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We read with great interest the study by Hegyi et al1 which reported that a commonly occurring haplotype spanning the PRSS1-PRSS2 locus (encoding human cationic and anionic trypsinogens) is associated with chronic pancreatitis. While PRSS1 is the major focus in many studies,2 3 PRSS2 is also a major trypsinogen isoform synthesised in human pancreas. In normal human, the PRSS1/PRSS2 ratio is approximately 2:1.4 Chronic alcoholism increases the risk of pancreatitis. Strikingly, in these patients, total trypsinogen secretion was increased with selective upregulation of PRSS2, reversing the PRSS1/PRSS2 ratio.5 In vitro studies have shown human PRSS2 more sensitive to autocatalytic degradation and with lower autoactivation than PRSS1.6 In test tube assays under conditions of intracellular pathological trypsinogen activation, mixtures of PRSS1 and PRSS2 with increasing ratios of PRSS2 had markedly decreased rates of trypsinogen activation and yields of active trypsin.6 These observations led to a hypothesis that upregulation of PRSS2 may play a protective role against pancreatitis.6 …
BJ and YB are co-senior authors.
Contributors JW coordinated the project and was involved in most experiments including data collection, statistical analysis and draft the manuscript. AH and BE managed mouse colony, genotyping, embedded and processed the tissues, H&E and immunohistochemistry staining. BJ and YB supervised the study, finalised the manuscript and secured funding support.
Funding This work was supported by Grants Department of Defense DoD W81XWH-15-1-0257, National Institute of Health NIH R01 DK117910 and National Cancer Institute NCI K12 CA090628-18 and NCI P50 CA102701.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; internally peer reviewed.
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