The PRSS3P2 and TRY7 deletion copy number variant modifies risk for chronic pancreatitis

Masson, Emmanuelle, Ewers, Maren, Paliwal, Sumit, Kume, Kiyoshi, Scotet, Virginie, Cooper, David N. ORCID: https://orcid.org/0000-0002-8943-8484, Rebours, Vinciane, Buscail, Louis, Rouault, Karen, Amandine, Abrantes, Lina, Aguilera Munoz, Jérémie, Albouys, Laurent, Alric, Amiot Xavier, Isabelle, Archambeaud, Solène, Audiau, Laetitia, Bastide, Julien, Baudon, Guy, Bellaiche, Serge, Bellon, Valérie, Bertrand, Karine, Bideau, Kareen, Billiemaz, Claire, Billioud, Sabine, Bonnefoy, Corinne, Borderon, Barbara, Bournet, Estelle, Breton, Mathias, Brugel, Louis, Buscail, Guillaume, Cadiot, Marine, Camus, Marine, Carpentier-Pourquier, Patrick, Chamouard, Ulriikka, Chaput, Jian-Min, Chen, Franck, Cholet, Marius, Ciocan Dragos, Christine, Clavel, Benoit, Coffin, Laura, Coimet-Berger, Simona, Cosconea, Isabelle, Creveaux, Adrian, Culetto, Oussama, Daboussi, Louis, De Mestier, Thibault, Degand, Christelle, D'engremont, Bernard, Denis, Solène, Dermine, Romain, Desgrippes, D'Aubigny Augustin, Drouet, Raphaël, Enaud, Alexandre, Fabre, Claude, Ferec, Dany, Gargot, Eve, Gelsi, Elena, Gentilcore, Rodica, Gincul, Emmanuelle, Ginglinger-Favre, Marc, Giovannini, Cécile, Gomercic, Hannah, Gondran, Thomas, Grainville, Philippe, Grandval, Denis, Grasset, Stéphane, Grimaldi, Sylvie, Grimbert, Hervé, Hagege, Sophie, Heissat, Olivia, Hentic, Anne, Herber-Mayne, Marc, Hervouet, Solene, Hoibian, Jérémie, Jacques, Bénédicte, Jais, Mehdi, Kaassis, Stéphane, Koch, Elodie, Lacaze, Joël, Lacroute, Thierry, Lamireau, Lucie, Laurent, Xavier, Le Guillou, Marc, Le Rhun, Sarah, Leblanc, Philippe, Levy, Astrid, Lievre, Diane, Lorenzo, Frédérique, Maire, Kévin, Marcel, Emmanuelle, Masson, Jacques, Mauillon, Stéphanie, Morgant, Driffa, Moussata, Nelly, Muller, Sophie, Nambot, Bertrand, Napoleon, Anne, Olivier, Maël, Pagenault, Anne-laure, Pelletier, Olivier, Pennec, Fabien, Pinard, Mathieu, Pioche, Bénédicte, Prost, Lucille, Queneherve, Vinciane, Rebours, Noemi, Reboux, Samia, Rekik, Ghassan, Riachi, Barbara, Rohmer, Bertrand, Roquelaure, Isabelle, Rosa Hezode, Florian, Rostain, Jean-Christophe, Saurin, Laure, Servais, Roxana, Stan-Iuga, Clément, Subtil, Jérémy, Tanneche, Charles, Texier, Lucie, Thomassin, David, Tougeron, Lucine, Vuitton, Timothée, Wallenhorst, Marc, Wangerme, Hélène, Zanaldi, Frank, Zerbib, Bhaskar, Seema, Kikuta, Kazuhiro, Rao, G Venkat, Hamada, Shin, Reddy, D Nageshwar, Masamune, Atsushi, Chandak, Giriraj Ratan, Witt, Heiko, Férec, Claude and Chen, Jian-Min 2023. The PRSS3P2 and TRY7 deletion copy number variant modifies risk for chronic pancreatitis. Pancreatology 23 (1) , pp. 48-56. 10.1016/j.pan.2022.11.013

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Abstract

Background PRSS1 and PRSS2 constitute the only functional copies of a tandemly-arranged five-trypsinogen-gene cluster (i.e., PRSS1, PRSS3P1, PRSS3P2, TRY7 and PRSS2) on chromosome 7q35. Variants in PRSS1 and PRSS2, including missense and copy number variants (CNVs), have been reported to predispose to or protect against chronic pancreatitis (CP). We wondered whether a common trypsinogen pseudogene deletion CNV (that removes two of the three trypsinogen pseudogenes, PRSS3P2 and TRY7) might be associated with CP causation/predisposition. Methods We analyzed the common PRSS3P2 and TRY7 deletion CNV in a total of 1536 CP patients and 3506 controls from France, Germany, India and Japan by means of quantitative fluorescent multiplex polymerase chain reaction. Results We demonstrated that the deletion CNV variant was associated with a protective effect against CP in the French, German and Japanese cohorts whilst a trend toward the same association was noted in the Indian cohort. Meta-analysis under a dominant model yielded a pooled odds ratio (OR) of 0.68 (95% confidence interval (CI) 0.52–0.89; p = 0.005) whereas an allele-based meta-analysis yielded a pooled OR of 0.84 (95% CI 0.77–0.92; p = 0.0001). This protective effect is explicable by reference to the recent finding that the still functional PRSS3P2/TRY7 pseudogene enhancers upregulate pancreatic PRSS2 expression. Conclusions The common PRSS3P2 and TRY7 deletion CNV was associated with a reduced risk for CP. This finding provides additional support for the emerging view that dysregulated PRSS2 expression represents a discrete mechanism underlying CP predisposition or protection.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Additional Information:	License information from Publisher: LICENSE 1: Title: This article is under embargo with an end date yet to be finalised.
Publisher:	Elsevier
ISSN:	1424-3903
Date of First Compliant Deposit:	8 December 2022
Date of Acceptance:	30 November 2022
Last Modified:	06 Dec 2023 09:08
URI:	https://orca.cardiff.ac.uk/id/eprint/154777

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