A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis

Karianne Fjeld; Frank Ulrich Weiss; Denise Lasher; Jonas Rosendahl; Jian Min Chen; Bente B. Johansson; Holger Kirsten; Claudia Ruffert; Emmanuelle Masson; Solrun J. Steine; Peter Bugert; Miriam Cnop; Robert Grützmann; Julia Mayerle; Joachim Mössner; Monika Ringdal; Hans Ulrich Schulz; Matthias Sendler; Peter Simon; Pawea Sztromwasser; Janniche Torsvik; Markus Scholz; Erling Tjora; Claude Férec; Heiko Witt; Markus M. Lerch; Pål R. Njølstad; Stefan Johansson; Anders Molven

doi:10.1038/ng.3249

A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis

Karianne Fjeld, Frank Ulrich Weiss, Denise Lasher, Jonas Rosendahl, Jian Min Chen, Bente B. Johansson, Holger Kirsten, Claudia Ruffert, Emmanuelle Masson, Solrun J. Steine, Peter Bugert, Miriam Cnop, Robert Grützmann, Julia Mayerle, Joachim Mössner, Monika Ringdal, Hans Ulrich Schulz, Matthias Sendler, Peter Simon, Pawea SztromwasserJanniche Torsvik, Markus Scholz, Erling Tjora, Claude Férec, Heiko Witt, Markus M. Lerch, Pål R. Njølstad, Stefan Johansson, Anders Molven

Associate Professorship of Paediatric Nutritional Medicine

Research output: Contribution to journal › Article › peer-review

158 Scopus citations

Abstract

Carboxyl ester lipase is a digestive pancreatic enzyme encoded by the CEL gene. Mutations in CEL cause maturity-onset diabetes of the young as well as pancreatic exocrine dysfunction. Here we describe a hybrid allele (CEL-HYB) originating from a crossover between CEL and its neighboring pseudogene, CELP. In a discovery series of familial chronic pancreatitis cases, we observed CEL-HYB in 14.1% (10/71) of cases compared to 1.0% (5/478) of controls (odds ratio (OR) = 15.5; 95% confidence interval (CI) = 5.1-46.9; P = 1.3 × 10 -6 by two-tailed Fisher's exact test). In three replication studies of nonalcoholic chronic pancreatitis, we identified CEL-HYB in a total of 3.7% (42/1,122) cases and 0.7% (30/4,152) controls (OR = 5.2; 95% CI = 3.2-8.5; P = 1.2 × 10 -11; formal meta-analysis). The allele was also enriched in alcoholic chronic pancreatitis. Expression of CEL-HYB in cellular models showed reduced lipolytic activity, impaired secretion, prominent intracellular accumulation and induced autophagy. These findings implicate a new pathway distinct from the protease-antiprotease system of pancreatic acinar cells in chronic pancreatitis.

Original language	English
Pages (from-to)	518-522
Number of pages	5
Journal	Nature Genetics
Volume	47
Issue number	5
DOIs	https://doi.org/10.1038/ng.3249
State	Published - 30 May 2015

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/ng.3249

Cite this

Fjeld, K., Weiss, F. U., Lasher, D., Rosendahl, J., Chen, J. M., Johansson, B. B., Kirsten, H., Ruffert, C., Masson, E., Steine, S. J., Bugert, P., Cnop, M., Grützmann, R., Mayerle, J., Mössner, J., Ringdal, M., Schulz, H. U., Sendler, M., Simon, P., ... Molven, A. (2015). A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis. Nature Genetics, 47(5), 518-522. https://doi.org/10.1038/ng.3249

@article{85a18691ab3841a18b03db63de9cb932,

title = "A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis",

abstract = "Carboxyl ester lipase is a digestive pancreatic enzyme encoded by the CEL gene. Mutations in CEL cause maturity-onset diabetes of the young as well as pancreatic exocrine dysfunction. Here we describe a hybrid allele (CEL-HYB) originating from a crossover between CEL and its neighboring pseudogene, CELP. In a discovery series of familial chronic pancreatitis cases, we observed CEL-HYB in 14.1% (10/71) of cases compared to 1.0% (5/478) of controls (odds ratio (OR) = 15.5; 95% confidence interval (CI) = 5.1-46.9; P = 1.3 × 10 -6 by two-tailed Fisher's exact test). In three replication studies of nonalcoholic chronic pancreatitis, we identified CEL-HYB in a total of 3.7% (42/1,122) cases and 0.7% (30/4,152) controls (OR = 5.2; 95% CI = 3.2-8.5; P = 1.2 × 10 -11; formal meta-analysis). The allele was also enriched in alcoholic chronic pancreatitis. Expression of CEL-HYB in cellular models showed reduced lipolytic activity, impaired secretion, prominent intracellular accumulation and induced autophagy. These findings implicate a new pathway distinct from the protease-antiprotease system of pancreatic acinar cells in chronic pancreatitis.",

author = "Karianne Fjeld and Weiss, {Frank Ulrich} and Denise Lasher and Jonas Rosendahl and Chen, {Jian Min} and Johansson, {Bente B.} and Holger Kirsten and Claudia Ruffert and Emmanuelle Masson and Steine, {Solrun J.} and Peter Bugert and Miriam Cnop and Robert Gr{\"u}tzmann and Julia Mayerle and Joachim M{\"o}ssner and Monika Ringdal and Schulz, {Hans Ulrich} and Matthias Sendler and Peter Simon and Pawea Sztromwasser and Janniche Torsvik and Markus Scholz and Erling Tjora and Claude F{\'e}rec and Heiko Witt and Lerch, {Markus M.} and Nj{\o}lstad, {P{\aa}l R.} and Stefan Johansson and Anders Molven",

