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CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated?
  1. Jonas Rosendahl1,2,
  2. Olfert Landt3,
  3. Jana Bernadova1,
  4. Peter Kovacs4,
  5. Niels Teich5,
  6. Hans Bödeker6,
  7. Volker Keim7,
  8. Claudia Ruffert7,
  9. Joachim Mössner7,
  10. Andreas Kage8,
  11. Michael Stumvoll9,
  12. David Groneberg10,
  13. Renate Krüger4,
  14. Werner Luck1,
  15. Matthias Treiber11,
  16. Michael Becker1,
  17. Heiko Witt1,12
  1. 1Department for Paediatrics, Charité, Berlin, Germany
  2. 2Department for Gastroenterology, University of Leipzig, Leipzig, Germany
  3. 3TIB Molbiol, Berlin, Germany
  4. 4Interdisciplinary Centre for Clinical Research Leipzig, University of Leipzig, Leipzig, Germany
  5. 5Internistische Gemeinschaftspraxis für Verdauungs- und Stoffwechselerkrankungen, Leipzig, Germany
  6. 6Department for Internal Medicine, Hospital Freiberg, Freiberg, Germany
  7. 7Department for Gastroenterology, University of Leipzig, Leipzig, Germany
  8. 8Department for Laboratory Medicine, Charité, Berlin, Germany
  9. 9Department for Endocrinology, University of Leipzig, Leipzig, Germany
  10. 10Department of Occupational Medicine, University of Frankfurt, Frankfurt, Germany
  11. 11Department for Gastroenterology, Technische Universität München (TUM), Munich, Germany
  12. 12Department for Paediatrics & Else Kröner-Fresenius-Zentrum für Ernährungsmedizin (EKFZ), Technische Universität München (TUM), Munich, Germany
  1. Correspondence to Professor Heiko Witt, Department for Paediatrics & Else Kröner-Fresenius-Zentrum (EKFZ), Technical University Munich (TUM), Gregor-Mendel-Str. 2, 85350 Freising, Germany; heiko.witt{at}


Objective In chronic pancreatitis (CP), alterations in several genes have so far been described, but only small cohorts have been extensively investigated for all predisposing genes.

Design 660 patients with idiopathic or hereditary CP and up to 1758 controls were enrolled. PRSS1, SPINK1 and CTRC were analysed by DNA sequencing, and cystic fibrosis transmembrane conductance regulator (CFTR) by melting curve analysis.

Results Frequencies of CFTR variants p.R75Q, p.I148T, 5T-allele and p.E528E were comparable in patients and controls. We identified 103 CFTR variants, which represents a 2.7-fold risk increase (p<0.0001). Severe cystic fibrosis (CF)-causing variants increased the risk of developing CP 2.9-fold, and mild CF-causing variants 4.5-fold (p<0.0001 for both). Combined CF-causing variants increased CP risk 3.4-fold (p<0.0001), while non-CF-causing variants displayed a 1.5-fold over-representation in patients (p=0.14). CFTR compound heterozygous status with variant classes CF-causing severe and mild represented an OR of 16.1 (p<0.0001). Notably, only 9/660 (1.4%) patients were compound heterozygotes in this category. Trans-heterozygosity increased CP risk, with an OR of 38.7, with 43/660 (6.5%) patients and 3/1667 (0.2%) controls being trans-heterozygous (p<0.0001).

Conclusions Accumulation of CFTR variants in CP is less pronounced than reported previously, with ORs between 2.7 and 4.5. Only CF-causing variants reached statistical significance. Compound and trans-heterozygosity is an overt risk factor for the development of CP, but the number of CFTR compound heterozygotes in particular is rather low. In summary, the study demonstrates the complexity of genetic interactions in CP and a minor influence of CFTR alterations in CP development.

  • Chronic pancreatitis
  • genetics
  • CFTR
  • SPINK1
  • CTRC
  • PRSS1
  • genotype
  • general practice
  • gene mutation
  • genetic testing
  • pancreatic disorders
  • pancreatic enzymes
  • Crohn's disease
  • 6-mercaptopurine
  • IBD
  • azathioprine
  • IBD clinical
  • chronic ulcerative colitis
  • pancreas
  • pancreatitis
  • genetic polymorphisms
  • genetic testing

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  • Funding This work was supported by the Deutsche Forschungsgemeinschaft WI 2036/2-1, WI 2036/2-2 and WI 2036/2-3 (to HW) and RO 3929/1-1 and RO 3939/2-1 (to JR), by the Sonnenfeld-Stiftung (to HW and to RN), and by a grant from the Colora Stiftung GmbH (to JR).

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Ethics approval was provided by the University of Berlin and the University of Leipzig.

  • Provenance and peer review Not commissioned; externally peer reviewed.