Genetic Factors in Acute Pancreatitis

While many cases of acute pancreatitis (AP) among adults are attributed to gallstones and alcohol, the majority of people with these risk factors never develop AP. It is increasingly recognized that these stimuli are modulated by other susceptibility factors, including trypsinogen activity, pancreatic ductal clearance, and endoplasmic reticulum (ER) stress. The risk of AP is dependent on the balance between environmental/metabolic stressors and the strength of protective counter-mechanisms, which are linked to genetic variations of their translated products. Thus, the magnitude of an extrinsic stressor that is required to trigger AP appears to be reduced in proportion to the effect of genetic polymorphisms related to the mechanisms protecting the pancreas from injury. A number of germline pathogenic variants have been identified that are overrepresented among patients with recurrent AP and chronic pancreatitis (CP), and may provide an explanation for some subjects with previously unexplained AP. Pathogenic variants in PRSS1 were found to be causative of hereditary pancreatitis, and since that time variants in SPINK1 , CFTR , CLDN2 , and CASR have been identified as predisposing factors for the development of AP. Variants in several additional genes, including CTRC and CPA-1 , appear to influence the progression from AP to CP but are not identified at higher rates among subjects who have only experienced a single episode of AP. Single nucleotide polymorphisms in the genes for TNF-α, IL-8, and MCP-1 have been identified as predisposing factors for the development of severe AP. While directed therapies are not available for most of these pathogenic variants, patients may benefit from specific counselling related to the mechanism of their variant and ways to reduce future recurrences of AP.