Genetic susceptibility is an accepted risk factor for chronic pancreatitis, particularly early-onset disease. However, PRSS1, SPINK1 and CTRC mutations, which lead to intrapancreatic trypsin activity, are not found in numerous patients.

Heiko Witt, Miklόs Sahin-Tόth and colleagues report that variants in CPA1 (which encodes carboxypeptidase A1, a digestive carboxypeptidase in pancreatic juice) increase the chronic pancreatitis risk independent of trypsin activity.

Of 34 CPA1 variants identified in a German discovery set, 17 were functionally defective (reducing CPA1 activity to <20%). Defective variants were significantly over-represented in cases (3.1%) versus controls (0.1%). “CPA1 mutations were strong risk factors, stronger than CTRC or SPINK1 mutations and closer to PRSS1 mutations,” explains Sahin-Tόth. In this cohort, the odds ratio was 24.9, increasing to 84 in those <10 years of age. “Carrying a defective CPA1 mutation increases the risk for pancreatitis 84-fold, that is close to 100-fold, in children.” The association between functionally defective variants and chronic pancreatitis was confirmed in replication sets from Europe, India and Japan.

Further work suggests limited interaction between CPA1 variants and variants in known susceptibility genes.“It is unclear why loss of CPA1 function might lead to pancreatitis,” says Sahin-Tόth. In the future, the team will investigate whether misfolding-induced endoplasmic reticulum stress is responsible, but “our immediate plans are to extend these studies to CPA2 and CPB1, the two other pancreatic carboxypeptidases expressed in humans.”