Digestive Diseases and Sciences

, Volume 48, Issue 6, pp 1110–1115 | Cite as

Limited Contribution of the SPINK1 N34S Mutation to the Risk and Severity of Alcoholic Chronic Pancreatitis: A Report from the United States

  • Alexander Schneider
  • Roland H. Pfützer
  • M. Michael Barmada
  • Adam Slivka
  • John Martin
  • David C. Whitcomb


Mutations in the SPINK1 gene (e.g. N34S) have been reported in patients with idiopathic, familial, tropical, and alcoholic pancreatitis. The prevalence of SPINK1 N34S differs between different patient populations, and its contribution to the risk and the severity of alcoholic chronic pancreatitis has not been defined in the United States. Mutational analysis of the exon 3 was performed in 32 patients with alcoholic chronic pancreatitis, 39 patients with nonalcoholic chronic pancreatitis or recurrent acute pancreatitis, and 190 previously studied healthy controls. The course of alcoholic chronic pancreatitis with and without N34S was compared in age of onset- and sex-matched patients. All SPINK1 gene sequence variations were heterozygous. SPINK1 N34S was present in 3/190 (1.6%) and P55S was found in 2/190 (1.1%) of controls. In alcoholics, the N34S mutation was identified in 2/32 patients (6.3%, P < 0.05). In nonalcoholics, N34S and P55S were identified in 6/39 patients (15.4%, P < 0.005, N34S N = 4, P55S N = 1, N34S/P55S N = 1). The clinical course of alcoholic chronic pancreatitis was similar between patients with and without the N34S mutation. The N34S mutation is uncommon in patients with alcoholic chronic pancreatitis in the United States; its prevalence is similar to other countries and appears not to alter the onset or the severity of alcoholic chronic pancreatitis.

