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Trypsinogen (PRSS1 and PRSS2) gene dosage correlates with pancreatitis risk across genetic and transgenic studies: a systematic review and re-analysis

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Abstract

Trypsinogen (PRSS1, PRSS2) copy number gains and regulatory variants have both been proposed to elevate pancreatitis risk through a gene dosage effect (i.e., by increasing the expression of wild-type protein). However, to date, their impact on pancreatitis risk has not been thoroughly evaluated whilst the underlying pathogenic mechanisms remain to be explicitly investigated in mouse models. Genetic studies of the rare trypsinogen duplication and triplication copy number variants (CNVs), and the common rs10273639C variant, were collated from PubMed and/or ClinVar. Mouse studies that analyzed the influence of a transgenically expressed wild-type human PRSS1 or PRSS2 gene on the development of pancreatitis were identified from PubMed. The genetic effects of the different risk genotypes, in terms of odds ratios, were calculated wherever appropriate. The genetic effects of the rare trypsinogen duplication and triplication CNVs were also evaluated by reference to their associated disease subtypes. We demonstrate a positive correlation between increased trypsinogen gene dosage and pancreatitis risk in the context of the rare duplication and triplication CNVs, and between the level of trypsinogen expression and disease risk in the context of the heterozygous and homozygous rs10273639C-tagged genotypes. We retrospectively identify three mouse transgenic studies that are informative in relation to the pathogenic mechanism underlying the trypsinogen gene dosage effect in pancreatitis. Trypsinogen gene dosage correlates with pancreatitis risk across genetic and transgenic studies, highlighting the fundamental role of dysregulated expression of wild-type trypsinogen in the etiology of pancreatitis. Specifically downregulating trypsinogen expression in the pancreas may serve as a potential therapeutic and/or prevention strategy for pancreatitis.

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Acknowledgements

We are most grateful to Kathryn Hatchell, John Garcia, Daniel Pineda and Brandie Leach of Invitae Corporation for providing data and reviewing the draft manuscript.

Funding

This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), the Association des Pancréatites Chroniques Héréditaires and the Association Gaétan Saleün, France; the National Natural Science Foundation of China (nos. 82070661 [W.B.Z.] and 82120108006 [Z.L.]) and the Scientific Innovation Program of Shanghai Municipal Education Committee (no. 201901070007E00052 [Z.L.]). N.P. received a one-year visiting PhD student scholarship from the China Scholarship Council, the Ministry of Education of the People's Republic of China (no. 202006190267). The funding sources did not play any role in the study design, collection, analysis and interpretation of the data or in the writing of the report.

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Authors and Affiliations

  1. Department of Gastroenterology, Changhai Hospital, The Secondary Military Medical University, Shanghai, China

    Wen-Bin Zou & Zhuan Liao

  2. Shanghai Institute of Pancreatic Diseases, Shanghai, China

    Wen-Bin Zou & Zhuan Liao

  3. Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, UK

    David N. Cooper

  4. Univ Brest, Inserm, EFS, UMR 1078, GGB, F-29200, Brest, France

    Emmanuelle Masson, Na Pu, Claude Férec & Jian-Min Chen

  5. Service de Génétique Médicale et de Biologie de la Reproduction, CHRU Brest, F-29200, Brest, France

    Emmanuelle Masson & Claude Férec

  6. Department of Critical Care Medicine, Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China

    Na Pu

  7. INSERM UMR1078, EFS, UBO, 22 avenue Camille Desmoulins, Brest, France

    Jian-Min Chen

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  1. Wen-Bin Zou
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Contributions

W-BZ designed the study, performed the literature search, obtained funding and drafted the manuscript. DNC contributed to the study design and critically revised the manuscript with important intellectual input. EM and NP assisted in performing the literature search and data extraction and revised the manuscript. ZL and CF contributed to the study design, obtained funding and revised the manuscript. J-MC designed and coordinated the study, performed the literature search, obtained funding and drafted the manuscript. All authors have approved the final draft submitted.

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Correspondence to Jian-Min Chen.

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Zou, WB., Cooper, D.N., Masson, E. et al. Trypsinogen (PRSS1 and PRSS2) gene dosage correlates with pancreatitis risk across genetic and transgenic studies: a systematic review and re-analysis. Hum Genet 141, 1327–1338 (2022). https://doi.org/10.1007/s00439-022-02436-x

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