Introduction
Acinar cell–derived susceptibility genes
Cationic trypsinogen (PRSS1)
Serine protease inhibitor Kazal-type 1 (SPINK1)
Carboxypeptidase A1 (CPA1)
Chymotrypsinogen C (CTRC)
Carboxyl ester lipase (CEL-HYPB1 allele)
Ductal risk genes
Cystic fibrosis transmembrane conductance regulator (CFTR)
Claudin-2 (CLDN2)
Calcium-sensing receptor (CASR)
Transient receptor potential vanilloid superfamily member 6 (TRPV6)
Genetic testing in diagnostic workup: current recommendations and potential future perspectives
Pathogenic gene | Molecular/functional consequence | Clinical manifestations/phenotype |
---|---|---|
Acinar risk genes | ||
PRSS1 | CTRC-dependent stimulation of trypsinogen activation, inhibition of CTRC-dependent trypsinogen degradation, and misfolding resulting in ER stress | Commonest mutation in hereditary CP (prevalence), elevation of risk for CP development and pancreatic cancer, cumulative life time risk up to 40% |
CPA1 | ER stress caused by protein misfolding and intracellular accumulation | Susceptibility gene. Elevated risk for CP development |
CEL-HYPB1 | Hybrid gene with reduced secretion of encoded protein resulting in intracellular accumulation and ER stress via misfolding pathway | Susceptibility gene. Elevated risk of CP development, especially non-alcoholic CP |
SPINK1 | Gene encoding for most prevailing trypsin inhibitor; hypothesis that reduced expression and/or activity leads to trypsinogen mediated autodigestion, precise effect not known to date | In homozygous carriers causative of CP (sometimes termed hereditary pancreatitis), in heterozygous carriers increased risk of CP |
CTRC | Decreased secretion, inactive protein, or reduced enzyme activity of chymotrypsinogen | Elevated risk of CP and alcoholic CP, depending on site of mutation |
Ductal risk genes | ||
CFTR | Channel dysfunction with reduction of secrete alkalization, augmented fluid viscosity, failure of zymogen washout, and intraluminal zymogen activation | Various phenotypes depending on zygosity and variant, elevated risk of RAP and CP mostly in pancreatic sufficient subjects |
CLDN2 | Unknown; possible imbalance in pancreatic fluid composition or intraluminal calcium homeostasis | Elevated risk of CP, especially alcoholic CP. Conflicting data from GWAS analysis |
CASR | Imbalance in intraluminal calcium levels, calcium salt precipitation, pancreatic stone formation | Potential risk elevation of RAP and CP |
TRPV6 | Unknown; potential regulation of ductal fluid calcium concentration | Elevated risk of non-alcoholic, familial, and hereditary CP |