Genetics of pancreatitis with a focus on the pancreatic ducts

Abstract

Genetic risk for acute pancreatitis (AP), recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) are increasingly recognized. The exocrine pancreas is composed of both acinar cells and duct cells, with genetic factors associated with AP, RAP and CP linked to one cell type or the other. Increased susceptibility to pancreatitis occurs when the normal physiological mechanisms that allow the pancreas to respond to common stresses or injury are altered. Currently, most our knowledge about genetics focuses on three genes that play critical roles in pancreatic function (PRSS1, CFTR, SPINK1) such that isolated defects lead to disease. However, recent data suggest that more complex combination of genetic and environmental factors are also as important, or more important than Mendelian genetic risk. Understanding of complex interactions requires modeling of these factors so that the response to stresses or injury can be simulated and critical interactions understood. A simple duct cell model is given to illustration the relationship between CFTR, CASR, aquaporins, claudins, and SPINK1, and how they interact. The role of CFTR variants in pancreatic diseases is then discussed.

Figure 1. Pancreatic Duct cell – duct model

An organizational model of the pancreatic duct cell illustrating the relationship between key proteins. CLDN-2 and CLDN-4 are genes coding for claudin-2 and claudin-4 which are the primary claudins that make up the tight junction in the proximal duct cells. PAR2 is a protease-activated receptor that senses trypsin activity in the duct. PAR2 and CASR are believed to regulate CFTR opening to clear trypsin or excessive calcium from the duct. cAMP is the primary regulator of CFTR.