Conducted by a research team in Italy, the study, “Trans-heterozygosity for mutations enhances the risk of recurrent/chronic pancreatitis in patients with Cystic Fibrosis,” was published in the journal Molecular Medicine.
Pancreatic insufficiency due to a lack of digestive enzymes causes malnutrition in about 80% of CF patients. Genes involved in the pancreatic secretion pathway (PSP) regulate the availability of these digestive enzymes.
Trypsin is one of the potent digestive enzymes synthesized by the pancreas. It is produced in an inactive form that is activated by a set of genes involved in intra-pancreatic activation of trypsin (IPAT). Premature activation of trypsin triggers inflammation of the pancreas, called pancreatitis.
According to the authors, about 17-22% of CF patients are estimated to have recurrent pancreatitis or chronic pancreatitis (RP/CP).
A previous study conducted by this group showed the presence of mutations in PSP and IPAT genes in patients with idiopathic pancreatitis.
Due to the frequency of pancreatic insufficiency (PI) and pancreatitis in CF patients, the research team evaluated the presence of mutations in the genes involved in IPAT and PSP in CF patients.
A total of 48 CF patients with RP/CP, 35 CF patients without pancreatitis, and 80 healthy controls participated in the study. Patients were recruited from nine different CF centers across Italy.
Using next-generation targeted sequencing techniques, the team specifically screened for mutations in eight genes in IPAT (PRSS1, PRSS2, SPINK1, CTRC, CASR, CFTR, CTSB, and KRT8) and 23 genes in the PSP pathway. They compared the results between the two groups to determine the specific prevalence of mutations in CF patients with RP/CP.
Mutations in the PRSS1, PRSS2, CTRC, CASR, and KRT8 genes of the IPAT pathway were found in 29.2% (14) of the CF patients with RP/CP, compared with 5.7% (two) CF patients without pancreatitis and 3.8% (three) of the healthy individuals.
Among the detected mutations, eight were deemed pathogenic through existing literature. Pathogenicity-predicting software identified the remaining six mutations as harmful and absent in the general population.
Researchers found that 22.9% (11) of the CF patients with RP/CP had mutations in 12 genes involved in the PSP pathway. These mutations were classified as harmful by the authors.
Overall, 39.6% (19) of CF patients with RP/CP exhibited trans-heterozygous mutations — one or more mutations in a single copy of the genes involved in IPAT and PSP — in addition to the CFTR gene mutation. Simply put, these patients had multiple mutations involving CFTR and other genes from IPAT and PSP.
Such trans-heterozygosity was observed in 11.4% (four) of the CF patients without pancreatitis and 13.7% (11) of the healthy controls.
“The trans-heterozygosity for mutations in the CFTR and in other genes represents a risk factor for pancreatitis even in patients with CF,” the researchers wrote.
They said additional studies are needed to determine whether patients with “trans-heteroygous mutations have a more severe outcome of pancreatitis, and functional studies are necessary to elucidate the pathogenetic mechanism of pancreatitis in patients bearing mutated genes/proteins,” they added.