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Do genetic variants in the SPINK1 gene affect the level of serum PSTI?

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

The serine protease inhibitor Kazal type 1 (SPINK1), also known as pancreatic secretory trypsin inhibitor (PSTI), is a peptide secreted by pancreatic acinar cells. Genetic studies have shown an association between SPINK1 gene variants and chronic pancreatitis or recurrent acute pancreatitis. The aim of this study was to clarify whether the SPINK1 variants affect the level of serum PSTI.

Methods

One hundred sixty-three patients with chronic pancreatitis or recurrent acute pancreatitis and 73 healthy controls were recruited. Serum PSTI concentrations were determined with a commercial radioimmunoassay kit.

Results

Ten patients with the p.N34S variant, 7 with the IVS3+2T>C variant, two with both the p.N34S and the IVS3+2T>C variants, and one with the novel missense p.P45S variant in the SPINK1 gene were identified. The serum PSTI level in patients with no SPINK1 variants was 14.3 ± 9.6 ng/ml (mean ± SD), and that in healthy controls was 10.7 ± 2.2 ng/ml. The PSTI level in patients carrying the IVS3+2T>C variant (5.1 ± 3.4 ng/ml), but not in those with the p.N34S variant (8.9 ± 3.5 ng/ml), was significantly lower than that in the patients without the SPINK1 variants and the healthy controls. The serum PSTI level in the patient with the p.P45S variant was 4.9 ng/ml. Low levels of serum PSTI (<6.0 ng/ml) showed sensitivity of 80 %, specificity of 97 %, and accuracy of 96 % in the differentiation of IVS3+2T>C and p.P45S carriers from non-carriers.

Conclusion

Serum PSTI levels were decreased in patients with the IVS3+2T>C and p.P45S variants of the SPINK1 gene.

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Abbreviations

BMI:

Body mass index

CP:

Chronic pancreatitis

RAP:

Recurrent acute pancreatitis

SPINK1:

Serine protease inhibitor Kazal type 1

PSTI:

Pancreatic secretory trypsin inhibitor

ROC:

Receiver operating characteristic

SD:

Standard deviation

References

  1. Steer ML, Waxman I, Freedman S. Chronic pancreatitis. N Engl J Med. 1995;332:1482–90.

    Article  PubMed  CAS  Google Scholar 

  2. Etemad B, Whitcomb DC. Chronic pancreatitis: diagnosis, classification, and new genetic developments. Gastroenterology. 2001;120:682–707.

    Article  PubMed  CAS  Google Scholar 

  3. Whitcomb DC, Gorry MC, Preston RA, Furey W, Sossenheimer MJ, Ulrich CD, et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet. 1996;14:141–5.

    Article  PubMed  CAS  Google Scholar 

  4. Masson E, Le Maréchal C, Delcenserie R, Chen JM, Férec C. Hereditary pancreatitis caused by a double gain-of-function trypsinogen mutation. Hum Genet. 2008;123:521–9.

    Article  PubMed  CAS  Google Scholar 

  5. Witt H, Luck W, Hennies HC, Classen M, Kage A, Lass U, et al. Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat Genet. 2000;25:213–6.

    Article  PubMed  CAS  Google Scholar 

  6. Pfützer RH, Barmada MM, Brunskill AP, Finch R, Hart PS, Neoptolemos J, et al. SPINK1/PSTI polymorphisms act as disease modifiers in familial and idiopathic chronic pancreatitis. Gastroenterology. 2000;119:615–23.

    Article  PubMed  Google Scholar 

  7. 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. 2001;120:1061–4.

    Article  PubMed  CAS  Google Scholar 

  8. Kume K, Masamune A, Mizutamari H, Kaneko K, Kikuta K, Satoh M, et al. Mutations in the serine protease inhibitor Kazal type 1 (SPINK1) gene in Japanese patients with pancreatitis. Pancreatology. 2005;5:354–60.

    Article  PubMed  CAS  Google Scholar 

  9. Aoun E, Chang CC, Greer JB, Papachristou GI, Barmada MM, Whitcomb DC. Pathways to injury in chronic pancreatitis: decoding the role of the high-risk SPINK1 N34S haplotype using meta-analysis. PLoS ONE. 2008;3:e2003.

