Abstract
Background
Risk factors for chronic pancreatitis (CP) are largely unknown except for alcohol. Identification of environmental and genetic risk factors is important for the early diagnosis of CP. We here examined the prevalence of the serine protease inhibitor Kazal type 1 (SPINK1) gene mutations in Japanese patients with CP, and whether the disease course was different between mutation-positive and -negative patients.
Methods
Genomic DNA was prepared from 96 CP patients and 165 healthy controls. All exons and the promoter region of the SPINK1 gene were amplified by polymerase chain reaction, and directly sequenced. Clinical courses of the patients were reviewed.
Results
The prevalence of [N34S; IVS1−37T>C] and [−215G>A; IVS3+2T>C] mutations was higher in patients with familial (55.6% and 11.1%, respectively) and idiopathic (15.2% and 18.1%) CP than in controls (0.6% and 0%). The N34S and IVS3+2T>C mutations were present in 0% and 4.5% (P < 0.05 vs control) of patients with alcoholic CP. Patients with the N34S mutation presented with earlier symptom onset and more dilatation of the main pancreatic duct, followed by more frequent surgical and/or endoscopic intervention and pancreatic cancer development than those without SPINK1 mutations.
Conclusions
SPINK1 mutations were associated with idiopathic and familial CP, whereas the contribution was less evident in alcoholic CP. Patients with the N34S mutation presented more severe clinical courses, implying that genetic risk assessment might be useful to identify individuals who are likely to develop severe CP, and allow targeted attention to slow or prevent disease progression.
Similar content being viewed by others
References
ML Steer I Waxman S Freedman (1995) ArticleTitleChronic pancreatitis N Engl J Med 332 1482–90 Occurrence Handle7739686 Occurrence Handle10.1056/NEJM199506013322206 Occurrence Handle1:STN:280:DyaK2M3lvVSqtQ%3D%3D
RW Ammann (2001) ArticleTitleThe natural history of alcoholic chronic pancreatitis Intern Med 40 368–75 Occurrence Handle11393404 Occurrence Handle1:STN:280:DC%2BD3MzhvVKrtA%3D%3D
B Estemad DC Whitcomb (2001) ArticleTitleChronic pancreatitis: diagnosis, classification, and new genetic developments Gastroenterology 120 682–707 Occurrence Handle10.1053/gast.2001.22586
M Otsuki (2003) ArticleTitleChronic pancreatitis in Japan: epidemiology, prognosis, diagnostic criteria, and future problems J Gastroenterol 38 315–26 Occurrence Handle12743770 Occurrence Handle10.1007/s005350300058
DC Whitcomb MC Gorry RA Preson W Furey MJ Sossenheimer CD Ulrich et al. (1996) ArticleTitleHereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene Nat Genet 14 141–5 Occurrence Handle8841182 Occurrence Handle10.1038/ng1096-141 Occurrence Handle1:CAS:528:DyaK28XmtVKnt7g%3D
H Witt W Luck HC Hennies M Classen A Kage U Lass et al. (2000) ArticleTitleMutations in the gene encoding the serine protease inhibitor, Kazal type 1, are associated with chronic pancreatitis Nat Genet 25 213–6 Occurrence Handle10835640 Occurrence Handle10.1038/76088 Occurrence Handle1:CAS:528:DC%2BD3cXjvFOgtLk%3D
RH Pfutzer MM Barmada AP Brunskill R Finch PS Hart J Neoptolemos et al. (2000) ArticleTitleSPINK1/PSTI polymorphisms act as disease modifiers in familial and idiopathic chronic pancreatitis Gastroenterology 119 615–3 Occurrence Handle10982753 Occurrence Handle10.1053/gast.2000.18017 Occurrence Handle1:CAS:528:DC%2BD3cXmslSku7g%3D
