Advertisement

Pathogenetics of Chronic Pancreatitis

  • Zhuan Liao
  • Zhao-Shen Li
  • David N. Cooper
  • Claude Férec
  • Jian-Min Chen
Chapter

Abstract

Chronic pancreatitis is a condition that is associated with the progressive inflammation of the pancreas which over time gives rise to irreversible morphological changes accompanied by impairment of both exocrine and endocrine functions (Majumder and Chari 2016). Over the last 20 years, molecular genetics has played an increasingly important role in elucidating the aetiology of chronic pancreatitis. The dawn of the new era in the genetic analysis of autosomal dominant hereditary pancreatitis (OMIM #167800) was heralded by the mapping of a disease locus to the long arm of chromosome 7 (Le Bodic et al. 1996; Pandya et al. 1996; Whitcomb et al. 1996b) and the subsequent identification of a gain-of-function missense mutation (i.e., p.Arg122His) in the cationic trypsinogen gene (PRSS1; OMIM #276000) (Whitcomb et al. 1996a). Thereafter, a steady stream of chronic pancreatitis susceptibility (or protective) variants in different genes has been reported. The analysis of variants in four specific genes, all highly expressed in human pancreatic acinar cells [PRSS1, PRSS2 (encoding anionic trypsinogen; OMIM #601564), SPINK1 (encoding pancreatic secretory trypsin inhibitor; OMIM #167790) and CTRC (encoding chymotrypsin C, which specifically degrades all human trypsinogen/trypsin isoforms (OMIM #601405) (Szmola and Sahin-Tóth 2007))] has firmly established the importance of a homeostatic balance between the activation and inactivation of trypsinogen within the pancreas, thereby defining a trypsin-dependent pathway in the pathogenesis of chronic pancreatitis. Whereas gain-of-function missense mutations and copy number variants in PRSS1 (Le Maréchal et al. 2006; Whitcomb et al. 1996a) and loss-of-function variants in SPINK1 (Witt et al. 2000) and CTRC (Masson et al. 2008b; Rosendahl et al. 2008) predispose to chronic pancreatitis, loss-of-function variants in PRSS1 (Boulling et al. 2015; Chen et al. 2003; Derikx et al. 2015; Whitcomb et al. 2012) and PRSS2 (Witt et al. 2006) protect against the disease.

Keywords

Chronic pancreatitis Genetics Human pancreatic acinar cells Pathogenesis Susceptibility genes 

Abbreviations

CEL

Carboxyl ester lipase

CFTR

Cystic fibrosis transmembrane conductance regulator

CLDN2

Claudin-2

CPA1

Carboxypeptidase A1

CTRC

Chymotrypsin C

ERS

Endoplasmic reticulum stress

FUT2

Fucosyltransferase 2

GWAS

Genome-wide association study

ICP

Idiopathic chronic pancreatitis

MODY

Maturity-onset diabetes of the young

NACP

Nonalcoholic chronic pancreatitis

NAHR

Non-allelic homologous recombination

NMD

Nonsense-mediated mRNA decay

OR

Odds ratio

PCR

Polymerase chain reaction

RAP

Recurrent acute pancreatitis

RT-PCR

Reverse transcription polymerase chain reaction

SNP

Single nucleotide polymorphism

VNTR

Variable number tandem repeat

Notes

Acknowledgments

The work was supported by the Conseil Régional de Bretagne, the Association des Pancréatites Chroniques Héréditaires, the Association de Transfusion Sanguine et de Biogénétique Gaetan Saleun, and the Institut National de la Santé et de la Recherche Médicale (INSERM), France; and the National Natural Science Foundation of China (81470884 and 81422010 to ZL), the Shuguang Program of Shanghai Education Development Foundation and Shanghai Municipal Education Commission (15SG33 to ZL) and the Chang Jiang Scholars Program of Ministry of Education (Q2015190 to ZL), China.