    Article  PubMed  Google Scholar 

  10. Rosendahl J, Witt H, Szmola R, Bhatia E, Ozsvári B, Landt O, et al. Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. Nat Genet. 2008;40:78–82.

    Article  PubMed  CAS  Google Scholar 

  11. Rinderknecht H. Activation of pancreatic zymogens. Normal activation, premature intrapancreatic activation, protective mechanisms against inappropriate activation. Dig Dis Sci. 1986;31:314–21.

    Article  PubMed  CAS  Google Scholar 

  12. Bhatia E, Choudhuri G, Sikora SS, Landt O, Kage A, Becker M, et al. Tropical calcific pancreatitis: strong association with SPINK1 trypsin inhibitor mutations. Gastroenterology. 2002;123:1020–5.

    Article  PubMed  CAS  Google Scholar 

  13. Kereszturi E, Király O, Sahin-Tóth M. Minigene analysis of intronic variants in common SPINK1 haplotypes associated with chronic pancreatitis. Gut. 2009;58:545–9.

    Article  PubMed  CAS  Google Scholar 

  14. Aoun E, Muddana V, Papachristou GI, Whitcomb DC. SPINK1 N34S is strongly associated with recurrent acute pancreatitis but is not a risk factor for the first or sentinel acute pancreatitis event. Am J Gastroenterol. 2010;105:446–51.

    Article  PubMed  CAS  Google Scholar 

  15. Masamune A, Ariga H, Kume K, Kakuta Y, Satoh K, Satoh A, et al. Genetic background is different between sentinel and recurrent acute pancreatitis. J Gastroenterol Hepatol. 2011;26:974–8.

    Article  PubMed  Google Scholar 

  16. Ota Y, Masamune A, Inui K, Kume K, Shimosegawa T, Kikuyama M. Phenotypic variability of the homozygous IVS3+2T>C mutation in the serine protease inhibitor Kazal type 1 (SPINK1) gene in patients with chronic pancreatitis. Tohoku J Exp Med. 2010;221:197–201.

    Article  PubMed  CAS  Google Scholar 

  17. Ogawa M, Kitahara T, Fujimoto K, Tanaka S, Takatsuka Y, Kosaki G. Serum pancreatic secretory trypsin inhibitor in acute pancreatitis. Lancet. 1980;2:205.

    Article  PubMed  CAS  Google Scholar 

  18. Lasson A, Borgström A, Ohlsson K. Elevated pancreatic secretory trypsin inhibitor levels during severe inflammatory disease, renal insufficiency, and after various surgical procedures. Scand J Gastroenterol. 1986;21:1275–80.

    Article  PubMed  CAS  Google Scholar 

  19. Paju A, Stenman UH. Biochemistry and clinical role of trypsinogens and pancreatic secretory trypsin inhibitor. Crit Rev Clin Lab Sci. 2006;43:103–42.

    Article  PubMed  CAS  Google Scholar 

  20. Nakano I, Funakoshi A, Sumii T, Miyazaki K, Oogami Y, Kimura T, et al. Appearance mechanism and molecular heterogeneity of serum pancreatic secretory trypsin inhibitor (PSTI). Gastroenterol Jpn. 1985;20:354–60.

    PubMed  CAS  Google Scholar 

  21. Satake K, Inui A, Sogabe T, Yoshii Y, Nakata B, Tanaka H, et al. The measurement of serum immunoreactive pancreatic secretory trypsin inhibitor in gastrointestinal cancer and pancreatic disease. Int J Pancreatol. 1988;3:323–31.

    PubMed  CAS  Google Scholar 

  22. Kume K, Masamune A, Kikuta K, Shimosegawa T. [-215G>A; IVS3+2T>C] mutation in the SPINK1 gene causes exon 3 skipping and loss of the trypsin binding site. Gut. 2006;55:1214.

    Article  PubMed  CAS  Google Scholar 

  23. Király O, Wartmann T, Sahin-Tóth M. Missense mutations in pancreatic secretory trypsin inhibitor (SPINK1) cause intracellular retention and degradation. Gut. 2007;56:1433–8.

