Extensive Molecular Analysis Suggested the Strong Genetic Heterogeneity of Idiopathic Chronic Pancreatitis

Abstract

Genetic features of chronic pancreatitis (CP) have been investigated extensively, mainly by testing genes associated to the trypsinogen activation pathway. However, different molecular pathways involving other genes may be implicated in CP pathogenesis. A total of 80 patients with idiopathic chronic pancreatitis (ICP) were investigated using a Next-Generation Sequencing (NGS) 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 signaling and zymogen granules (ZG) exocytosis, autophagy and autoimmune pancreatitis-related genes. We detected mutations in 34 out of 70 genes examined; of the 80 patients, 64 (80.0%) were positive for mutations in one or more genes and 16 (20.0%) had no mutations. Mutations in CFTR were detected in 32 of the 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 (59.3%) of the 64 patients positive for mutations showed variants in two or more genes. Our data, although to be extended with functional analysis of novel mutations, suggest a high rate of genetic heterogeneity in CP and that trans-heterozygosity may predispose to the ICP phenotype. online address: http://www.molmed.org

Genetic risk in chronic pancreatitis: the misfolding-dependent pathway

“…Mutation p.C139S was identified in 12 cases so far, all sporadic with no family history [ 16 , 21 – 23 ]. The p.C139F mutation, which affects the same position, was detected in five cases and in one unaffected family member [ 13 , 19 , 21 , 24 ]. Mutation p.L104P was first described in three heterozygous carriers of a German family with a history of abdominal pain and diabetes but without clinically proven chronic pancreatitis [ 13 ].…”

TRPV6 variants confer susceptibility to chronic pancreatitis in the Chinese population

“…Recently, we demonstrated putative associations between CP and rare variants of the STIM1 gene, which encodes stromal interaction molecule‐1, the main regulator of Ca 2+ homeostasis in pancreatic acinar cells, in both French and Chinese populations (Masson et al, 2019). Moreover, the TPRV6 gene (contained within a panel of 70 genes) was recently analyzed in 80 patients with idiopathic CP and three missense variants (i.e., c.776T>A [p.Leu259Gln], c.1490T>C [p.Met497Thr], and c.1391G>A [p.Glu535Lys]) were found (Sofia et al, 2016). However, this study did not include controls and functional analysis of the variants.…”

p.E152K-STIM1 mutation deregulates Ca2+signaling contributing to chronic pancreatitis

“…The importance of Ca 2+ signaling for the regulation of pancreatic zymogen activation and the key role of STIM1 in this process suggests that variants in the STIM1 gene may also contribute to chronic pancreatitis by disturbing Ca 2+ homeostasis within the pancreatic tissue. In this regard, Sofia and colleagues have recently analyzed the STIM1 in 80 patients with idiopathic chronic pancreatitis (ICP) and found three missense mutations in different patients (Sofia et al, 2016). Indeed, a recently genetic study of the Ca 2+ channel TRPV6 in pancreatitis cohorts described variants of the protein linked to Ca 2+ deregulation leading to the appearance of pancreatitis features (Masamune et al, 2020).…”