Do common PRSS1/PRSS2 and CTRB1/CTRB2 variants increase risk of chronic pancreatitis and exocrine pancreatic insufficiency?

Chronic pancreatitis (CP) is characterized by a progressive fibro-inflammatory process where recurrent bouts of pancreatic injury eventually lead to irreversible loss of organ function. Genetic susceptibility plays a critical role in determining an individual's threshold for this injury and their likelihood of progressing to end-stage complications like exocrine pancreatic insufficiency (EPI).

Clinical and genetic evidence

Common genetic variants in the PRSS1/PRSS2 and CTRB1/CTRB2 loci are major determinants of pancreatitis risk. Large-scale genome-wide association studies (GWAS) have demonstrated that these variants modulate the protease-antiprotease balance within the pancreas.

• PRSS1/PRSS2: The common variant rs10273639 (c.-408C>T) tags a protective haplotype that reduces the expression of cationic trypsinogen. Lower levels of this enzyme decrease the risk of premature intrapancreatic trypsin activation, the primary driver of autodigestion and injury.
• CTRB1/CTRB2: Variants in this locus affect the degradation of trypsinogen, further influencing the susceptibility to recurrent acute pancreatitis (RAP) and its transition to CP.
• Progression to EPI: As CP progresses, the destruction of acinar cells leads to EPI. Studies indicate that EPI affects 30% to 50% of CP patients overall, with prevalence reaching up to 84.6% in advanced cohorts. Overt symptoms usually appear once approximately 90% of pancreatic exocrine capacity is lost.

Mechanistic explanations

The progression from genetic susceptibility to functional failure follows the "Sentinel Acute Pancreatitis Event" (SAPE) model.

• Protease activation: Variants in PRSS1 and CTRB1 alter the regulation of trypsin, either by increasing its production or impairing its clearance.
• Inflammatory cascade: Excessive active trypsin within the pancreatic ducts triggers autodigestion, causing recurrent injury (RAP).
• Fibrosis and atrophy: Chronic inflammation activates pancreatic stellate cells, leading to collagen deposition and the replacement of healthy acinar tissue with non-functional fibrous tissue.
• Functional failure: The cumulative loss of acinar cells eventually reduces the secretion of digestive enzymes (lipase, protease, amylase) below the threshold required for normal digestion, resulting in EPI.

Bottom line

Common variants in PRSS1/PRSS2 and CTRB1/CTRB2 significantly increase susceptibility to the recurrent pancreatic injury that drives chronic pancreatitis. This disease is a well-established cause of exocrine pancreatic insufficiency, which develops in roughly half of all patients as the cumulative damage to the pancreas reaches critical levels.