A high prevalence of genetic polymorphisms in idiopathic and alcohol-associated chronic pancreatitis patients in Ireland

Abstract

Background: Rare pathogenic variants in serine protease inhibitor Kazal type-1 (SPINK1), cationic trypsinogen (PRSS1), cystic fibrosis transmembrane conductance regulator (CFTR) genes are strongly associated with the development and progression of chronic pancreatitis (CP), but are not routinely tested. For a considerable number of CP patients, the cause of disease is unknown or ambiguous despite sophisticated imaging and biochemical investigations. We hypothesised that some patients diagnosed with idiopathic or alcohol-induced CP may carry CP-related mutations. Therefore, we investigated the presence of CP-related gene mutations in idiopathic and alcohol-associated CP patients, compared to controls. Methods: 126 patients with idiopathic and alcohol-induced CP and 167 controls were enrolled following ethical approval. Mutations were assessed by Taqman© genotyping assay. The study was further reinforced by post hoc analysis of SPINK1 N34S with additional controls (total n=508). Results: Mutations were detected in 25 patients (19.8%) and 10 controls (6%)(P<0.001). The presence of a gene mutation increased disease risk three-fold (odds ratio (OR) 3.4). The majority of mutations were found in SPINK1 N34S (12.7%), which increased disease risk six-fold (OR 5.9). CFTR severe mutation (F508del) was present equally in patients and controls (P=0.746). CFTR mild variant (R117H) was not significantly represented amongst patients (P=0.169). PRSS1 variants were not detected in either group. SPINK1 N34S mutations were more common in patients (12.7%) than in controls (2.4% of n=508)(P=5*10-7). Conclusion: 20% of CP patients carried disease-associated / disease-modifying gene mutations, with SPINK1 N34S disease-altering mutation being unexpectedly high. We therefore suggest that the presence of a SPINK1 mutation should be considered in patients with idiopathic or alcohol-induced CP, particularly where diagnosis is uncertain. Early identification of the presence of variants will allow for modification of risk factors and improve CP management. Furthermore, identifying underlying heritable risk factors may contribute to improved options for disease prevention and treatment.