Advertisement

Genetics of Pancreatitis

  • Atsushi MasamuneEmail author
  • Tooru Shimosegawa
Chapter

Abstract

The association between alcohol misuse and chronic pancreatitis (CP) has been recognized for a long time. CP is a multifactorial and a complex disease, and the combination of genetic, environmental, and metabolic factors contributes to its development. Extensive research has been done to clarify the genetic factors. Candidate-gene approaches have focused on variants in the alcohol metabolizing enzymes (alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2)) and known pancreatitis susceptibility genes such as cationic trypsinogen (PRSS1), serine protease inhibitor Kazal type 1 (SPINK1), and chymotrypsin C (CTRC). It has been increasingly acknowledged that these previously known pancreatitis susceptibility genes identified in non-alcoholic (hereditary and idiopathic) CP also play a role in alcoholic CP. In addition, recent genome-wide association studies have identified new risk loci: the polymorphisms in the PRSS1-PRSS2 and the CLDN2-RIPPLY1-MORC4 loci and the inversion in the CTRB1-CTRB2 locus. The genetic alterations might at least in part explain a long-standing unsolved question: why only a small portion of heavy drinkers develop pancreatitis.

Keywords

Alcohol dehydrogenase Aldehyde dehydrogenase CTRB CTRC Genome-wide association study Pancreatitis PRSS1 PRSS2 SPINK1 Trypsin 

Notes

Conflict of Interest

None declared.