SPINK1 PSTI chronic pancreatitis alcohol 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Dreiling DA, Koller M: The natural history of alcoholic pancreatitis: update 1985. Mt Sinai J Med 52:340-342, 1985Google Scholar
  2. 2.
    Haber P, Wilson J, Apte M, Korsten M, Pirola R: Individual susceptibility to alcoholic pancreatitis: Still an enigma. J Lab Clin Med 125:305-312, 1995Google Scholar
  3. 3.
    Pitchumoni CS: Pathogenesis of alcohol-induced chronic pancreatitis: facts, perceptions, and misperceptions. Surg Clin North Am 81:379-390, 2001Google Scholar
  4. 4.
    Schneider A, Whitcomb DC, Singer MV: Animal models in alcoholic pancreatitis—what can we learn? Pancreatology 2:189-203, 2002Google Scholar
  5. 5.
    Durbec J, Sarles H: Multicenter survey of the etiology of pancreatic diseases. Relationship between the relative risk of developing chronic pancreatitis and alcohol, protein, and lipid consumption. Digestion 18:337-350, 1978Google Scholar
  6. 6.
    Whitcomb DC, Gorry MC, Preston RA, Furey W, Sossenheimer MJ, Ulrich CD, Martin SP, Gates LK, Amann ST, Toskes PP, Liddle R, McGrath K, Uomo G, Post JC, Ehrlich GD: Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet 14:141-145, 1996Google Scholar
  7. 7.
    Etemad B, Whitcomb DC: Chronic pancreatitis: diagnosis, classification, and new genetic developments. Gastroenterology 120:682-707, 2001Google Scholar
  8. 8.
    Teich N, Mössner J, Keim V: Screening for mutations of the cationic trypsinogen gene: are they of relevance in chronic alcoholic pancreatitis? Gut 44:413-416, 1999Google Scholar
  9. 9.
    Truninger K, Köck J, Wirth HP, Muellhaupt B, Arnold C, von Weizsäcker F, Seifert B, Ammann RW, Blum HE: Trypsinogen gene mutations in patients with chronic or recurrent acute pancreatitis. Pancreas 22:18-23, 2001Google Scholar
  10. 10.
    Cohn JA, Friedmann KJ, Noone PG, Knowles MR, Silverman LM, Jowell PS: Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. N Engl J Med 339:653-658, 1998Google Scholar
  11. 11.
    Sharer N, Schwarz M, Malone G, Howarth A, Painter J, Super M, Braganza J: Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. N Engl J Med 339:645-652, 1998Google Scholar
  12. 12.
    Ockenga J, Stuhrmann M, Ballmann M, Teich N, Keim V, Dörk T, Manns MP: Mutations of the cystic fibrosis gene, but not cationic trypsiogen gene, are associated with recurrent or chronic idiopathic pancreatitis. Am J Gastroenterol 95:2061-2067, 2000Google Scholar
  13. 13.
    Norton ID, Apte MV, Dixson H, Trent RJ, Haber PS, Pirola RC, Wilson JS: Cystic fibrosis genotypes and alcoholic pancreatitis. J Gastroenterol Hepatol 13:496-499, 1998Google Scholar
  14. 14.
    Monaghan KG, Jackson CE, KuKuruga DL, Feldman GL: Mutation analysis of the cystic fibrosis and cationic trypsinogen genes in patients with alcohol-related pancreatitis. Am J Med Genet 94:120-124, 2000Google Scholar
  15. 15.
    Rinderknecht H: Pancreatic secretory enzymes. In The Pancreas: Biology, Pathobiology, and Disease. VL Go, EP DiMagno, JD Gardner, E Lebenthal, HA Reber, GA Scheele (eds). New York, Raven Press, 1993, pp 219-251Google Scholar
  16. 16.
    Witt H, Luck W, Hennies HC, Classen M, Kage A, Lass U, Landt O, Becker M: Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat Genet 25:213-216, 2000Google Scholar
  17. 17.
    Pfützer RH, Barmada MM, Brunskill AP, Finch R, Hart PS, Neoptolemos J, Furey WF, Whitcomb DC: SPINK1/PSTI polymorphisms act as disease modifiers in familial and idiopathic chronic pancreatitis. Gastroenterology 119:615-623, 2000Google Scholar
  18. 18.
    Chen JM, Mercier B, Audrezet MP, Raguenes O, Quere I, Ferec C: Mutations of the pancreatic secretory trypsin inhibitor (PSTI) gene in idiopathic chronic pancreatitis. Gastroenterology 120:1061-1062, 2001Google Scholar
  19. 19.
    Ockenga J, Dörk T, Stuhrmann M: Low prevalence of SPINK1 gene mutations in adult patients with chronic idiopathic pancreatitis. J Med Genet 38:243-244, 2001Google Scholar
  20. 20.
    Plendl H, Siebert R, Steinemann D, Grote W: High frequency of the N34S mutation in the SPINK1 gene in chronic pancreatitis detected by a new PCR-RFLP assay. Am J Med Genet 100:252-253, 2001Google Scholar
  21. 21.
