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Protease-Sensitive Pancreatic Lipase Variants Are Associated With Early Onset Chronic Pancreatitis

Lasher, Denise, MD1; Szabó, András, PhD2,3; Masamune, Atsushi, MD, PhD4; Chen, Jian-Min, MD, PhD5; Xiao, Xunjun, PhD6; Whitcomb, David C., MD, PhD7; Barmada, M. Michael, PhD8,16; Ewers, Maren, MSc1; Ruffert, Claudia9; Paliwal, Sumit, PhD10,11; Issarapu, Prachand, MSc10; Bhaskar, Seema, PhD10; Mani, K. Radha, BSc10; Chandak, Giriraj R., MD, PhD10; Laumen, Helmut, PhD1; Masson, Emmanuelle, PhD5; Kume, Kiyoshi, MD, PhD4; Hamada, Shin, MD, PhD4; Nakano, Eriko, MD, PhD4; Seltsam, Katharina9; Bugert, Peter, MD12; Müller, Thomas, MD13; Groneberg, David A., MD14; Shimosegawa, Tooru, MD4; Rosendahl, Jonas, MD9,15; Férec, Claude, MD, PhD5; Lowe, Mark E., MD, PhD6; Witt, Heiko, MD1; Sahin-Tóth, Miklós, MD, PhD2

American Journal of Gastroenterology: June 2019 - Volume 114 - Issue 6 - p 974–983
doi: 10.14309/ajg.0000000000000051
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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.

1Else Kröner-Fresenius-Zentrum für Ernährungsmedizin (EKFZ), Paediatric Nutritional Medicine, Technische Universität München (TUM), Freising, Germany;

2Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, Massachusetts, USA;

3Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary;

4Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan;

5UMR1078 “Génétique, Génomique Fonctionnelle et Biotechnologies,” INSERM, EFS—Bretagne, Université de Brest, CHRU Brest, Brest, France;

6Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA;

7Departments of Medicine, Cell Biology & Molecular Physiology, and Human Genetics, University of Pittsburgh and UPMC, Pittsburgh, Pennsylvania, USA;

8Departments of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA;

9Department of Internal Medicine, Neurology and Dermatology, Division of Gastroenterology, University of Leipzig, Leipzig, Germany;

10Genomic Research on Complex diseases (GRC Group), CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India;

11Epithelial Carcinogenesis Group, Cancer Cell Biology Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain;

12Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service of Baden-Württemberg, Mannheim, Germany;

13Department of Pediatrics I, Medical University, Innsbruck, Austria;

14Institute of Occupational Medicine, Social Medicine and Environmental Medicine, Goethe-University, Frankfurt, Germany;

15Department of Internal Medicine I, Martin Luther University, Halle, Germany.

16Deceased: December 2, 2016.

Correspondence: Heiko Witt, MD. E-mail: heiko.witt@tum.de. Miklós Sahin-Tóth, MD, PhD. E-mail: miklos@bu.edu.

SUPPLEMENTARY MATERIAL accompanies this paper at http://links.lww.com/AJG/A3, http://links.lww.com/AJG/A4, http://links.lww.com/AJG/A5, http://links.lww.com/AJG/A6, http://links.lww.com/AJG/A7, and http://links.lww.com/AJG/A8.

Received June 19, 2018

Accepted October 31, 2018

© The American College of Gastroenterology 2019. All Rights Reserved.
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