Cystic fibrosis gene mutations and pancreatitis risk: Relation to epithelial ion transport and trypsin inhibitor gene mutations

Abstract Background & Aims: Nonalcoholic chronic pancreatitis is usually idiopathic and often associated with cystic fibrosisgene ( CFTR ) mutations. It is unknown whether pancreatitis risk correlates with having 1 or 2 CFTR mutations, abnormal epithelial ion transport, or mutationsof other genes. Methods: We tested 39 patients with idiopathic chronic pancreatitis (mean age at diagnosis, 33 years) for common mutationsof CFTR and of genes encoding a trypsin inhibitor( PSTI) and trypsinogen( PRSS1 ). To exclude hereditary pancreatitis, we initially relied on family history and subsequently tested for PRSS1 mutations. Twenty subjects were tested for rare CFTR mutations(DNA sequencing) and 11 were tested for extrapancreatic CFTR function (clinical and physiologic evaluation). Results: Mutationswere identified in 24 of 39 subjects. Nine patients had cystic fibrosis–causing mutations, 8 of whom also had mild-variable mutations. Eight others had only mild-variable mutations. Nine subjects had the N34S PSTI mutationand 1 had hereditary pancreatitis(R122H, PRSS1 ). Pancreatitis risk was increased approximately 40-fold by having 2 CFTR mutations( P P P CFTR mutationshad abnormal nasal epithelial ion transportand clinical findings suggesting residual CFTR function between that in cystic fibrosisand in carriers. By contrast, subjects with only PSTI mutationshad normal CFTR function. Conclusions: CFTR-related pancreatitis risk correlates with having 2 CFTR mutationsand reduced extrapancreatic CFTR function. The N34S PSTI mutationincreased risk separately. Testingfor pancreatitis-associated CFTR and PSTIgenotypes may be useful in nonalcoholic pancreatitis. GASTROENTEROLOGY 2001;121:1310-1319