Background and aims: Mutations in the cationic trypsinogen (protease, serine, 1 (trypsin 1); PRSS1) gene are causally associated with recurrent acute and chronic pancreatitis. We investigated whether mutations in the PRSS1 gene are associated with hereditary and non-hereditary pancreatitis. As a modifier role has been proposed for trypsin inhibitor (serine protease inhibitor, Kazal type I; SPINK1) mutations, the role of SPINK1 mutations in these patients was also analysed.

Subjects and methods: The coding regions of PRSS1 and SPINK1 genes were sequenced in 290 controls and 198 patients, of whom 120 were diagnosed as idiopathic (ICP), 41 as alcoholic (ACP), and 37 as hereditary pancreatitis (HP). Twenty four unaffected relatives of HP probands were also analysed and genotype-phenotype correlations and statistical analyses were performed.

Results: No mutations in the PRSS1 gene were detected in any of the patients, including HP patients, while the N34S mutation was observed in the SPINK1 gene in the majority of HP patients (73%). Similarly, 26.8% of ACP (11 of 41) and 32.5% (39 of 120) of ICP patients also had SPINK1 mutations. The N34S mutation was observed in both homozygous and heterozygous conditions. In comparison, only 2.76% of the control population had the N34S allele (p<0.001). The P55S mutation was observed in one ICP and one ACP patient, and in three normal individuals. Genotype-phenotype correlations did not suggest any significant difference in the age of onset, severity of disease, or pancreatic endocrine insufficiency in patients with or without mutated SPINK1 and irrespective of the allelic status of N34S SPINK1.

Conclusions: Irrespective of the aetiology, mutations in the PRSS1 gene are not associated with chronic pancreatitis, including HP. In contrast, the N34S mutation in the SPINK1 gene shows a significant correlation in these patients. A comparable phenotype in terms of age of onset, diabetes mellitus, and other phenotypic features in patients with or without SPINK1 mutations and N34S homozygotes and heterozygotes suggests that there may still be involvement of other genetic or environmental factors.