JM Chen B Mercier MP Audrezet O Raguenes I Quere C Ferec (2001) ArticleTitleMutations of the pancreatic secretory trypsin inhibitor (PSTI) gene in idiopathic chronic pancreatitis Gastroenterology 120 1061–4 Occurrence Handle11265669 Occurrence Handle1:STN:280:DC%2BD3M7msVyitg%3D%3D
K Kaneko Y Nagasaki T Furukawa H Mizutamari A Sato A Masamune et al. (2001) ArticleTitleAnalysis of the human pancreatic secretory trypsin inhibitor (PSTI) gene mutations in Japanese patients with chronic pancreatitis J Hum Genet 46 293–7 Occurrence Handle11355022 Occurrence Handle10.1007/s100380170082 Occurrence Handle1:CAS:528:DC%2BD3MXjslKks7s%3D
K Truninger H Witt J Kock A Kage B Seifert RW Ammann et al. (2002) ArticleTitleMutations of the Serine Protease Inhibitor, Kazal type 1 in patients with idiopathic chronic pancreatitis Am J Gastroenterol 97 1133–7 Occurrence Handle12014716 Occurrence Handle10.1111/j.1572-0241.2002.05673.x Occurrence Handle1:CAS:528:DC%2BD38XktlWmsrg%3D
K Kuwata M Hirota I Nishimori M Otsuki M Ogawa (2003) ArticleTitleMutational analysis of the pancreatic secretory trypsin inhibitor gene in familial and juvenile pancreatitis in Japan J Gastroenterol 38 365–70 Occurrence Handle12743777 Occurrence Handle10.1007/s005350300065 Occurrence Handle1:CAS:528:DC%2BD3sXjslWhtrw%3D
N Sharer M Schwarz G Malone A Howarth J Painter M Super et al. (1998) ArticleTitleMutations of the cystic fibrosis gene in patients with chronic pancreatitis N Engl J Med 339 645–52 Occurrence Handle9725921 Occurrence Handle10.1056/NEJM199809033391001 Occurrence Handle1:CAS:528:DyaK1cXmtVWmt7g%3D
JA Cohn KJ Friedman PG Noone MR Knowles LM Silverman PS Jowell (1998) ArticleTitleRelation between mutations of the cystic fibrosis gene and idiopathic pancreatitis N Engl J Med 339 653–8 Occurrence Handle9725922 Occurrence Handle10.1056/NEJM199809033391002 Occurrence Handle1:CAS:528:DyaK1cXmtVWmt7k%3D
M Laskowski SuffixJr I Kato (1980) ArticleTitleProtein inhibitors of proteinases Annu Rev Biochem 49 593–626 Occurrence Handle6996568 Occurrence Handle10.1146/annurev.bi.49.070180.003113 Occurrence Handle1:CAS:528:DyaL3cXks1ChtLo%3D
E Bhatia G Choudhuri SS Sikora O Landt A Kage M Becker et al. (2002) ArticleTitleTropical calcific pancreatitis: strong association with SPINK1 trypsin inhibitor mutations Gastroenterology 123 1020–5 Occurrence Handle12360463 Occurrence Handle10.1053/gast.2002.36028 Occurrence Handle1:CAS:528:DC%2BD38Xotl2gtbk%3D
InstitutionalAuthorNameThe Criteria Committee for Chronic Pancreatitis of the Japan Pancreas Society (2001) ArticleTitleClinical diagnostic criteria of chronic pancreatitis (in Japanese) Suizo (J Jpn Pancreas Soc) 16 560–1
A Masamune H Mizutamari K Kume T Asakura K Satoh T Shimosegawa (2004) ArticleTitleHereditary pancreatitis as the premalignant disease: a Japanese case of pancreatic cancer involving the SPINK1 gene mutation N34S Pancreas 28 305–10 Occurrence Handle15084977 Occurrence Handle10.1097/00006676-200404000-00018
K Okazaki T Chiba (2002) ArticleTitleAutoimmune related pancreatitis Gut 51 1–4 Occurrence Handle12077078 Occurrence Handle10.1136/gut.51.1.1 Occurrence Handle1:STN:280:DC%2BD38zjtl2rtA%3D%3D
K Kume A Masamune H Mizutamari K Kaneko K Kikuta M Satoh et al. (2005) ArticleTitleMutations in the serine protease inhibitor Kazal Type 1 (SPINK1) gene in Japanese patients with pancreatitis Pancreatology 5 354–60 Occurrence Handle15980664 Occurrence Handle10.1159/000086535 Occurrence Handle1:CAS:528:DC%2BD2MXntFSmsb4%3D
K Truninger H Witt J Kock A Kage B Seifert RW Ammann et al. (2002) ArticleTitleMutations of the serine protease inhibitor, Kazal type 1 gene, in patients with idiopathic chronic pancreatitis Am J Gastroenterol 97 1133–7 Occurrence Handle12014716 Occurrence Handle10.1111/j.1572-0241.2002.05673.x Occurrence Handle1:CAS:528:DC%2BD38XktlWmsrg%3D