References

  1. Aghdassi AA, Weiss FU, Mayerle J, Lerch MM, Simon P. Genetic susceptibility factors for alcohol-induced chronic pancreatitis. Pancreatology. 2015;15:S23–31.CrossRefPubMedGoogle Scholar
  2. Avanthi SU, Ravi Kanth VV, Agarwal J, Lakhtakia S, Gangineni K, Rao GV, Reddy DN, Talukdar R. Association of claudin2 and PRSS1-PRSS2 polymorphisms with idiopathic recurrent acute and chronic pancreatitis: a case-control study from India. J Gastroenterol Hepatol. 2015;30:1796–801.CrossRefPubMedGoogle Scholar
  3. Beer S, Zhou J, Szabo A, Keiles S, Chandak GR, Witt H, Sahin-Tóth M. Comprehensive functional analysis of chymotrypsin C (CTRC) variants reveals distinct loss-of-function mechanisms associated with pancreatitis risk. Gut. 2013;62:1616–24.CrossRefPubMedGoogle Scholar
  4. Behar DM, Basel-Vanagaite L, Glaser F, Kaplan M, Tzur S, Magal N, Eidlitz-Markus T, Haimi-Cohen Y, Sarig G, Bormans C, Shohat M, Zeharia A. Identification of a novel mutation in the PNLIP gene in two brothers with congenital pancreatic lipase deficiency. J Lipid Res. 2014;55:307–12.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Boulling A, Chen JM, Callebaut I, Férec C. Is the SPINK1 p.Asn34Ser missense mutation per se the true culprit within its associated haplotype? Webmed Central Gene. 2012;3:WMC003084.Google Scholar
  6. Boulling A, Sato M, Masson E, Genin E, Chen JM, Férec C. Identification of a functional PRSS1 promoter variant in linkage disequilibrium with the chronic pancreatitis-protecting rs10273639. Gut. 2015;64:1837–8.CrossRefPubMedGoogle Scholar
  7. Boulling A, Abrantes A, Masson E, Cooper DN, Robaszkiewicz M, Chen JM, Férec C. Discovery and functional annotation of PRSS1 promoter variants in chronic pancreatitis. Hum Mutat. 2016;37:1149–52.CrossRefPubMedGoogle Scholar
  8. Chen JM, Férec C. Gene conversion-like missense mutations in the human cationic trypsinogen gene and insights into the molecular evolution of the human trypsinogen family. Mol Genet Metab. 2000a;71:463–9.CrossRefPubMedGoogle Scholar
  9. Chen JM, Férec C. Origin and implication of the hereditary pancreatitis-associated N21I mutation in the cationic trypsinogen gene. Hum Genet. 2000b;106:125–6.CrossRefPubMedGoogle Scholar
  10. Chen JM, Férec C. Chronic pancreatitis: genetics and pathogenesis. Annu Rev Genomics Hum Genet. 2009;10:63–87.CrossRefPubMedGoogle Scholar
  11. Chen JM, Férec C. Genetics and pathogenesis of chronic pancreatitis: the 2012 update. Clin Res Hepatol Gastroenterol. 2012;36:334–40.CrossRefPubMedGoogle Scholar
  12. Chen JM, Audrézet MP, Mercier B, Quéré I, Férec C. Exclusion of anionic trypsinogen and mesotrypsinogen involvement in hereditary pancreatitis without cationic trypsinogen gene mutations. Scand J Gastroenterol. 1999;34:831–2.CrossRefPubMedGoogle Scholar
  13. Chen JM, Raguénès O, Férec C, Deprez PH, Verellen-Dumoulin C. A CGC>CAT gene conversion-like event resulting in the R122H mutation in the cationic trypsinogen gene and its implication in the genotyping of pancreatitis. J Med Genet. 2000;37:E36.CrossRefPubMedPubMedCentralGoogle Scholar
  14. Chen JM, Le Maréchal C, Lucas D, Raguénès O, Férec C. “Loss of function” mutations in the cationic trypsinogen gene (PRSS1) may act as a protective factor against pancreatitis. Mol Genet Metab. 2003;79:67–70.CrossRefPubMedGoogle Scholar
  15. Chen JM, Cooper DN, Chuzhanova N, Férec C, Patrinos GP. Gene conversion: mechanisms, evolution and human disease. Nat Rev Genet. 2007;8:762–75.CrossRefPubMedGoogle Scholar
  16. Chen JM, Cooper DN, Férec C. Trypsinogen genes: insights into molecular evolution from the study of pathogenic mutations. In: eLS. Chichester: Wiley. 2013a. http://www.els.net. doi:  10.1002/9780470015902.a0006140.pub3.
  17. Chen JM, Radisky ES, Férec C. Human trypsins. In: Rawlings ND, Salvesen GS, editors. Handbook of proteolytic enzymes. Oxford: Academic; 2013b. p. 2600–9.CrossRefGoogle Scholar
  18. Choi AM, Ryter SW, Levine B. Autophagy in human health and disease. N Engl J Med. 2013;368:651–62.CrossRefPubMedGoogle Scholar
  19. Derikx MH, Szmola R, te Morsche RH, Sunderasan S, Chacko A, Drenth JP. Tropical calcific pancreatitis and its association with CTRC and SPINK1 (p.N34S) variants. Eur J Gastroenterol Hepatol. 2009;21:889–94.CrossRefPubMedGoogle Scholar
  20. Derikx MH, Kovacs P, Scholz M, Masson E, Chen JM, Ruffert C, Lichtner P, Te Morsche RH, Cavestro GM, Férec C, Drenth JP, Witt H, Rosendahl J. 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.CrossRefPubMedGoogle Scholar
  21. Férec C, Raguénès O, Salomon R, Roche C, Bernard JP, Guillot M, Quéré I, Faure C, Mercier B, Audrézet MP, Guillausseau PJ, Dupont C, Munnich A, Bignon JD, Le Bodic L. