Pathologic genetic variations play a central role in pancreatic diseases. Multiple pancreatic disease risk genes have been identified, and they play different roles in susceptibility, severity, progression, complications and outcomes. Identification of genetic variations provides insight into mechanisms that eventuate in disease. Since the germ line genetic code remains stable (with the exception of neoplasia), genetic testing may make it possible to classify patients based on genomics, and develop early treatment plans based on predictions of future progression and complications, and likely response to specific therapeutic interventions. The interacting role of environmental factors such as alcohol consumption and cigarette smoking are likely potentiated genetic factors in complex ways.

A basic review of pancreatic anatomy and physiology serves as a foundation for organizing and understanding the effects of pathogenic variants in pancreatic disease-associated genes. A key mechanism of pancreatic injury mechanism is premature activation of trypsin, which then activates other digestive enzymes within the pancreas leading to recurrent injury. The TIGAR-O etiologic classification system is used to identify all combinations of risk factors related to recurrent acute and chronic pancreatitis. The SAPE model of chronic pancreatitis is useful in organizing factors that are important in initiating injury, and those that alter progression to fibrosis, pain, atrophy, diabetes or cancer. Key genes include cationic trypsinogen (PRSS1 – causing hereditary pancreatitis), pancreatic secretory trypsin inhibitor (SPINK1), chymotrypsinogen C (CTRC) and the cystic fibrosis transmemberane conductance regulator (CFTR – causing cystic fibrosis and other related disorders). Other genes have been implicated as risk factors of pancreatitis independent of trypsin. These include the high-risk CLDN2-locus haplotype, CPA1, GGT1, and others that are yet to be replicated. Rare multi-organ genetic syndromes also cause pancreatic insufficiency such as Shwachman-Diamond Syndrome (SBDS).

Understanding the role of simple and complex genetics in pancreatic disease is important because it provides a new approach to prevent the progression or severity of some pancreatic diseases. It also offers a strategy for targeted therapies and decisions on the potential merits of total pancreatectomy with islet autotransplantation.