A Schneider RH Pfutzer MM Barmada A Slivka J Martin DC Whitcomb (2003) ArticleTitleLimited contribution of the SPINK1 N34S mutation to the risk and severity of alcoholic chronic pancreatitis: a report from the United States Dig Dis Sci 48 1110–15 Occurrence Handle12822871 Occurrence Handle10.1023/A:1023768829772 Occurrence Handle1:CAS:528:DC%2BD3sXjslyitbo%3D
H Witt W Luck M Becker M Bohmig A Kage K Truninger et al. (2001) ArticleTitleMutation in the SPINK1 trypsin inhibitor gene, alcohol use, and chronic pancreatitis JAMA 285 2716–7 Occurrence Handle11386926 Occurrence Handle10.1001/jama.285.21.2716-a Occurrence Handle1:STN:280:DC%2BD3MzltVChtA%3D%3D
A Ekbom C Helmick M Zack HO Adami (1990) ArticleTitleUlcerative colitis and colorectal cancer. A population-based study N Engl J Med 323 1228–33 Occurrence Handle2215606 Occurrence Handle1:STN:280:DyaK3M%2FhsFamtg%3D%3D Occurrence Handle10.1056/NEJM199011013231802
EB Gold JL Cameron (1993) ArticleTitleChronic pancreatitis and pancreatic cancer N Engl J Med 328 1485–6 Occurrence Handle8479469 Occurrence Handle10.1056/NEJM199305203282010 Occurrence Handle1:STN:280:DyaK3s3ktFagtA%3D%3D
E Fernandez C La Vecchia M Porta E Negri B d'Avanzo P Boyle (1995) ArticleTitlePancreatitis and the risk of pancreatic cancer Pancreas 11 185–9 Occurrence Handle7479677 Occurrence Handle10.1097/00006676-199508000-00012 Occurrence Handle1:STN:280:DyaK28%2Fotlaksg%3D%3D
AB Lowenfels P Maisonneuve EP DiMagno Y Elitsur LK Gates SuffixJr J Perrault et al. (1997) ArticleTitleHereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group J Natl Cancer Inst 89 442–6 Occurrence Handle9091646 Occurrence Handle10.1093/jnci/89.6.442 Occurrence Handle1:STN:280:DyaK2s3ivVWhug%3D%3D
DC Whitcomb S Applebaum SP Martin (1999) ArticleTitleHereditary pancreatitis and pancreatic carcinoma Ann N Y Acad Sci 880 201–9 Occurrence Handle10415865 Occurrence Handle10.1111/j.1749-6632.1999.tb09524.x Occurrence Handle1:STN:280:DyaK1MzksVemtg%3D%3D
N Teich HU Schulz H Witt M Bohmig V Keim (2003) ArticleTitleN34S, a pancreatitis associated SPINK1 mutation, is not associated with sporadic pancreatic cancer Pancreatology 3 67–8 Occurrence Handle12649567 Occurrence Handle10.1159/000069145
K Kuwata M Hirota M Nakae S Nishihara A Takimoto K Mitsushima et al. (2002) ArticleTitleFunctional analysis of recombinant pancreatic secretory trypsin inhibitor protein with amino-acid substitution J Gastroenterol 37 928–34 Occurrence Handle12483248 Occurrence Handle10.1007/s005350200156 Occurrence Handle1:CAS:528:DC%2BD38XptFGisLo%3D
JP Venables (2004) ArticleTitleAberrant and alternative splicing in cancer Cancer Res 64 7647–54 Occurrence Handle15520162 Occurrence Handle10.1158/0008-5472.CAN-04-1910 Occurrence Handle1:CAS:528:DC%2BD2cXptFemtb8%3D
K Kume A Masamune K Kikuta T Shimosegawa (2006) ArticleTitle[−215G>A; IVS3+2T>C] mutation in the SPINK1 gene causes exon 3 skipping and loss of the trypsin binding site Gut 55 1214 Occurrence Handle16849362 Occurrence Handle10.1136/gut.2006.095752 Occurrence Handle1:STN:280:DC%2BD28vis12hsA%3D%3D
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Masamune, A., Kume, K. & Shimosegawa, T. Differential roles of the SPINK1 gene mutations in alcoholic and nonalcoholic chronic pancreatitis. J Gastroenterol 42 (Suppl 17), 135–140 (2007). https://doi.org/10.1007/s00535-006-1921-z
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00535-006-1921-z