Agnieszka Magdalena Rygiel1, Lara Sophie Unger2, Franziska Lena Sörgel3, Emmanuelle Masson4, Ryotaro Matsumoto5, Maren Ewers3, Jian-Min Chen6, Peter Bugert7, Louis Buscail8, Tomasz Gambin9, Grzegorz Oracz10, Maria Winiewska-Szajewska11, Agnieszka Mianowska10, Jarosław Poznanski11, Joanna Kosińska12, Piotr Stawinski12, Rafał Płoski12, Dorota Koziel13, Stanisław Gluszek13, Helmut Laumen14, Fredrik Lindgren15, J Matthias Löhr16, Anna Orekhova17, Vinciane Rebours18, Jonas Rosendahl19, Andrea Párniczky20, Péter Hegyi21, Akira Sasaki5, Fumiya Kataoka5, Yu Tanaka5, Shin Hamada5, Miklós Sahin-Tóth22, Eszter Hegyi23, Claude Férec4, Atsushi Masamune5, Heiko Witt24. 1. Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland. Electronic address: agnieszka.rygiel@imid.med.pl. 2. Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University, Henry M. Goldman School of Dental Medicine, Boston, MA, 02118, United States; Pediatric Nutritional Medicine & Else Kröner-Fresenius-Centre for Nutritional Medicine EKFZ, Technical University Munich TUM, Freising, Germany. 3. Pediatric Nutritional Medicine & Else Kröner-Fresenius-Centre for Nutritional Medicine EKFZ, Technical University Munich TUM, Freising, Germany. 4. Univ Brest, Inserm, EFS, UMR 1078, GGB, F-29200, Brest, France; Service de Génétique Médicale et de Biologie de la Reproduction, CHRU Brest, F-29200, Brest, France. 5. Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan. 6. Univ Brest, Inserm, EFS, UMR 1078, GGB, F-29200, Brest, France. 7. Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service of Baden-Württemberg, Mannheim, Germany. 8. Department of Gastroenterology and Pancreatology, CHU Rangueil and University of Toulouse, Toulouse, France. 9. Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland; Institute of Computer Science, Warsaw University of Technology, Warsaw, Poland. 10. Department of Gastroenterology, Hepatology, Feeding Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland. 11. Department of Biophysics, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland. 12. Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland. 13. Collegium Medicum, Jan Kochanowski University of Kielce, Poland. 14. Pediatric Nutritional Medicine & Else Kröner-Fresenius-Centre for Nutritional Medicine EKFZ, Technical University Munich TUM, Freising, Germany; Department of Internal Medicine I, Martin Luther University, Halle, Germany. 15. Department of Pediatric, Karolinska University Hospital, Stockholm, Sweden. 16. Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden. 17. Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University, Henry M. Goldman School of Dental Medicine, Boston, MA, 02118, United States. 18. Pancreatology and Digestive Oncology Department, Beaujon Hospital, Clichy, APHP, Université de Paris, Paris, France. 19. Department of Internal Medicine I, Martin Luther University, Halle, Germany. 20. Heim Pál National Pediatric Institute, Budapest, Hungary; Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary; Center for Translational Medicine, Semmelweis University, Budapest, Hungary. 21. Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary; Division of Pancreatic Diseases, Heart and Vascular Center, Semmelweis University, Budapest, Hungary. 22. Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University, Henry M. Goldman School of Dental Medicine, Boston, MA, 02118, United States; Department of Surgery, University of California Los Angeles, Los Angeles, CA, 90095, United States. 23. Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University, Henry M. Goldman School of Dental Medicine, Boston, MA, 02118, United States; Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary. 24. Pediatric Nutritional Medicine & Else Kröner-Fresenius-Centre for Nutritional Medicine EKFZ, Technical University Munich TUM, Freising, Germany. Electronic address: heiko.witt@tum.de.
Abstract
OBJECTIVE: Non-alcoholic chronic pancreatitis (NACP) frequently develops in the setting of genetic susceptibility associated with alterations in genes that are highly expressed in the pancreas. However, the genetic basis of NACP remains unresolved in a significant number of patients warranting a search for further risk genes. DESIGN: We analyzed CUZD1, which encodes the CUB and zona pellucida-like domains 1 protein that is found in high levels in pancreatic acinar cells. We sequenced the coding region in 1163 European patients and 2018 European controls. In addition, we analyzed 297 patients and 1070 controls from Japan. We analyzed secretion of wild-type and mutant CUZD1 from transfected cells using Western blotting. RESULTS: In the European cohort, we detected 30 non-synonymous variants. Using different prediction tools (SIFT, CADD, PROVEAN, PredictSNP) or the combination of these tools, we found accumulation of predicted deleterious variants in patients (p-value range 0.002-0.013; OR range 3.1-5.2). No association was found in the Japanese cohort, in which 13 non-synonymous variants were detected. Functional studies revealed >50% reduced secretion of 7 variants, however, these variants were not significantly enriched in European CP patients. CONCLUSION: Our data indicate that CUZD1 might be a novel susceptibility gene for NACP. How these variants predispose to pancreatitis remains to be elucidated.
OBJECTIVE: Non-alcoholic chronic pancreatitis (NACP) frequently develops in the setting of genetic susceptibility associated with alterations in genes that are highly expressed in the pancreas. However, the genetic basis of NACP remains unresolved in a significant number of patients warranting a search for further risk genes. DESIGN: We analyzed CUZD1, which encodes the CUB and zona pellucida-like domains 1 protein that is found in high levels in pancreatic acinar cells. We sequenced the coding region in 1163 European patients and 2018 European controls. In addition, we analyzed 297 patients and 1070 controls from Japan. We analyzed secretion of wild-type and mutant CUZD1 from transfected cells using Western blotting. RESULTS: In the European cohort, we detected 30 non-synonymous variants. Using different prediction tools (SIFT, CADD, PROVEAN, PredictSNP) or the combination of these tools, we found accumulation of predicted deleterious variants in patients (p-value range 0.002-0.013; OR range 3.1-5.2). No association was found in the Japanese cohort, in which 13 non-synonymous variants were detected. Functional studies revealed >50% reduced secretion of 7 variants, however, these variants were not significantly enriched in European CP patients. CONCLUSION: Our data indicate that CUZD1 might be a novel susceptibility gene for NACP. How these variants predispose to pancreatitis remains to be elucidated.
Authors: Grzegorz Oracz; Michał Zaród; Maren Ewers; Helmut Laumen; Tomasz Gambin; Paweł Kamiński; Iwona Grabowska; Anna Drożak; Sebastian Kwiatkowski; Katarzyna Wertheim-Tysarowska; Elwira Kołodziejczyk; Alicja Domaszewicz; Barbara Dorożko; Joanna Kosińska; Stanisław Głuszek; Dorota Kozieł; Rafał Płoski; Jonas Rosendahl; Heiko Witt; Jakub Drożak; Agnieszka Magdalena Rygiel Journal: Pancreatology Date: 2021-09-10 Impact factor: 3.996
Authors: Jaroslav Bendl; Jan Stourac; Ondrej Salanda; Antonin Pavelka; Eric D Wieben; Jaroslav Zendulka; Jan Brezovsky; Jiri Damborsky Journal: PLoS Comput Biol Date: 2014-01-16 Impact factor: 4.475