Andrea Tóth1, Alexandra Demcsák2, Florence Zankl1, Grzegorz Oracz3, Lara Sophie Unger1, Peter Bugert4, Helmut Laumen5, Andrea Párniczky6, Péter Hegyi7, Jonas Rosendahl8, Tomasz Gambin9, Rafał Płoski10, Dorota Koziel11, Stanisław Gluszek11, Fredrik Lindgren12, J Matthias Löhr13, Miklós Sahin-Tóth2, Heiko Witt1, Agnieszka Magdalena Rygiel14, Maren Ewers15, Eszter Hegyi16. 1. Pediatric Nutritional Medicine & Else Kröner-Fresenius-Centre for Nutritional Medicine (EKFZ), Technical University Munich (TUM), Freising, Germany. 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; Department of Surgery, University of California Los Angeles, Los Angeles, CA, 90095, United States. 3. Department of Gastroenterology, Hepatology, Feeding Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland. 4. Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service of Baden-Württemberg, Mannheim, Germany. 5. 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-Wittenberg, Halle (Saale), Germany. 6. Heim Pál National Pediatric Institute, Budapest, Hungary; Institute for Translational Medicine, Medical School, Szentágothai Research Center, University of Pécs, Pécs, Hungary; Center for Translational Medicine, Semmelweis University, Budapest, Hungary. 7. Institute for Translational Medicine, Medical School, Szentágothai Research Center, University of Pécs, Pécs, Hungary; Center for Translational Medicine, Semmelweis University, Budapest, Hungary; Division of Pancreatic Diseases, Heart and Vascular Center, Semmelweis University, Budapest, Hungary. 8. Department of Internal Medicine I, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany. 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 Medical Genetics, Medical University of Warsaw, Warsaw, Poland. 11. Collegium Medicum, Jan Kochanowski University of Kielce, Poland. 12. Department of Pediatric, Karolinska University Hospital, Stockholm, Sweden. 13. Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden. 14. Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland. 15. Pediatric Nutritional Medicine & Else Kröner-Fresenius-Centre for Nutritional Medicine (EKFZ), Technical University Munich (TUM), Freising, Germany. Electronic address: maren.ewers@tum.de. 16. 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, Szentágothai Research Center, University of Pécs, Pécs, Hungary. Electronic address: eszter.hegyi@aok.pte.hu.
Abstract
BACKGROUND: Genetic alterations in digestive enzymes have been associated with chronic pancreatitis (CP). Recently, chymotrypsin like elastase 3B (CELA3B) emerged as a novel risk gene. Thus, we evaluated CELA3B in two European cohorts with CP. METHODS: We analyzed all 8 CELA3B exons in 550 German non-alcoholic CP (NACP) patients and in 241 German controls by targeted DNA sequencing. In addition, we analyzed exons 6 and 7 by Sanger sequencing and the c.129+1G>A variant by melting curve analysis in 1078 further German controls. As replication cohort, we investigated up to 243 non-German European NACP patients and up to 1665 controls originating from Poland, Hungary, and Sweden. We assessed the cellular secretion and the elastase activity of recombinant CELA3B variants. RESULTS: In the German discovery cohort, we detected a splice-site variant in intron 2, c.129+1G>A, in 9/550 (1.64%) CP patients and in 5/1319 (0.38%) controls (P=0.007, OR=4.4, 95% CI=1.5-13.0). In the European replication cohort, this variant was also enriched in patients (9/178 [5.06%]) versus controls (13/1247 [1.04%]) (P=0.001, OR=5.1, 95% CI=2.1-12.0). We did not find the two previously reported codon 90 variants, p.R90C and p.R90L. CONCLUSIONS: Our data indicate that CELA3B is a susceptibility gene for CP. In contrast to previous reports suggesting that increased CELA3B activity is associated with CP risk, the splice-site variant identified here is predicted to cause diminished CELA3B expression. How reduced CELA3B function predisposes to pancreatitis remains to be elucidated.
BACKGROUND: Genetic alterations in digestive enzymes have been associated with chronic pancreatitis (CP). Recently, chymotrypsin like elastase 3B (CELA3B) emerged as a novel risk gene. Thus, we evaluated CELA3B in two European cohorts with CP. METHODS: We analyzed all 8 CELA3B exons in 550 German non-alcoholic CP (NACP) patients and in 241 German controls by targeted DNA sequencing. In addition, we analyzed exons 6 and 7 by Sanger sequencing and the c.129+1G>A variant by melting curve analysis in 1078 further German controls. As replication cohort, we investigated up to 243 non-German European NACP patients and up to 1665 controls originating from Poland, Hungary, and Sweden. We assessed the cellular secretion and the elastase activity of recombinant CELA3B variants. RESULTS: In the German discovery cohort, we detected a splice-site variant in intron 2, c.129+1G>A, in 9/550 (1.64%) CP patients and in 5/1319 (0.38%) controls (P=0.007, OR=4.4, 95% CI=1.5-13.0). In the European replication cohort, this variant was also enriched in patients (9/178 [5.06%]) versus controls (13/1247 [1.04%]) (P=0.001, OR=5.1, 95% CI=2.1-12.0). We did not find the two previously reported codon 90 variants, p.R90C and p.R90L. CONCLUSIONS: Our data indicate that CELA3B is a susceptibility gene for CP. In contrast to previous reports suggesting that increased CELA3B activity is associated with CP risk, the splice-site variant identified here is predicted to cause diminished CELA3B expression. How reduced CELA3B function predisposes to pancreatitis remains to be elucidated.
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