    Kaneko K, Nagasaki Y, Furukawa T, Mitzutamari H, Sato A, Masamune A, Shimosegawa T, Horii A: Analysis of the human pancreatic secretory trypsin inhibitor (PSTI) gene mutations in japanese patients with chronic pancreatitis. J Hum Genet 46:293-297, 2001Google Scholar
  22. 22.
    Kuwata K, Hirota M, Sugita H, Kai M, Hayashi N, Nakamura M, Matsuura T, Adachi N, Nishimori I, Ogawa M: Genetic mutations in exon 3 and 4 of the pancreatic secretory trypsin inhibitor in patients with pancreatitis. J Gastroenterol 36:612-618, 2001Google Scholar
  23. 23.
    Threadgold J, Greenhalf W, Ellis I, Howes N, Lerch MM, Simon P, Jansen J, Charnley R, Laugier R, Frulloni L, Olah A, Delhaye M, Ihse I, Schaffalitzky de Muckadell OB, Andren-Sandberg A, Imrie CW, Martinek J, Gress TM, Mountford R, Whitcomb D, Neoptolemos JP: The N34S mutation of SPINK1 (PSTI) is associated with a familial pattern of idiopathic chronic pancreatitis but does not cause the disease. Gut 50:675-681, 2002Google Scholar
  24. 24.
    Drenth JP, te Morsche R, Jansen JB: Mutations in serine protease inhibitor Kazal type 1 are strongly associated with chronic pancreatitis. Gut 50:687-692, 2002Google Scholar
  25. 25.
    Rossi L, Pfützer RH, Parvin S, Ali L, Sattar S, Azad Kahn AK, Gyr N, Whitcomb DC: SPINK1/PSTI mutations are associated with tropical pancreatitis in Bangladesh: a preliminary report. Pancreatology 1:242-245, 2001Google Scholar
  26. 26.
    Chandak GR, Idris MM, Reddy DN, Bhaskar S, Sriram PV, Singh L: Mutations in the pancreatic secretory trypsin inhibitor gene (PSTI/SPINK1) rather than the cationic trypsinogen gene (PRSS1) are significantly associated with tropical calcific pancreatitis. J Med Genet 39:347-351, 2002Google Scholar
  27. 27.
    Hassan Z, Mohan V, Ali L, Allotey R, Barakat K, Faruque O, Deepa R, McDemott MF, Jackson AE, Cassell P, Curtis D, Gelding SV, Vijayaravaghan S, Gyr N, Whitcomb DC, Azad Khan AK, Hitman GA: SPINK1 is a susceptibility gene for fibrocalculous pancreatic diabetes in subjects from the Southern Indian sub-continent. Am J Hum Genet 71:964-968, 2002Google Scholar
  28. 28.
    Bhatia E, Choudhuri G, Sikora SS, Landt O, Kage A, Becker M, Witt H: Tropical calcific pancreatitis: strong association with SPINK1 trypsin inhibitor mutations. Gastroenterology 123:1020-1025, 2002Google Scholar
  29. 29.
    Schneider A, Suman A, Rossi L, Barmada MM, Parvin S, Sattar S, Ali L, Azad Kahn A, Gyr N, Whitcomb DC: SPINK1/PSTI mutations are associated with tropical pancreatitis and type II diabetes mellitus in Bangladesh. Gastroenterology 123:1026-1030, 2002Google Scholar
  30. 30.
    Witt H, Luck W, Becker M, Böhmig M, Kage A, Truninger K, Ammann RW, O'Reilly DA, Kingsnorth A, Schulz HU, Halangk W, Kielstein V, Knoefel WT, Teich N, Keim V: Mutation in the SPINK1 trypsin inhibitor gene, alcohol abuse, and chronic pancreatitis. JAMA 285:2716-2717, 2001Google Scholar
  31. 31.
    National Institutes of Health: Drinking in the United States: main findings from the 1992 National Longitudinal Alcohol Epidemiologic Survey (NLAES). NIH, Bethesda, Maryland, 1998Google Scholar
  32. 32.
    Bradley KA, Boyd-Wickizer J, Powell SH, Burman ML: Alcohol screening questionnaires in women. JAMA 280:166-171, 1998Google Scholar
  33. 33.
    Chan AW, Pristach EA, Welte JW, Russell M: Use of the TWEAK test in screening for alcoholism/heavy drinking in three populations. Alcohol Clin Exp Res 17:1188-1192, 1993Google Scholar
  34. 34.
    Ammann RW: A clinically based classification system for alcoholic chronic pancreatitis: summary of an international workshop on chronic pancreatitis. Pancreas 14:215-221, 1997Google Scholar

Copyright information

© Plenum Publishing Corporation 2003

Authors and Affiliations

  • Alexander Schneider
    • 1
  • Roland H. Pfützer
    • 2
  • M. Michael Barmada
    • 1
  • Adam Slivka
    • 1
  • John Martin
    • 1
  • David C. Whitcomb
    • 1
  1. 1.Departments of Medicine, Division of Gastroenterology, Human Genetics, Cell Biology and Physiology, and the Center for Genomic SciencesUniversity of Pittsburgh, PittsburghPennsylvaniaUSA
  2. 2.Department of Medicine IIUniversity Hospital of Heidelberg at MannheimGermany

Personalised recommendations