References

  1. 1.
    Yadav D, Lowenfels AB. The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology. 2013;144:1252–61.CrossRefGoogle Scholar
  2. 2.
    Lankisch PG, Lowenfels AB, Maisonneuve P. What is the risk of alcoholic pancreatitis in heavy drinkers? Pancreas. 2002;25:411–2.CrossRefGoogle Scholar
  3. 3.
    Whitcomb DC. Genetic risk factors for pancreatic disorders. Gastroenterology. 2013;144:1292–302.CrossRefGoogle Scholar
  4. 4.
    Aghdassi AA, Weiss FU, Mayerle J, et al. Genetic susceptibility factors for alcohol-induced chronic pancreatitis. Pancreatology. 2015;15:S23–31.CrossRefGoogle Scholar
  5. 5.
    Chiang CP, Wu CW, Lee SP, et al. Expression pattern, ethanol-metabolizing activities, and cellular localization of alcohol and aldehyde dehydrogenases in human pancreas: implications for pathogenesis of alcohol-induced pancreatic injury. Alcohol Clin Exp Res. 2009;33:1059–68.CrossRefGoogle Scholar
  6. 6.
    Hurley TD, Edenberg HJ. Genes encoding enzymes involved in ethanol metabolism. Alcohol Res. 2012;34:339–44.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Li D, Zhao H, Gelernter J. Strong association of the alcohol dehydrogenase 1B gene (ADH1B) with alcohol dependence and alcohol-induced medical diseases. Biol Psychiatry. 2011;70:504–12.CrossRefGoogle Scholar
  8. 8.
    Matsumoto M, Takahashi H, Maruyama K, et al. Genotypes of alcohol-metabolizing enzymes and the risk for alcoholic chronic pancreatitis in Japanese alcoholics. Alcohol Clin Exp Res. 1996;20:289A–92A.CrossRefGoogle Scholar
  9. 9.
    Shimosegawa T, Kume K, Masamune A. SPINK1, ADH2, and ALDH2 gene variants and alcoholic chronic pancreatitis in Japan. J Gastroenterol Hepatol. 2008;23:S82–6.CrossRefGoogle Scholar
  10. 10.
    Yokoyama A, Mizukami T, Matsui T, et al. Genetic polymorphisms of alcohol dehydrogenase-1B and aldehyde dehydrogenase-2 and liver cirrhosis, chronic calcific pancreatitis, diabetes mellitus, and hypertension among Japanese alcoholic men. Alcohol Clin Exp Res. 2013;37:1391–401.CrossRefGoogle Scholar
  11. 11.
    Rosendahl J, Kirsten H, Hegyi E, et al. Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis. Gut. 2017;67(10):1855–63.. pii: gutjnl-2017-314454.CrossRefGoogle Scholar
  12. 12.
    Whitcomb DC, Gorry MC, Preston RA, et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet. 1996;14:141–5.CrossRefGoogle Scholar
  13. 13.
    Masamune A, Kikuta K, Hamada S, et al. Nationwide survey of hereditary pancreatitis in Japan. J Gastroenterol. 2018;53:152–60.CrossRefGoogle Scholar
  14. 14.
    Schnúr A, Beer S, Witt H, et al. Functional effects of 13 rare PRSS1 variants presumed to cause chronic pancreatitis. Gut. 2014;63:337–43.CrossRefGoogle Scholar
  15. 15.
    Masamune A, Nakano E, Kume K, et al. PRSS1 c.623G>C (p.G208A) variant is associated with pancreatitis in Japan. Gut. 2014;63:366.CrossRefGoogle Scholar
  16. 16.
    Rinderknecht H. Activation of pancreatic zymogens. Normal activation, premature intrapancreatic activation, protective mechanisms against inappropriate activation. Dig Dis Sci. 1986;31:314–21.CrossRefGoogle Scholar
  17. 17.
    Witt H, Luck W, Hennies HC, 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.CrossRefGoogle Scholar
  18. 18.
    Masamune A. Genetics of pancreatitis: the 2014 update. Tohoku J Exp Med. 2014;232:69–77.CrossRefGoogle Scholar
  19. 19.
    Aoun E, Chang CC, Greer JB, et al. Pathways to injury in chronic pancreatitis: decoding the role of the high-risk SPINK1 N34S haplotype using meta-analysis. PLoS One. 2008;3:e2003.CrossRefGoogle Scholar
  20. 20.
    Witt H, Luck W, Becker M, et al. Mutation in the SPINK1 trypsin inhibitor gene, alcohol use, and chronic pancreatitis. JAMA. 2001;285:2716–7.CrossRefGoogle Scholar
  21. 21.
    Threadgold J, Greenhalf W, Ellis I, et al. The N34S mutation of SPINK1 (PSTI) is associated with a familial pattern of idiopathic chronic pancreatitis but does not cause the disease. Gut. 2002;50:675–81.CrossRefGoogle Scholar
  22. 22.
    Drenth JP, te Morsche R, Jansen JB. Mutations in serine protease inhibitor Kazal type 1 are strongly associated with chronic pancreatitis. Gut. 2002;50:687–92.CrossRefGoogle Scholar
  23. 23.
    Schneider A, Pfützer RH, Barmada MM, et al. Limited contribution of the SPINK1 N34S mutation to the risk and severity of alcoholic chronic pancreatitis: a report from the United States. Dig Dis Sci. 2003;48:1110–5.CrossRefGoogle Scholar
  24. 24.
    Perri F, Piepoli A, Stanziale P, et al. Mutation analysis of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, the cationic trypsinogen (PRSS1) gene, and the serine protease inhibitor, Kazal type 1 (SPINK1) gene in patients with alcoholic chronic pancreatitis. Eur J Hum Genet. 2003;11:687–92.CrossRefGoogle Scholar
