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Table 1. Overview of pancreatitis-associated genetic variants
Gene Variant Pathophysiologic change Publication
PRSS1 R122H Impaired autolysis of trypsin by mesotrypsin, enzyme Y, and Whitcomb et al. 1996
trypsin
PRSS1 N29I Enhanced autoactivation of trypsinogen Gorry et al. 1997, Sahin-
Toth 2000
PRSS1 E79K Reduced autoactivation, but increased activation of anionic Teich et al. 2004
trypsinogen (PRSS2)
PRSS1 R116C Misfolded trypsin, reduced secretion Teich et al. 2006, Kereszturi
et al. 2009
SPINK1 L14R Enhanced intracellular autodigestion, reduced secretion Kiraly et al. 2007
SPINK1 L14P Enhanced intracellular autodigestion, reduced secretion Kiraly et al. 2007
SPINK1 N34S Unknown, probably part of a polygenic model Witt et al. 2000
CTRC R254W Reduced secretion, reduced expression Rosendahl et al. 2008
CTRC K247_R254del No secretion, reduced catalytic activity Rosendahl et al. 2008
CFTR Several, mostly in combination with Reduction of chloride and bicarbonate secretion, detainment of Chang et al. 2007
other genetic factors trypsinogen inside of the pancreas
CPA1 Several variants Increased protein misfolding and ER stress Witt et al. 2014
CEL CEL-HYB Increased protein misfolding and ER stress Fjeld et al. 2015
Fjeld et al. 2022
CELA3B R90C Translational upregulation resulting in uncontrolled proteolysis Moore et al. 2019

and promotes the degradation of not only cationic trypsin with high specificity but also the other two
trypsinogen isoforms . The two best-characterized CTRC variants related to hereditary pancreatitis are
[19]
R254W and K247_R254del, both cause reduced secretion and activity of this enzyme .
[20]
Mutations in the CFTR gene can influence the course and severity of pancreatitis as well. The CFTR protein
functions as an adenosine monophosphate (AMP)-dependent chloride channel and regulator of
transcellular bicarbonate transport [21-24] . Mutations in the CFTR gene lead to a defective CFTR protein and
are associated with cystic fibrosis (CF) in humans, usually with impaired exocrine pancreatic function.
Among CF patients without pancreas insufficiency, 20% develop acute recurrent or chronic pancreatitis .
[25]
The underlying reason for this large number of diseased individuals is that a critical mass of intact
pancreatic acinar cells seems to be required for the development of pancreatitis, which is not the case for
pancreatic-insufficient patients. More than 1,700 CFTR mutations have already been discovered in CF
patients. Despite their high carrier frequency in the population, the occurrence of pancreatitis among those
carrying one mutation is extremely low and suggests that multiple interacting factors, i.e. in combination
with other mutations in the PRSS1 or SPINK1 genes, are likely to be involved in the pathogenesis of
pancreatitis .
[26]

The entirety of the consequences of CFTR dysfunction in association with pancreatitis remains unknown,
but some hypotheses have been advanced. Due to the reduced secretion of bicarbonate in the pancreatic
duct, the pH increases and can promote the activation of trypsinogen and the loss of the integrity of cell-cell
junctions [27,28] . Carboxyl ester lipase (CEL) is a lipolytic enzyme that is localized in pancreatic acinar cells and
lactating mammary glands and is capable of hydrolysis of both water-soluble and water-insoluble lipids .
[29]
The CEL gene is highly polymorphic and contains a variable number of tandem repeat (VNTR) regions.
Single base deletions cause maturity-onset diabetes of the young (MODY). The CEL hybrid allele
(CEL-HYB), originating from a cross-over between CEL and its neighboring pseudogene CELP, has been
found to be significantly overrepresented in chronic pancreatitis patients . From a knock-in mouse model
[30]
of chronic pancreatitis, where the endogenous VNTR of the mouse CEL gene has been substituted with the
VNTR of the human CEL-HYB1, it could be concluded that protein misfolding with the formation of CEL