twelve of 124 patients (9.7%) with early-onset CP had such variants. In the replication set from Europe, 18 patients with CP (2.0%) carried variants that affected the function of the TRPV6 product compared with 0 control individuals (P = 6.2 × 10-8). Variants that did not affect the function of the TRPV6 product (p.I223T and p.D324N) were overrepresented in Japanese patients vs control individuals (OR, 10.9; 95% CI, 4.5-25.9; P = 7.4 × 10-9 for p.I223T and P = .01 for p.D324N), whereas the p.L299Q was overrepresented in European patients vs control individuals (OR, 3.0; 95% CI, 1.9-4.8; P = 1.2 × 10-5). TRPV6mut/mut mice given cerulein developed more severe pancreatitis than control mice, as shown by increased levels of pancreatic enzymes, histologic alterations, and pancreatic fibrosis. CONCLUSIONS: We found that patients with early-onset CP not associated with alcohol consumption carry variants in TRPV6 that affect the function of its product, perhaps by altering Ca2+ balance in pancreatic cells. TRPV6 regulates Ca2+ homeostasis and pancreatic inflammation.
Authors: Andrea Tóth; Alexandra Demcsák; Florence Zankl; Grzegorz Oracz; Lara Sophie Unger; Peter Bugert; Helmut Laumen; Andrea Párniczky; Péter Hegyi; Jonas Rosendahl; Tomasz Gambin; Rafał Płoski; Dorota Koziel; Stanisław Gluszek; Fredrik Lindgren; J Matthias Löhr; Miklós Sahin-Tóth; Heiko Witt; Agnieszka Magdalena Rygiel; Maren Ewers; Eszter Hegyi Journal: Pancreatology Date: 2022-06-23 Impact factor: 3.977
Authors: Amanda Takáts; Gergő Berke; Andrea Szentesi; Gyula Farkas; Ferenc Izbéki; Bálint Erőss; László Czakó; Áron Vincze; Péter Hegyi; Miklós Sahin-Tóth; Eszter Hegyi Journal: Pancreatology Date: 2021-08-26 Impact factor: 3.977
Authors: Agnieszka Magdalena Rygiel; Lara Sophie Unger; Franziska Lena Sörgel; Emmanuelle Masson; Ryotaro Matsumoto; Maren Ewers; Jian-Min Chen; Peter Bugert; Louis Buscail; Tomasz Gambin; Grzegorz Oracz; Maria Winiewska-Szajewska; Agnieszka Mianowska; Jarosław Poznanski; Joanna Kosińska; Piotr Stawinski; Rafał Płoski; Dorota Koziel; Stanisław Gluszek; Helmut Laumen; Fredrik Lindgren; J Matthias Löhr; Anna Orekhova; Vinciane Rebours; Jonas Rosendahl; Andrea Párniczky; Péter Hegyi; Akira Sasaki; Fumiya Kataoka; Yu Tanaka; Shin Hamada; Miklós Sahin-Tóth; Eszter Hegyi; Claude Férec; Atsushi Masamune; Heiko Witt Journal: Pancreatology Date: 2022-05-01 Impact factor: 3.977
Authors: Ellyn Dunbar; Phil J Greer; Nadine Melhem; Samer Alkaade; Stephen T Amann; Randall Brand; Gregory A Coté; Christopher E Forsmark; Timothy B Gardner; Andres Gelrud; Nalini M Guda; Jessica LaRusch; Michele D Lewis; Jorge D Machicado; Thiruvengadam Muniraj; Georgios I Papachristou; Joseph Romagnuolo; Bimaljit S Sandhu; Stuart Sherman; Charles M Wilcox; Vikesh K Singh; Dhiraj Yadav; David C Whitcomb Journal: J Gastroenterol Date: 2020-07-17 Impact factor: 6.772
Authors: Savio George Barreto; Aida Habtezion; Anna Gukovskaya; Aurelia Lugea; Christie Jeon; Dhiraj Yadav; Peter Hegyi; Viktória Venglovecz; Robert Sutton; Stephen J Pandol Journal: Gut Date: 2020-09-24 Impact factor: 23.059
Authors: Ellyn K Dunbar; Phil J Greer; Stephen T Amann; Samer Alkaade; Peter Banks; Randall Brand; Darwin L Conwell; Christopher E Forsmark; Timothy B Gardner; Nalini M Guda; Michele D Lewis; Jorge D Machicado; Thiruvengadam Muniraj; Georgios I Papachristou; Joseph Romagnuolo; Bimaljit S Sandhu; Stuart Sherman; Adam Slivka; C Mel Wilcox; Dhiraj Yadav; David C Whitcomb Journal: Am J Gastroenterol Date: 2021-10-01 Impact factor: 12.045