• CHRONIC PANCREATITIS
• TRYPSINOGEN
• ACUTE PANCREATITIS
• PANCREATIC DISORDERS

We read with great interest the recent articles by Wang et al,1 Génin et al,2 Sun et al,3 and Németh et al,4 in which the authors studied various genetic risk factors for chronic pancreatitis (CP). The ever increasing catalogue of risk genes and variants supports the long-held notion that CP is a complex genetic disorder. Thus, patients often carry multiple genetic alterations that interact in synergy and elicit disease onset and/or promote progression. To offer a conceptual framework for genetic risk in CP, we organised risk factors into mechanism-based schemes, which include the trypsin-dependent, misfolding-dependent and ductal pathways.5

More recently, novel mouse models harbouring human pancreatitis-associated mutations emerged, providing strong evidence for the pathogenic nature of these risk variants.3 6–10 All mouse models of genetic CP published to date carry a single genetic alteration and none models CP as a complex genetic disease. We set out to fill this knowledge gap by generating a novel strain carrying both the T7K24R trypsinogen mutant and the Ctrb1-del chymotrypsin deletion alleles. The T7K24R mice have the p.K24R mutation in mouse cationic trypsinogen (isoform T7), which is analogous to the human hereditary pancreatitis-associated p.K23R PRSS1 mutation.9 This mutation increases …