Gastroenterology

Gastroenterology

Volume 140, Issue 1, January 2011, Pages 153-161
Gastroenterology

Clinical—Liver, Pancreas, and Biliary Tract
Type of CFTR Mutation Determines Risk of Pancreatitis in Patients With Cystic Fibrosis

https://doi.org/10.1053/j.gastro.2010.09.046Get rights and content

Background & Aims

Different mutations in the cystic fibrosis gene (CFTR) are associated with different functional status of the exocrine pancreas. We investigated whether CFTR genotypes determine the risk of pancreatitis in patients with cystic fibrosis (CF).

Methods

Patients with pancreatic-sufficient CF were identified from 2 CF population-based databases (N = 277; 62 with pancreatitis and 215 without pancreatitis); patients' genotypes and clinical characteristics were analyzed. The loss of pancreatic function associated with each CFTR genotype was determined based on the pancreatic insufficiency prevalence (PIP) score.

Results

Patients with pancreatitis were more likely to have genotypes associated with mild (70%) than moderate-severe (30%) PIP scores (P = .004). The cumulative proportion of patients who developed pancreatitis through to the age of 50 years was significantly greater for genotypes associated with mild (50%) than moderate-severe (27%) PIP scores (P = .006). The genotype associated with mild PIP scores had a hazard ratio of 2.4 for pancreatitis (95% confidence interval, 1.3–4.5; P = .006). Patients with pancreatitis were diagnosed with CF at an older median age than those without pancreatitis (14.9 years [interquartile range, 9.5–27.7] vs 9.3 years [interquartile range, 1.5–21.4]; P = .003) and had lower mean levels of sweat chloride than patients without pancreatitis (74.5 ± 26.2 mmol/L vs 82.8 ± 25.2 mmol/L; P = .03).

Conclusions

Specific CFTR genotypes are significantly associated with pancreatitis. Patients with genotypes associated with mild phenotypic effects have a greater risk of developing pancreatitis than patients with genotypes associated with moderate-severe phenotypes. This observation provides further insight into the complex pathogenesis of pancreatitis.

Section snippets

Study Population

This study was approved by the research ethics boards of all participating institutions. All eligible patients with CF were identified from the Canadian Consortium for CF Genetic Studies and Verona CF Centre databases, which are representative of the CF population in Canada19 and the Veneto/Trentino-Alto Adige regions of Italy,20 respectively. The diagnosis of CF was established based on the current US Cystic Fibrosis Foundation consensus report.2 Because PI patients carry no (or little) risk

Characteristics of Study Population

The study population was derived from 3264 patients with CF (PS and PI), including 2481 from Canada and 783 from Verona. Among this population, a total of 459 patients (14%) were defined as PS. Of these, 182 were excluded from the analysis because CFTR genotyping failed to identify mutations on both alleles, the diagnosis of pancreatitis could not be definitively excluded or established, or a PIP score could not be determined. Among the remaining 277 patients (46.6% male) included for analyses,

Discussion

This is the largest study to date of subjects with PS-CF (with and without pancreatitis) to determine for evidence of an association between severity of CFTR genotype and risk of pancreatitis. Moreover, by limiting our subjects to patients with CF and only those who carry 2 CFTR mutations, we were able to refine our focus on the role of CFTR in the pathogenesis of pancreatitis. Patients developing pancreatitis were more likely to carry mild than moderate-severe genotypes. In addition, patients

Acknowledgments

The authors thank the following members of the Canadian Consortium for CF Genetic Studies and foreign CF clinics for ascertaining patient data blood samples from patients with CF and their families: St. Paul's Adult CF Clinic, Vancouver, British Columbia, Canada: E. M. Nakielna, MD; British Columbia Children's Hospital, Vancouver, British Columbia, Canada; G. Davidson, MD, A. Gravelle; Alberta Children's Hospital, Calgary, Alberta, Canada: M. Montgomery, MD, Lisa Semple; Royal University

References (45)

  • P. Kristidis et al.

    Genetic determination of exocrine pancreatic function in cystic fibrosis

    Am J Hum Genet

    (1992)
  • N. Ahmed et al.

    Molecular consequences of cystic fibrosis transmembrane regulator (CFTR) gene mutations in the exocrine pancreas

    Gut

    (2003)
  • A. Augarten et al.

    The changing face of the exocrine pancreas in cystic fibrosis: the correlation between pancreatic status, pancreatitis and cystic fibrosis genotype

    Eur J Gastroenterol Hepatol

    (2008)
  • H. Shwachman et al.

    Recurrent acute pancreatitis in patients with cystic fibrosis with normal pancreatic enzymes

    Pediatrics

    (1975)
  • J.R. Imrie et al.

    Quantitative evaluation of the development of the exocrine pancreas in cystic fibrosis and control infants

    Am J Pathol

    (1979)
  • K. De Boeck et al.

    Pancreatitis among patients with cystic fibrosis: correlation with pancreatic status and genotype

    Pediatrics

    (2005)
  • N. Sharer et al.

    Mutations of the cystic fibrosis gene in patients with chronic pancreatitis

    N Engl J Med

    (1998)
  • J.A. Cohn et al.

    Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis

    N Engl J Med

    (1998)
  • F.U. Weiss et al.

    Complete cystic fibrosis transmembrane conductance regulator gene sequencing in patients with idiopathic chronic pancreatitis and controls

    Gut

    (2005)
  • C. Castellani et al.

    Analysis of the entire coding region of the cystic fibrosis transmembrane regulator gene in idiopathic pancreatitis

    Hum Mutat

    (2001)
  • M.D. Bishop et al.

    The cystic fibrosis transmembrane conductance regulator gene and ion channel function in patients with idiopathic pancreatitis

    Hum Genet

    (2005)
  • R. Dorfman et al.

    Do in silico tools predict the clinical consequences of amino acid substitutions in the CFTR gene?

    Clin Genet

    (2010)
  • Cited by (196)

    View all citing articles on Scopus

    Conflicts of interes The authors disclose no conflicts.

    Funding Supported by the Canadian Cystic Fibrosis Foundation (P.R.D., M.C., and J.Z.), Genome Canada through the Ontario Genomics Institute as per research agreement 2004-OGI-3-05 (P.R.D., M.C., J.Z., and Y.B.), the Ontario Research Foundation (P.R.D., M.C., and J.Z.), the Canadian Cystic Fibrosis Foundation Fellowship Awards (to C.Y.O. and T.G.), and the Canadian Child Health Clinician Scientist Program Career Enhancement Award (to C.Y.O.).

    View full text