Genetic risk factors for pancreatic disorders

Abstract

A combination of genetic, environmental, and metabolic factors contribute to the development and recurrence of acute and chronic pancreatitis; information on all of these is required to manage patients effectively. For example, variants that affect regulation of the protease, serine (PRSS)1-PRSS2, and claudin (CLDN)2 loci, rather than their coding sequences, interact with other genetic and environmental factors to affect disease development. New strategies are needed to use these data and determine their contribution to pathogenesis, because these variants differ from previously studied, rare variants in exons (coding regions) of genes such as PRSS1, SPINK1, cystic fibrosis transmembrane conductance regulator (CFTR), chymotrypsin (CTR)C, and calcium-sensing receptor (CASR). Learning how various genetic factors affect pancreatic cells and systems could lead to etiology-based therapies rather than treatment of symptoms.

Figure 1. General Models of Inflammation

Chronic pancreatitis is illustrated as a syndrome that develops over time (left to right). A. Individuals may live for years with multiple susceptibility factors. Patients with very high risk may be candidates for new prevention strategies such as avoiding alcohol. B. When a stochastic event leads to pancreatic injures it initiates the Sentinel Acute Pancreatitis Event (SAPE) with intra-pancreatic immune system activation. Management includes identification of actionable risk and prevention of RAP. C. Factors such as alcohol, smoking and genetic mutations or presently unidentified factors affect the specialized cells of the pancreas and infiltrating cells to cause various complications. Research efforts are focusing on identifying risk, mechanisms and biomarkers of the progression pathways.

Figure 2. Genetic and Environmental Factors that Affect Acinar Cells or Ducts

Premature trypsin activation may occur within the acinar cell or within the duct to initiate pancreatitis. The majority of known risk factors can be classified as primarily affecting the acinar cells or pancreatic ducts. Understanding the site of likely trypsin activation and mechanism may guide preventative strategies in the future. (from Solomon and Whitcomb).

Figure 3. Risks of RAP and CP

Data collected in population-based analysis of 7456 residents of Allegheny County, PA following their first (sentinel) episode of AP. A. Risk of developing RAP based on etiology, B. Risk of CP based on the presence or absence of documented RAP. From Yadav, O’Connell and Papachristou. .

Figure 4. Factors that Contribute to Pancreatic Fibrosis

A combination of factors contribute to pancreatitis. The first hit increases susceptibility to injury, whereas the second hit affects the immune response (and includes leukocytes, such as M2 macrophages) to promote stellate cell-associated fibrosis. Alcohol could injure the pancreas via its effects on acinar cells, but it is probably more important in the second group, as a modifier of the immune response. For example it could promote a Th17-cell response, or act directly on stellate cells (dashed lines). Altered trypsin functions in acinar cells or ducts could also initiate disease. In either case, similar second hit factors then contribute to development of fibrosis (via variants in SPINK1 and/or CTRC). Severe acute pancreatitis involves widespread pancreatic necrosis (about 90% of tissue), which leads directly to scaring and fibrosis in the recovery phase. Obese patients could have areas of adipose tissue that contain local necrosis of acinar tissue, which has been linked to lipotoxicity. Progressive fibrosis could occur in patients with RAP. Other pathways include autoimmune pancreatitis in which the pathway to fibrosis is less well understood.