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The N34S mutation of SPINK1 (PSTI) is associated with a familial pattern of idiopathic chronic pancreatitis but does not cause the disease
  1. J Threadgold1,
  2. W Greenhalf1,
  3. I Ellis2,
  4. N Howes1,
  5. M M Lerch3,
  6. P Simon3,
  7. J Jansen4,
  8. R Charnley5,
  9. R Laugier6,
  10. L Frulloni7,
  11. A Oláh8,
  12. M Delhaye9,
  13. I Ihse10,
  14. O B Schaffalitzky de Muckadell11,
  15. Å Andrén-Sandberg,
  16. C W Imrie,
  17. J Martinek,
  18. T M Gress,
  19. R Mountford,
  20. D Whitcomb,
  21. J P Neoptolemos
  1. 1Department of Surgery, University of Liverpool, 5th Floor UCD Building, Daulby Street, Liverpool L69 3GA, UK
  2. 2Department of Clinical Genetics, Alder Hey Children's Hospital, Eaton Road, Liverpool L12 2AP, UK
  3. 3Department of Medicine, Westfälische Wilhelms-Universität, 48129 Münster, Germany
  4. 4University Medical Centre, Radboud Hospital, Geert Grooteplein, 6500 Nijmegen, the Netherlands
  5. 5Hepatopancreatiobiliary Surgery Unit, Freeman Hospital, Newcastle Upon Tyne NE7 7DN, UK
  6. 6Department of Gastroenterology, La Timone Hospital, 147 Boulevard Baille, 13385 Marseille, Cedex 5, France
  7. 7Department of Surgical and Gastroenterological Sciences, Policlinico GB Rossi, Piazzale LA Scuro, 37134 Verona, Italy
  8. 8PETZ Aladár Megyel Oktató Kórház, Sebészeti Osztály, 9002 Györ, PF 92, Hungary
  9. 9Department of Medicine, Universite Libre de Bruxelles, Hopital Erasme, B-1070 Brussels, Belgium
  10. 10Department of Surgery, Lund University Hospital, S-221 85 Lund, Sweden
  11. 11Department of Medical Gastroenterology S, Odense University Hospital, DK-5000 Odense C, Denmark
  1. Correspondence to:
    Professor J P Neoptolemos, Department of Surgery, 5th Floor UCD Building, Daulby Street, Liverpool L69 3GA, UK;


Background: Mutations in the PRSS1 gene explain most occurrences of hereditary pancreatitis (HP) but many HP families have no PRSS1 mutation. Recently, an association between the mutation N34S in the pancreatic secretory trypsin inhibitor (SPINK1 or PSTI) gene and idiopathic chronic pancreatitis (ICP) was reported. It is unclear whether the N34S mutation is a cause of pancreatitis per se, whether it modifies the disease, or whether it is a marker of the disease.

Patients and methods: A total of 327 individuals from 217 families affected by pancreatitis were tested: 152 from families with HP, 108 from families with ICP, and 67 with alcohol related CP (ACP). Seven patients with ICP had a family history of pancreatitis but no evidence of autosomal dominant disease (f-ICP) compared with 87 patients with true ICP (t-ICP). Two hundred controls were also tested for the N34S mutation. The findings were related to clinical outcome.

Results: The N34S mutation was carried by five controls (2.5%; allele frequency 1.25%), 11/87 (13%) t-ICP patients (p=0.0013 v controls), and 6/7 (86%) affected (p<0.0001 v controls) and 1/9 (11%) unaffected f-ICP cases. N34S was found in 4/108 affected HP patients (p=0.724 v controls), in 3/27 (11%) with wild-type and in 1/81 (1%) with mutant PRSS1, and 4/67 ACP patients (all p>0.05 v controls). The presence of the N34S mutation was not associated with early disease onset or disease severity.

Conclusions: The prevalence of the N34S mutation was increased in patients with ICP and was greatest in f-ICP cases. Segregation of the N34S mutation in families with pancreatitis is unexplained and points to a complex association between N34S and another putative pancreatitis related gene.

  • chronic pancreatitis
  • idiopathic pancreatitis
  • alcohol
  • SPINK1
  • PSTI
  • HP, hereditary pancreatitis
  • ICP, idiopathic chronic pancreatitis
  • f-ICP, familial ICP
  • t-ICP, true ICP
  • ACP, alcohol related chronic pancreatitis
  • PCR, polymerase chain reaction
  • RFLP, restriction fragment length polymorphism
  • BSA, bovine serum albumin
  • CFTR, cystic fibrosis transmembrane conductance regulator
  • EUROPAC, European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer

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