    Article  PubMed  Google Scholar 

  24. Boulling A, Le Maréchal C, Trouvé P, Raguénès O, Chen JM, Férec C. Functional analysis of pancreatitis-associated missense mutations in the pancreatic secretory trypsin inhibitor (SPINK1) gene. Eur J Hum Genet. 2007;15:936–42.

    Article  PubMed  CAS  Google Scholar 

  25. Ogawa M. Normal level and normal range of serum PSTI concentration. In: Kosaki G, Ogawa M, editors. Pancreatic secretory trypsin inhibitor. Tokyo: Igaku Tosho Shuppan; 1985. p. 91–3 (in Japanese).

  26. Boulling A, Keiles S, Masson E, Chen JM, Férec C. Functional analysis of eight missense mutations in the SPINK1 gene. Pancreas. 2011;41:329–30.

    Article  Google Scholar 

  27. Kuwata K, Hirota M, Shimizu H, Nakae M, Nishihara S, Takimoto A, Mitsushima K, Kikuchi N, Endo K, Inoue M, Ogawa M. Functional analysis of recombinant pancreatic secretory trypsin inhibitor protein with amino-acid substitution. J Gastroenterol. 2002;37:928–34.

    Article  PubMed  CAS  Google Scholar 

  28. Masamune A, Kume K, Takagi Y, Kikuta K, Satoh K, Satoh A, Shimosegawa T. N34S mutation in the SPINK1 gene is not associated with alternative splicing. Pancreas. 2007;34:423–8.

    Article  PubMed  CAS  Google Scholar 

  29. Tonouchi A, Ohtsuka M, Ito H, Kimura F, Shimizu H, Kato M, Nimura Y, Iwase K, Hiwasa T, Seki N, Takiguchi M, Miyazaki M. Relationship between pancreatic secretory trypsin inhibitor and early recurrence of intrahepatic cholangiocarcinoma following surgical resection. Am J Gastroenterol. 2006;101:1601–10.

    Article  PubMed  CAS  Google Scholar 

  30. Gaber A, Johansson M, Stenman UH, Hotakainen K, Pontén F, Glimelius B, Bjartell A, Jirström K, Birgisson H. High expression of tumour-associated trypsin inhibitor correlates with liver metastasis and poor prognosis in colorectal cancer. Br J Cancer. 2009;100:1540–8.

    Article  PubMed  CAS  Google Scholar 

  31. Paju A, Hotakainen K, Cao Y, Laurila T, Gadaleanu V, Hemminki A, Stenman UH, Bjartell A. Increased expression of tumor-associated trypsin inhibitor, TATI, in prostate cancer and in androgen-independent 22Rv1 cells. Eur Urol. 2007;52:1670–9.

    Article  PubMed  CAS  Google Scholar 

  32. Ozaki N, Ohmuraya M, Hirota M, Ida S, Wang J, Takamori H, Higashiyama S, Baba H, Yamamura K. Serine protease inhibitor Kazal type 1 promotes proliferation of pancreatic cancer cells through the epidermal growth factor receptor. Mol Cancer Res. 2009;7:1572–81.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported in part by a Grant-in-Aid from the Japan Society for the Promotion of Science (to K. Kume, to A. Masamune, and to T. Shimosegawa), and by the Research Committee of Intractable Pancreatic Diseases (Principal investigator: T. Shimosegawa), provided with funding by the Ministry of Health, Labour, and Welfare of Japan.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aoba-ku, Sendai, 980-8574, Japan

    Kiyoshi Kume, Atsushi Masamune, Hiroyuki Ariga, Shintaro Hayashi, Tetsuya Takikawa, Shin Miura, Noriaki Suzuki, Kazuhiro Kikuta, Shin Hamada, Morihisa Hirota, Atsushi Kanno & Tooru Shimosegawa

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  1. Kiyoshi Kume
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  2. Atsushi Masamune
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  3. Hiroyuki Ariga
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  12. Tooru Shimosegawa
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Correspondence to Atsushi Masamune.

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Kume, K., Masamune, A., Ariga, H. et al. Do genetic variants in the SPINK1 gene affect the level of serum PSTI?. J Gastroenterol 47, 1267–1274 (2012). https://doi.org/10.1007/s00535-012-0590-3

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  • DOI: https://doi.org/10.1007/s00535-012-0590-3

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