A recombination allele of the lipase gene CEL and its pseudogene CELP encodes a hybrid protein and is a genetic risk factor for chronic pancreatitis. K. Fjeld1,2, J. Rosendahl3, J. M. Chen4, D. Lasher5, M. Cnop6, B. B. Johansson1, M. Ringdal1, E. Masson4, J. Mayerle7, J. Mössner3, C. Ruffert3, S. Steine8, E. Tjora1, J. Torsvik1, C. Ferec4, F. U. Weiss7, H. Witt5, M. M. Lerch7, P. R. Njølstad1, S. Johansson1,2, A. Molven1,8,9 1) Department of Clinical Science, University of Bergen, Norway; 2) Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway; 3) Department for Internal Medicine, Neurology and Dermatology, Division of Gastroenterology, University of Leipzig, Germany; 4) Institut National de la Santé et de la Recherche Médicale (INSERM), U1078, Etablissement Français du Sang (EFS)-Bretagne, France; 5) Else Kröner-Fresenius-Zentrum für Ernährungsmedizin (EKFZ), Technische Universität München (TUM), Freising, Germany; 6) Laboratory of Experimental Medicine, Université Libre de Bruxelles, Belgium; 7) Department of Internal Medicine A, Ernst-Moritz-Arndt University, Germany; 8) Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Norway; 9) Department of Pathology, Haukeland University Hospital, Bergen, Norway.

   Introduction: Carboxyl-ester lipase (CEL) is a digestive enzyme that plays an important role in hydrolysis and absorption of cholesterol and lipid-soluble vitamin esters. Human CEL consists of 11 exons and the last exon is highly polymorphic, containing a variable number of tandem repeats (VNTR). We have previously described a monogenic syndrome of diabetes and exocrine pancreatic dysfunction caused by mutations in the CEL VNTR. Copy number variations (CNVs) of the CEL gene have also been reported although their detailed structures were not worked out. Objectives: The aim of this study was to characterize the structure of CEL CNVs and to explore their role in chronic pancreatitis (CP). Methods: We developed long-range PCR-based assays for screening of CEL CNVs. German and French materials of idiopathic CP (n=1136), alcoholic-related CP (n=853), and controls (n=4630) were investigated. For functional analysis, we transfected human embryonic kidney (HEK293) and mouse acinar (266-6) cells with CEL constructs, and performed Western blotting, immunostaining, confocal microscopy, deglycosylation treatment, enzyme activity measurements, and quantitative RT-PCR. Results: We identified two CNVs of CEL, one duplication and one deletion allele, probably resulting from non-allelic homologous recombination between CEL and its neighbouring pseudogene CELP. The deletion variant, a CEL-CELP hybrid allele (CEL-HYB), was strongly associated with idiopathic CP (meta-analysis: OR=6.4, P=1.1 x 10-16). The CEL-HYB variant was also found in 15/853 (3.9%) subjects with alcoholic CP compared with 26/3409 (0.8%) controls (P=0.016). CEL-HYB encodes a CEL protein where the coding VNTR sequence of CEL has been exchanged with that of CELP. This results in a truncated C-terminal of the protein and functional analyses of CEL-HYB showed impaired secretion, reduced enzyme activity, and a stimulation of autophagy. Conclusion: We have identified CEL-HYB as a new genetic risk factor in chronic pancreatitis. To our knowledge, this is the first lipase associated with the disease. Stimulation of autophagy by CEL-HYB suggests that the disease process may involve mechanisms different from those seen for other genetic risk factors for pancreatitis.

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