note = "Publisher Copyright: {\textcopyright} 2015 Nature America, Inc.",

year = "2015",

month = may,

day = "30",

doi = "10.1038/ng.3249",

language = "English",

volume = "47",

pages = "518--522",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "5",

}

Fjeld, K, Weiss, FU, Lasher, D, Rosendahl, J, Chen, JM, Johansson, BB, Kirsten, H, Ruffert, C, Masson, E, Steine, SJ, Bugert, P, Cnop, M, Grützmann, R, Mayerle, J, Mössner, J, Ringdal, M, Schulz, HU, Sendler, M, Simon, P, Sztromwasser, P, Torsvik, J, Scholz, M, Tjora, E, Férec, C, Witt, H, Lerch, MM, Njølstad, PR, Johansson, S & Molven, A 2015, 'A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis', Nature Genetics, vol. 47, no. 5, pp. 518-522. https://doi.org/10.1038/ng.3249

TY - JOUR

T1 - A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis

AU - Fjeld, Karianne

AU - Weiss, Frank Ulrich

AU - Lasher, Denise

AU - Rosendahl, Jonas

AU - Chen, Jian Min

AU - Johansson, Bente B.

AU - Kirsten, Holger

AU - Ruffert, Claudia

AU - Masson, Emmanuelle

AU - Steine, Solrun J.

AU - Bugert, Peter

AU - Cnop, Miriam

AU - Grützmann, Robert

AU - Mayerle, Julia

AU - Mössner, Joachim

AU - Ringdal, Monika

AU - Schulz, Hans Ulrich

AU - Sendler, Matthias

AU - Simon, Peter

AU - Sztromwasser, Pawea

AU - Torsvik, Janniche

AU - Scholz, Markus

AU - Tjora, Erling

AU - Férec, Claude

AU - Witt, Heiko

AU - Lerch, Markus M.

AU - Njølstad, Pål R.

AU - Johansson, Stefan

AU - Molven, Anders

PY - 2015/5/30

Y1 - 2015/5/30

N2 - Carboxyl ester lipase is a digestive pancreatic enzyme encoded by the CEL gene. Mutations in CEL cause maturity-onset diabetes of the young as well as pancreatic exocrine dysfunction. Here we describe a hybrid allele (CEL-HYB) originating from a crossover between CEL and its neighboring pseudogene, CELP. In a discovery series of familial chronic pancreatitis cases, we observed CEL-HYB in 14.1% (10/71) of cases compared to 1.0% (5/478) of controls (odds ratio (OR) = 15.5; 95% confidence interval (CI) = 5.1-46.9; P = 1.3 × 10 -6 by two-tailed Fisher's exact test). In three replication studies of nonalcoholic chronic pancreatitis, we identified CEL-HYB in a total of 3.7% (42/1,122) cases and 0.7% (30/4,152) controls (OR = 5.2; 95% CI = 3.2-8.5; P = 1.2 × 10 -11; formal meta-analysis). The allele was also enriched in alcoholic chronic pancreatitis. Expression of CEL-HYB in cellular models showed reduced lipolytic activity, impaired secretion, prominent intracellular accumulation and induced autophagy. These findings implicate a new pathway distinct from the protease-antiprotease system of pancreatic acinar cells in chronic pancreatitis.

AB - Carboxyl ester lipase is a digestive pancreatic enzyme encoded by the CEL gene. Mutations in CEL cause maturity-onset diabetes of the young as well as pancreatic exocrine dysfunction. Here we describe a hybrid allele (CEL-HYB) originating from a crossover between CEL and its neighboring pseudogene, CELP. In a discovery series of familial chronic pancreatitis cases, we observed CEL-HYB in 14.1% (10/71) of cases compared to 1.0% (5/478) of controls (odds ratio (OR) = 15.5; 95% confidence interval (CI) = 5.1-46.9; P = 1.3 × 10 -6 by two-tailed Fisher's exact test). In three replication studies of nonalcoholic chronic pancreatitis, we identified CEL-HYB in a total of 3.7% (42/1,122) cases and 0.7% (30/4,152) controls (OR = 5.2; 95% CI = 3.2-8.5; P = 1.2 × 10 -11; formal meta-analysis). The allele was also enriched in alcoholic chronic pancreatitis. Expression of CEL-HYB in cellular models showed reduced lipolytic activity, impaired secretion, prominent intracellular accumulation and induced autophagy. These findings implicate a new pathway distinct from the protease-antiprotease system of pancreatic acinar cells in chronic pancreatitis.

UR - http://www.scopus.com/inward/record.url?scp=84929132425&partnerID=8YFLogxK

U2 - 10.1038/ng.3249

DO - 10.1038/ng.3249

M3 - Article

C2 - 25774637

AN - SCOPUS:84929132425

SN - 1061-4036

VL - 47

SP - 518

EP - 522

JO - Nature Genetics

JF - Nature Genetics

IS - 5

ER -

A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis

Abstract

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this