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

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