Denise Lasher1, András Szabó2,3, Atsushi Masamune4, Jian-Min Chen5, Xunjun Xiao6, David C Whitcomb7, M Michael Barmada8,9, Maren Ewers1, Claudia Ruffert10, Sumit Paliwal11,12, Prachand Issarapu11, Seema Bhaskar11, K Radha Mani11, Giriraj R Chandak11, Helmut Laumen1, Emmanuelle Masson5, Kiyoshi Kume4, Shin Hamada4, Eriko Nakano4, Katharina Seltsam10, Peter Bugert13, Thomas Müller14, David A Groneberg15, Tooru Shimosegawa4, Jonas Rosendahl10,16, Claude Férec5, Mark E Lowe6, Heiko Witt1, Miklós Sahin-Tóth2. 1. Else Kröner-Fresenius-Zentrum für Ernährungsmedizin (EKFZ), Paediatric Nutritional Medicine, Technische Universität München (TUM), Freising, Germany. 2. Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, Massachusetts, USA. 3. Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary. 4. Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan. 5. UMR1078 "Génétique, Génomique Fonctionnelle et Biotechnologies," INSERM, EFS-Bretagne, Université de Brest, CHRU Brest, Brest, France. 6. Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA. 7. Departments of Medicine, Cell Biology & Molecular Physiology, and Human Genetics, University of Pittsburgh and UPMC, Pittsburgh, Pennsylvania, USA. 8. Departments of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. 9. Deceased: December 2, 2016. 10. Department of Internal Medicine, Neurology and Dermatology, Division of Gastroenterology, University of Leipzig, Leipzig, Germany. 11. Genomic Research on Complex diseases (GRC Group), CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India. 12. Epithelial Carcinogenesis Group, Cancer Cell Biology Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain. 13. Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service of Baden-Württemberg, Mannheim, Germany. 14. Department of Pediatrics I, Medical University, Innsbruck, Austria. 15. Institute of Occupational Medicine, Social Medicine and Environmental Medicine, Goethe-University, Frankfurt, Germany. 16. Department of Internal Medicine I, Martin Luther University, Halle, Germany.
Abstract
OBJECTIVES: Premature activation of the digestive protease trypsin within the pancreatic parenchyma is a critical factor in the pathogenesis of pancreatitis. Alterations in genes that affect intrapancreatic trypsin activity are associated with chronic pancreatitis (CP). Recently, carboxyl ester lipase emerged as a trypsin-independent risk gene. Here, we evaluated pancreatic lipase (PNLIP) as a potential novel susceptibility gene for CP. METHODS: We analyzed all 13 PNLIP exons in 429 nonalcoholic patients with CP and 600 control subjects from Germany, in 632 patients and 957 controls from France, and in 223 patients and 1,070 controls from Japan by DNA sequencing. Additionally, we analyzed selected exons in further 545 patients with CP and 1,849 controls originating from Germany, United States, and India. We assessed the cellular secretion, lipase activity, and proteolytic stability of recombinant PNLIP variants. RESULTS: In the German discovery cohort, 8/429 (1.9%) patients and 2/600 (0.3%) controls carried a PNLIP missense variant (P = 0.02, odds ratio [OR] = 5.7, 95% confidence interval [CI] = 1.1-38.9). Variants detected in patients were prone to proteolytic degradation by trypsin and chymotrypsin. In the French replication cohort, protease-sensitive variants were also enriched in patients with early-onset CP (5/632 [0.8%]) vs controls (1/957 [0.1%]) (P = 0.04, OR = 7.6, 95% CI = 0.9-172.9). In contrast, we detected no protease-sensitive variants in the non-European populations. In the combined European data, protease-sensitive variants were found in 13/1,163 cases (1.1%) and in 3/3,000 controls (0.1%) (OR = 11.3, 95% CI = 3.0-49.9, P < 0.0001). CONCLUSIONS: Our data indicate that protease-sensitive PNLIP variants are novel genetic risk factors for the development of CP.
OBJECTIVES: Premature activation of the digestive protease trypsin within the pancreatic parenchyma is a critical factor in the pathogenesis of pancreatitis. Alterations in genes that affect intrapancreatic trypsin activity are associated with chronic pancreatitis (CP). Recently, carboxyl ester lipase emerged as a trypsin-independent risk gene. Here, we evaluated pancreatic lipase (PNLIP) as a potential novel susceptibility gene for CP. METHODS: We analyzed all 13 PNLIP exons in 429 nonalcoholic patients with CP and 600 control subjects from Germany, in 632 patients and 957 controls from France, and in 223 patients and 1,070 controls from Japan by DNA sequencing. Additionally, we analyzed selected exons in further 545 patients with CP and 1,849 controls originating from Germany, United States, and India. We assessed the cellular secretion, lipase activity, and proteolytic stability of recombinant PNLIP variants. RESULTS: In the German discovery cohort, 8/429 (1.9%) patients and 2/600 (0.3%) controls carried a PNLIP missense variant (P = 0.02, odds ratio [OR] = 5.7, 95% confidence interval [CI] = 1.1-38.9). Variants detected in patients were prone to proteolytic degradation by trypsin and chymotrypsin. In the French replication cohort, protease-sensitive variants were also enriched in patients with early-onset CP (5/632 [0.8%]) vs controls (1/957 [0.1%]) (P = 0.04, OR = 7.6, 95% CI = 0.9-172.9). In contrast, we detected no protease-sensitive variants in the non-European populations. In the combined European data, protease-sensitive variants were found in 13/1,163 cases (1.1%) and in 3/3,000 controls (0.1%) (OR = 11.3, 95% CI = 3.0-49.9, P < 0.0001). CONCLUSIONS: Our data indicate that protease-sensitive PNLIP variants are novel genetic risk factors for the development of CP.
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