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The description of a family with inherited chronic relapsing pancreatitis by Comfort and Steinberg (1952) provided the first indication towards a possible genetic component in the aetiology of chronic pancreatitis (CP).1 Subsequent genetic linkage studies and candidate gene sequencing in families with hereditary CP led to the identification of autosomal dominant mutations in the cationic trypsinogen (PRSS1) gene. Biochemical studies demonstrated that these mutations facilitated the activation of trypsinogen, suggesting that trypsinogen activation can trigger pancreatitis in humans, a concept previously proposed on the basis of animal experiments.2 Screening efforts for novel, CP-associated gene variants identified a number of other important genetic factors, which included loss-of-function variants in the genes for the serine protease inhibitor Kazal type 1 (SPINK1), the cystic fibrosis transmembrane conductance regulator (CFTR) and chymotrypsinogen C (CTRC). In 2006 a surprising study by Witt and co-workers demonstrated that the p.G191R mutation in the anionic typsinogen (PRSS2) gene conferred protection against chronic pancreatitis.3 In this European multicentre study the p.G191R mutation was detected in 1.3% of 2466 patients with CP and in 3.4% of 6459 healthy controls, indicating that subjects carrying a heterozygous p.G191R mutation have an approximately 3-fold decreased risk of developing CP compared to carriers of the wild-type allele. At the biochemical …
Competing interests: None declared.
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