Karianne Fjeld1, Emmanuelle Masson2, Jin-Huan Lin3, Patrick Michl4, Tomasz Stokowy5, Anny Gravdal6, Khadija El Jellas7, Solrun J Steine8, Dag Hoem9, Bente B Johansson10, Monica Dalva11, Claudia Ruffert4, Wen-Bin Zou3, Zhao-Shen Li3, Pål R Njølstad12, Jian-Min Chen13, Zhuan Liao3, Stefan Johansson14, Jonas Rosendahl4, Claude Férec2, Anders Molven15. 1. The Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway; Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway; Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway. Electronic address: karianne.fjeld@uib.no. 2. Univ Brest, Inserm, EFS, UMR 1078, GGB, F-29200, Brest, France; CHRU Brest, Service de Génétique, Brest, France. 3. Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China; Shanghai Institute of Pancreatic Diseases, Shanghai, China. 4. Department of Internal Medicine I, Martin Luther University, Halle, Germany. 5. Genomics Core Facility, Department of Clinical Science, University of Bergen, Bergen, Norway. 6. The Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway; Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway; Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway. 7. The Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway; Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway. 8. The Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway. 9. Department of Gastrointestinal Surgery, Haukeland University Hospital, Bergen, Norway. 10. Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway. 11. The Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway; Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway. 12. Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Pediatrics and Adolescent Medicine, Haukeland University Hospital, Bergen, Norway. 13. Univ Brest, Inserm, EFS, UMR 1078, GGB, F-29200, Brest, France. 14. Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway; Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway. 15. The Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway; Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Pathology, Haukeland University Hospital, Bergen, Norway.
Abstract
BACKGROUND/ OBJECTIVES: Carboxyl ester lipase is a pancreatic enzyme encoded by CEL, an extremely polymorphic human gene. Pathogenic variants of CEL either increases the risk for chronic pancreatitis (CP) or cause MODY8, a syndrome of pancreatic exocrine and endocrine dysfunction. Here, we aimed to characterize a novel duplication allele of CEL (CEL-DUP2) and to investigate whether it associates with CP or pancreatic cancer. METHODS: The structure of CEL-DUP2 was determined by a combination of Sanger sequencing, DNA fragment analysis, multiplex ligation-dependent probe amplification and whole-genome sequencing. We developed assays for screening of CEL-DUP2 and analyzed cohorts of idiopathic CP, alcoholic CP and pancreatic cancer. CEL protein expression was analyzed by immunohistochemistry. RESULTS: CEL-DUP2 consists of an extra copy of the complete CEL gene. The allele has probably arisen from non-allelic, homologous recombination involving the adjacent pseudogene of CEL. We found no association between CEL-DUP2 carrier frequency and CP in cohorts from France (cases/controls: 2.5%/2.4%; P = 1.0), China (10.3%/8.1%; P = 0.08) or Germany (1.6%/2.3%; P = 0.62). Similarly, no association with disease was observed in alcohol-induced pancreatitis (Germany: 3.2%/2.3%; P = 0.51) or pancreatic cancer (Norway; 2.5%/3.2%; P = 0.77). Notably, the carrier frequency of CEL-DUP2 was more than three-fold higher in Chinese compared with Europeans. CEL protein expression was similar in tissues from CEL-DUP2 carriers and controls. CONCLUSIONS: Our results support the contention that the number of CEL alleles does not influence the risk of pancreatic exocrine disease. Rather, the pathogenic CEL variants identified so far involve exon 11 sequence changes that substantially alter the protein's tail region.
BACKGROUND/ OBJECTIVES:Carboxyl ester lipase is a pancreatic enzyme encoded by CEL, an extremely polymorphic human gene. Pathogenic variants of CEL either increases the risk for chronic pancreatitis (CP) or cause MODY8, a syndrome of pancreatic exocrine and endocrine dysfunction. Here, we aimed to characterize a novel duplication allele of CEL (CEL-DUP2) and to investigate whether it associates with CP or pancreatic cancer. METHODS: The structure of CEL-DUP2 was determined by a combination of Sanger sequencing, DNA fragment analysis, multiplex ligation-dependent probe amplification and whole-genome sequencing. We developed assays for screening of CEL-DUP2 and analyzed cohorts of idiopathic CP, alcoholic CP and pancreatic cancer. CEL protein expression was analyzed by immunohistochemistry. RESULTS:CEL-DUP2 consists of an extra copy of the complete CEL gene. The allele has probably arisen from non-allelic, homologous recombination involving the adjacent pseudogene of CEL. We found no association between CEL-DUP2 carrier frequency and CP in cohorts from France (cases/controls: 2.5%/2.4%; P = 1.0), China (10.3%/8.1%; P = 0.08) or Germany (1.6%/2.3%; P = 0.62). Similarly, no association with disease was observed in alcohol-induced pancreatitis (Germany: 3.2%/2.3%; P = 0.51) or pancreatic cancer (Norway; 2.5%/3.2%; P = 0.77). Notably, the carrier frequency of CEL-DUP2 was more than three-fold higher in Chinese compared with Europeans. CEL protein expression was similar in tissues from CEL-DUP2 carriers and controls. CONCLUSIONS: Our results support the contention that the number of CEL alleles does not influence the risk of pancreatic exocrine disease. Rather, the pathogenic CEL variants identified so far involve exon 11 sequence changes that substantially alter the protein's tail region.