A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis

Abstract
Chronic pancreatitis is a common inflammatory disease
of the pancreas. Mutations in the genes encoding cationic
trypsinogen (PRSS1)1 and the pancreatic secretory trypsin
inhibitor (SPINK1)2 are associated with chronic pancreatitis.
Because increased proteolytic activity owing to mutated
PRSS1 enhances the risk for chronic pancreatitis, mutations
in the gene encoding anionic trypsinogen (PRSS2) may
also predispose to disease. Here we analyzed PRSS2 in
individuals with chronic pancreatitis and controls and found,
to our surprise, that a variant of codon 191 (G191R) is
overrepresented in control subjects: G191R was present
in 220/6,459 (3.4%) controls but in only 32/2,466 (1.3%)
affected individuals (odds ratio 0.37; P ¼ 1.1 " 10#8).
Upon activation by enterokinase or trypsin, purified
recombinant G191R protein showed a complete loss of
trypsin activity owing to the introduction of a new tryptic
cleavage site that renders the enzyme hypersensitive
to autocatalytic proteolysis. In conclusion, the G191R
variant of PRSS2 mitigates intrapancreatic trypsin activity
and thereby protects against chronic pancreatitis.