Trans-heterozygosity for mutations enhances the risk of recurrent/chronic pancreatitis in patients with Cystic Fibrosis

Abstract

BackgroundRecurrent (RP) and chronic pancreatitis (CP) may complicate Cystic Fibrosis (CF). It is still unknown if mutations in genes involved in the intrapancreatic activation of trypsin (IPAT) or in the pancreatic secretion pathway (PSP) may enhance the risk for RP/CP in patients with CF.MethodsWe enrolled: 48 patients affected by CF complicated by RP/CP and, as controls 35 patients with CF without pancreatitis and 80 unrelated healthy subjects. We tested a panel of 8 genes involved in the IPAT, i.e. PRSS1, PRSS2, SPINK1, CTRC, CASR, CFTR, CTSB and KRT8 and 23 additional genes implicated in the PSP.ResultsWe found 14/48 patients (29.2%) with mutations in genes involved in IPAT in the group of CF patients with RP/CP, while mutations in such genes were found in 2/35 (5.7%) patients with CF without pancreatitis and in 3/80 (3.8%) healthy subjects (p < 0.001). Thus, we found mutations in 12 genes of the PSP in 11/48 (22.9%) patients with CF and RP/CP. Overall, 19/48 (39.6%) patients with CF and RP/CP showed one or more mutations in the genes involved in the IPAT and in the PSP while such figure was 4/35 (11.4%) for patients with CF without pancreatitis and 11/80 (13.7%) for healthy controls (p < 0.001).ConclusionsThe trans-heterozygous association between CFTR mutations in genes involved in the pathways of pancreatic enzyme activation and the pancreatic secretion may be risk factors for the development of recurrent or chronic pancreatitis in patients with CF.Electronic supplementary materialThe online version of this article (10.1186/s10020-018-0041-6) contains supplementary material, which is available to authorized users.

Cystic Fibrosis: The Sense of Smell

“…4 CF is caused by more than 2000 mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). [5][6][7] This gene encodes a protein that transports chloride and sodium across the apical membranes of epithelial cells. 8,9 The involvement of the UAW in CF patients includes chronic rhinosinusitis (CRS) with or without nasal polyposis.…”

Natural history of SPINK1 germline mutation related-pancreatitis

“…Similarly, Sofia et al. [10] recently reported compound heterozygosity, involving various genes including SPINK1 , enhanced the risk for CP in patients with cystic fibrosis.…”

“…This is due to a variety of reasons including: limited number of small studies describing cohorts of 6 to 48 patients; genetic variants of unknown significance were included; evaluation for other risk factors is sometimes limited to tobacco consumption; finally, the frequent coexistence of other potential causes of pancreatitis [6,8,9] did not allow for clear conclusions to be drawn regarding the role of SPINK1 variants in pancreatitis. Furthermore the association between coexistent SPINK1 mutations and other germline mutations in genes involved in pancreatic diseases (trans-heterozygosity) needs to be further elucidated [10].…”

Functional prediction and comparative population analysis of variants in genes for proteases and innate immunity related to SARS-CoV-2 infection

“…Two rare variants in the PRSS1 gene, c.592-8C > T and p.Asn54Lys, were detected. Variant c.592-8C > T was previously detected in patients with cystic fibrosis presenting with chronic pancreatitis ( Sofia et al, 2018 ). Given that this is a splice region variant, it may affect splicing and therefore the level of trypsin-1 protein.…”