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

Background & Aims: Nonalcoholic chronic pancreatitis is usually idiopathic and often associated with cystic fibrosis gene (CFTR) mutations. It is unkn own whether pancreatitis risk correlates with having 1 or 2 CFTR mutations, abnormal epithelial ion transport, or mutations of other genes. Methods: W e tested 39 patients with idiopathic chronic pancreatitis (mean age at diag nosis, 33 years) for common mutations of CFTR and of genes encoding a tryps in inhibitor (PSTI) and trypsinogen (PRSS1). To exclude hereditary pancreat itis, we initially relied on family history and subsequently tested for PRS S1 mutations. Twenty subjects were tested for rare CFTR mutations (DNA sequ encing) and 11 were tested for extrapancreatic CFTR function (clinical and physiologic evaluation). Results: Mutations were identified in 24 of 39 sub jects. 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 mutation and 1 had hereditary pancreatitis (R122H, PRSS1). Pancreatitis risk was increased approximately 40-fold by h aving 2 CFTR mutations (P < 0.0001), 20-fold by having N34S (P < 0.0001), a nd 900-fold by having both (P < 0.0001). Subjects with 2 CFTR mutations had abnormal nasal epithelial ion transport and clinical findings suggesting r esidual CFTR function between that in cystic fibrosis and in carriers. By c ontrast, subjects with only PSTI mutations had normal CFTR function. Conclu sions: CFTR-related pancreatitis risk correlates with having 2 CFTR mutatio ns and reduced extrapancreatic CFTR function. The N34S PSTI mutation increa sed risk separately. Testing for pancreatitis-associated CFTR and PSTI geno types may be useful in nonalcoholic pancreatitis.