  25. 25.
    Chandak GR, Idris MM, Reddy DN, et al. Absence of PRSS1 mutations and association of SPINK1 trypsin inhibitor mutations in hereditary and non-hereditary chronic pancreatitis. Gut. 2004;53:723–8.CrossRefGoogle Scholar
  26. 26.
    Lempinen M, Paju A, Kemppainen E, et al. Mutations N34S and P55S of the SPINK1 gene in patients with chronic pancreatitis or pancreatic cancer and in healthy subjects: a report from Finland. Scand J Gastroenterol. 2005;40:225–30.CrossRefGoogle Scholar
  27. 27.
    Kume K, Masamune A, Mizutamari H, et al. Mutations in the serine protease inhibitor Kazal Type 1 (SPINK1) gene in Japanese patients with pancreatitis. Pancreatology. 2005;5:354–60.CrossRefGoogle Scholar
  28. 28.
    Kume K, Masamune A, Kikuta K, et al. [−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.CrossRefGoogle Scholar
  29. 29.
    Kukor Z, Tóth M, Sahin-Tóth M. Human anionic trypsinogen: properties of autocatalytic activation and degradation and implications in pancreatic diseases. Eur J Biochem. 2003;270:2047–58.CrossRefGoogle Scholar
  30. 30.
    Witt H, Sahin-Tóth M, Landt O, et al. A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis. Nat Genet. 2006;38:668–73.CrossRefGoogle Scholar
  31. 31.
    Kume K, Masamune A, Takagi Y, et al. A loss-of-function p.G191R variant in the anionic trypsinogen (PRSS2) gene in Japanese patients with pancreatic disorders. Gut. 2009;58:820–4.CrossRefGoogle Scholar
  32. 32.
    Rosendahl J, Witt H, Szmola R, et al. Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. Nat Genet. 2008;40:78–82.CrossRefGoogle Scholar
  33. 33.
    Masamune A, Nakano E, Kume K, et al. Identification of novel missense CTRC variants in Japanese patients with chronic pancreatitis. Gut. 2013;62:653–4.CrossRefGoogle Scholar
  34. 34.
    Szabó A, Ludwig M, Hegyi E, et al. Mesotrypsin signature mutation in a chymotrypsin C (CTRC) variant associated with chronic pancreatitis. J Biol Chem. 2015;290:17282–92.CrossRefGoogle Scholar
  35. 35.
    LaRusch J, Lozano-Leon A, Stello K, et al. The common chymotrypsinogen C (CTRC) variant G60G (C.180T) increases risk of chronic pancreatitis but not recurrent acute pancreatitis in a north American population. Clin Transl Gastroenterol. 2015;6:e68.CrossRefGoogle Scholar
  36. 36.
    Sharer N, Schwarz M, Malone G, et al. Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. N Engl J Med. 1998;339:645–52.CrossRefGoogle Scholar
  37. 37.
    Cohn JA, Friedman KJ, Noone PG, Knowles MR, Silverman LM, Jowell PS. Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. N Engl J Med. 1998;339:653–8.CrossRefGoogle Scholar
  38. 38.
    Audrézet MP, Chen JM, Le Maréchal C, et al. Determination of the relative contribution of three genes-the cystic fibrosis transmembrane conductance regulator gene, the cationic trypsinogen gene, and the pancreatic secretory trypsin inhibitor gene-to the etiology of idiopathic chronic pancreatitis. Eur J Hum Genet. 2002;10:100–6.CrossRefGoogle Scholar
  39. 39.
    Rosendahl J, Landt O, Bernadova J, et al. CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated? Gut. 2013;62:582–92.CrossRefGoogle Scholar
  40. 40.
    Maléth J, Balázs A, Pallagi P, et al. Alcohol disrupts levels and function of the cystic fibrosis transmembrane conductance regulator to promote development of pancreatitis. Gastroenterology. 2015;148:427–39.e16.CrossRefGoogle Scholar
  41. 41.
    Whitcomb DC, LaRusch J, Krasinskas AM, et al. Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis. Nat Genet. 2012;44:1349–54.CrossRefGoogle Scholar
  42. 42.
    Derikx MH, Kovacs P, Scholz M, et al. Polymorphisms at PRSS1-PRSS2 and CLDN2-MORC4 loci associate with alcoholic and non-alcoholic chronic pancreatitis in a European replication study. Gut. 2015;64:1426–33.CrossRefGoogle Scholar
  43. 43.
    Masamune A, Nakano E, Hamada S, et al. Common variants at PRSS1-PRSS2 and CLDN2-MORC4 loci associate with chronic pancreatitis in Japan. Gut. 2015;64:1345–6.CrossRefGoogle Scholar
  44. 44.
    Giri AK, Midha S, Banerjee P, et al. Common variants in CLDN2 and MORC4 genes confer disease susceptibility in patients with chronicpancreatitis. PLoS One. 2016;11:e0147345.CrossRefGoogle Scholar
  45. 45.
    Weiss FU, Schurmann C, Guenther A, et al. Fucosyltransferase 2 (FUT2) non-secretor status and blood group B are associated with elevated serum lipase activity in asymptomatic subjects, and an increased risk for chronic pancreatitis: a genetic association study. Gut. 2015;64:646–56.CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Division of GastroenterologyTohoku University Graduate School of MedicineSendaiJapan

Personalised recommendations