We provide evidence that rare pathogenic variants in the SPINK1, PRSS1, CTRC, and CFTR genes significantly influence the age of onset and clinical outcomes of CP.
Genetic studies in adults/adolescent patients with chronic pancreatitis (CP) identified chymotrypsinogen C (CTRC) genetic variants but their association with CP risk has been difficult to replicate.
Early-onset disease was associated with mutations in cationic trypsinogen (PRSS1) (P < .01), chymotrypsin C (CTRC) (P = .01), family history of acute pancreatitis (P = .02), family history of CP (P < .01), biliary cysts (P = .04), or chronic renal failure (P = .02).
Mutations in the cationic trypsinogen (PRSS1), cystic fibrosis transmembrane conductance regulator (CFTR), serine protease inhibitor Kazal type 1 (SPINK1), and chymotrypsin C (CTRC) genes are associated with an elevated risk for chronic pancreatitis, which is a known risk factor for pancreatic cancer (PC).
The CTRC-deleting complex rearrangement probably resulted from LINE-1-mediated Alu insertion, which represents a novel mutational mechanism causing chronic pancreatitis.
Mutations in the chymotrypsin C (CTRC) gene encoding the digestive enzyme CTRC have been shown to increase the risk of chronic pancreatitis in European and Asian populations.
Identification of gain-of-function missense and copy number mutations in the cationic trypsinogen gene (PRSS1) and loss-of-function variants in both the pancreatic secretory trypsin inhibitor (SPINK1) and chymotrypsinogen C (CTRC) genes has firmly established the pivotal role of prematurely activated trypsin within the pancreas in the etiology of CP.
Inactivating mutations in chymotrypsin C have been reported to predispose to the development of chronic pancreatitis, especially in those who are prone to alcohol abuse.