Insights into the genetic risk factors for the development of pancreatic disease

Abstract

Diseases of the exocrine pancreas such as recurrent acute pancreatitis (RAP), chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC) represent syndromes defined according to traditional clinicopathologic criteria. The failure of traditional approaches to identify primary mechanisms underlying these progressive disorders illustrates a greater problem of failure of the germ theory of disease for complex disorders. Multiple genetic discoveries and new complex disease models force consideration of a new paradigm of 'precision medicine', requiring a new mechanistic definition of CP. Recognizing the advances in understanding complex gene and environment interactions, as well as the development of new strategies that limit or prevent the development of devastating end-stage diseases of the pancreas may lead to substantial improvements in patient care.

Keywords: acute pancreatitis; chronic pancreatitis; diabetes; exocrine pancreatic insufficiency; genetic; modeling; pancreatic disease; precision medicine.

Figure 1.

Molecular modeling and simulations of CFTR WT and variants. The WT CFTR dimer is seen from the top (panel a) and bottom (panel b) views with the nucleotide-binding domains and membrane-spanning domains labeled and the lipid bilayer seen as the color grey. The black represents subunit 1 of CFTR with residues 1–859 and the blue represents subunit two with residues 860–1480. The red are the CFTR variants that were studied. Residues R170 and L967 are the hinge region. The role of R117 remains unknown. Panels c–f demonstrate the simulations comparing channel diameters of WT and mutants, with channel diameter decreasing at the pore region near the L997F amino acid substitution. CFTR, cystic fibrosis transmembrane conductance regulator; WT, wild type.

Figure 2.

Conceptual model of CP progression. A total of five progressive states are represented. (A) At-risk patients appear completely normal, and can remain so for years. A random (stochastic) injury triggers the inflammation (SAPE) resulting in (B). Acute pancreatitis. Mild AP completely resoles while more severe AP results in some changes suggestive of (C). Early CP. While AP or early CP may appear to resolve, the pancreas is markedly more sensitive to episodes of AP (RAP, dashed line). (D). Established CP requires two or more systems within the pancreas to develop inflammation-associated, ‘permanent’ morphologic and/or functional damage. (E). End-stage CP one or more systems fail, requiring supportive treatment (enzyme replacement, insulin replacement) or radical interventions (partial or total pancreatectomy for pain) or PDAC. T3cDM, diabetes mellitus from destruction of the islet cells from inflammation. AP, acute pancreatitis; CP, chronic pancreatitis; DM, diabetes mellitus; PDAC, pancreatic ductal adenocarcinoma; RAP, recurrent acute pancreatitis; SAPE, sentinel acute pancreatitis event.