Abstract
Rationale: Genetic features of Chronic Pancreatitis (CP) have been extensively investigated mainly testing genes associated to the trypsinogen activation pathway. However, different molecular pathways involving other genes may be implicated in CP pathogenesis. Objectives: 80 patients with Idiopathic CP were investigated using Next Generation Sequencing approach with a panel of 70 genes related to six different pancreatic pathways: premature activation of trypsinogen; modifier genes of Cystic Fibrosis phenotype; pancreatic secretion and ion homeostasis; Calcium signalling and zymogen granules exocytosis; autophagy; autoimmune pancreatitis related genes. Results: We detected mutations in 34 out of 70 genes examined; 64/80 patients (80.0%) were positive for mutations in one or more genes, 16/80 patients (20.0%) had no mutations. Mutations in CFTR were detected in 32/80 patients (40.0%) and 22 of them exhibited at least one mutation in genes of other pancreatic pathways. Of the remaining 48 patients, 13/80 (16.3%) had mutations in genes involved in premature activation of trypsinogen and 19/80 (23.8%) had mutations only in genes of the other pathways: 38/64 patients positive for mutations showed variants in two or more genes (59.3%). Conclusions: Our data, although to be extended with functional analysis of novel mutations, suggest a high rate of genetic heterogeneity in chronic pancreatitis and that trans-heterozygosity may predispose to the idiopathic CP phenotype.
Highlights
Chronic pancreatitis (CP) is a persistent inflammatory disease in which exocrine acinar tissue is gradually replaced by fibrotic tissue [1]
Exclusion criteria were any known etiology of CP and : (i) alcohol abuse; (ii) gallstones, pancreatic calcifications or congenital malformations; (iii) trauma or protracted assumption of drugs; (iv) metabolic diseases; (v) chronic viral infections; (vi) familial pancreatitis; (vii) autoimmune pancreatitis and (viii) cystic fibrosis (CF)
All individuals were investigated for 70 genes encoding proteins involved in six different pathways already reported to contribute to the pathogenesis of pancreatitis
Summary
Chronic pancreatitis (CP) is a persistent inflammatory disease in which exocrine acinar tissue is gradually replaced by fibrotic tissue [1]. The annual incidence of CP in adults is estimated to be 5–12 per 100,000 inhabitants each year in Japan, Europe and the United States [2]. Data on the incidence in children are not available [3]. CP is frequently secondary to alcohol abuse or to gallstones [2]. Such causes are uncommon in pediatric pancreatitis, where a percentage of the cases are due to congenital pancreatic malformations. More rare causes include trauma and drugs [4]
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