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

Nature Genetics
Karianne FjeldAnders Molven

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.

References

Apr 8, 1998·Mammalian Genome : Official Journal of the International Mammalian Genome Society·K MadeyskiJ Nilsson
Sep 3, 1998·The New England Journal of Medicine·N SharerJ Braganza
Sep 3, 1998·The New England Journal of Medicine·J A CohnP S Jowell
Jun 21, 2001·JAMA : the Journal of the American Medical Association·H WittV Keim
Aug 22, 2001·Biochimica Et Biophysica Acta·D Lombardo
Feb 16, 2002·European Journal of Biochemistry·Susanne LindquistOlle Hernell
Aug 9, 2002·Journal of Human Genetics·Shoko HiguchiSusumu Saito
Apr 29, 2004·European Journal of Human Genetics : EJHG·Sara H Bengtsson-EllmarkGunnar Bjursell
Dec 22, 2005·Nature Genetics·Helge RaederPål Rasmus Njølstad
Oct 31, 2006·Nature Genetics·Cédric Le MaréchalClaude Férec
Sep 9, 2008·Nature Genetics·Steven A McCarrollDavid Altshuler
Dec 11, 2008·Methods in Molecular Biology·Ragna SannerudJaakko Saraste
Jul 12, 2011·Toxicological Sciences : an Official Journal of the Society of Toxicology·Roberta CastinoCiro Isidoro
Jan 1, 2010·The International Journal of Biostatistics·Markus Scholz, Dirk Hasenclever
Sep 11, 2012·American Journal of Physiology. Gastrointestinal and Liver Physiology·Anna S Gukovskaya, Ilya Gukovsky
Feb 12, 2013·Pancreatology : Official Journal of the International Association of Pancreatology (IAP) ... [et Al.]·Anja RagvinAnders Molven
Aug 21, 2013·Nature Genetics·Heiko WittMiklós Sahin-Tóth
Aug 28, 2014·The Journal of Biological Chemistry·Janniche TorsvikAnders Molven
Sep 26, 2014·Gut·Monique H DerikxUNKNOWN PanEuropean Working group on Alcoholic Chronic Pancreatitis Members and Collaborators

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Citations

Jul 8, 2015·Pancreatology : Official Journal of the International Association of Pancreatology (IAP) ... [et Al.]·Ali A AghdassiPeter Simon
Aug 17, 2016·The American Journal of Gastroenterology·C Mel WilcoxDhiraj Yadav
Jul 20, 2016·Human Mutation·Arnaud BoullingClaude Férec
Oct 25, 2016·Pancreatology : Official Journal of the International Association of Pancreatology (IAP) ... [et Al.]·Monica DalvaAnders Molven
Jun 15, 2018·Current Opinion in Gastroenterology·Frank U WeissMarkus M Lerch
Jul 18, 2018·Current Opinion in Pediatrics·Tanja Gonska
Sep 8, 2017·Nature Reviews. Disease Primers·Jorg KleeffJohn P Neoptolemos
Jun 6, 2019·Clinical and Translational Gastroenterology·David C Whitcomb, UNKNOWN North American Pancreatitis Study Group
Jan 30, 2016·American Journal of Physiology. Gastrointestinal and Liver Physiology·Anita BalázsMiklós Sahin-Tóth
May 15, 2019·The American Journal of Gastroenterology·Mahya Faghih, Vikesh K Singh
Feb 23, 2019·The American Journal of Gastroenterology·Denise LasherMiklós Sahin-Tóth
Jun 27, 2017·Current Opinion in Gastroenterology·Miklós Sahin-Tóth
Mar 3, 2020·American Journal of Physiology. Gastrointestinal and Liver Physiology·Anna OrekhovaMiklós Sahin-Tóth
Nov 26, 2019·The American Journal of Gastroenterology·Phil A Hart, Darwin L Conwell
Jan 4, 2020·Journal of Pediatric Gastroenterology and Nutrition·Kate M Ellery, Aliye Uc
Jan 29, 2016·PloS One·Anil K GiriUNKNOWN INDIPAN and INDICO Consortium
Jun 25, 2016·Current Opinion in Gastroenterology·Walter G Park
Jul 4, 2020·Current Opinion in Gastroenterology·Frank U WeissMarkus M Lerch
Feb 14, 2019·Human Genomics·Xin-Ying TangJian-Min Chen
Jul 17, 2015·Current Opinion in Gastroenterology·John F Pohl, Aliye Uc
Oct 12, 2018·Experimental & Molecular Medicine·Gerrit Wolters-EisfeldMaximilian Bockhorn
Aug 1, 2019·Cellular and Molecular Life Sciences : CMLS·Sudarshan R MallaJulia Mayerle
Oct 3, 2020·Pediatrics in Review·Thanh Huong L NguyenRoberto Gugig
Mar 2, 2017·Therapeutic Advances in Gastroenterology·Zachary Zator, David C Whitcomb
Oct 27, 2016·Journal of Pediatric Gastroenterology and Nutrition·Cheryl E GariepyAliye Uc
Apr 20, 2018·Proceedings of the National Academy of Sciences of the United States of America·Koji TamuraMichael Goggins
Dec 21, 2019·JAMA : the Journal of the American Medical Association·Vikesh K SinghPramod K Garg

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Datasets Mentioned

BETA
AF072711.1

Methods Mentioned

BETA
PCR
exome sequencing
genotyping
transfection
Protein Assay

Software Mentioned

SeqScape
Stata
Tagger
IC
FinchTV
SHAPEIT
Illumina GenomeStudio
Ensembl
IMPUTE
Adobe Photoshop

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