title: Cystic fibrosis gene mutations and pancreatitis risk: relation to epithelial ion transport and trypsin inhibitor gene mutations.
abstract: OBJECTIVE
  Nonalcoholic chronic pancreatitis is usually idiopathic and often associated with cystic fibrosis gene (CFTR) mutations. It is unknown whether pancreatitis risk correlates with having 1 or 2 CFTR mutations, abnormal epithelial ion transport, or mutations of other genes.
  
  
  METHODS
  We tested 39 patients with idiopathic chronic pancreatitis (mean age at diagnosis, 33 years) for common mutations of 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
  Mutations were 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 mutation and 1 had hereditary pancreatitis (R122H, PRSS1). Pancreatitis risk was increased approximately 40-fold by having 2 CFTR mutations (P < 0.0001), 20-fold by having N34S (P < 0.0001), and 900-fold by having both (P < 0.0001). Subjects with 2 CFTR mutations had abnormal nasal epithelial ion transport and clinical findings suggesting residual CFTR function between that in cystic fibrosis and in carriers. By contrast, subjects with only PSTI mutations had normal CFTR function.
  
  
  CONCLUSIONS
  CFTR-related pancreatitis risk correlates with having 2 CFTR mutations and reduced extrapancreatic CFTR function. The N34S PSTI mutation increased risk separately. Testing for pancreatitis-associated CFTR and PSTI genotypes may be useful in nonalcoholic pancreatitis.
authors.affiliation: Department of Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: P G
authors.initials: PG
authors.lastname: Noone
authors.forename: Z
authors.initials: Z
authors.lastname: Zhou
authors.forename: L M
authors.initials: LM
authors.lastname: Silverman
authors.forename: P S
authors.initials: PS
authors.lastname: Jowell
authors.forename: M R
authors.initials: MR
authors.lastname: Knowles
authors.forename: J A
authors.initials: JA
authors.lastname: Cohn
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D002648:Child; D002712:Chlorides / Q000378:metabolism; D003550:Cystic Fibrosis / Q000235:genetics*; D004848:Epithelium / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D017136:Ion Transport; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010195:Pancreatitis / Q000235:genetics*; D010940:Plant Proteins / Q000235:genetics; D011110:Polymorphism, Genetic; D013542:Sweat / Q000378:metabolism; D014361:Trypsin Inhibitors; D014362:Trypsinogen / Q000235:genetics; D000516:alpha-Amylases / Q000037:antagonists & inhibitors
chemical_list: D002712:Chlorides; D010940:Plant Proteins; D014361:Trypsin Inhibitors; D014362:Trypsinogen; D000516:alpha-Amylases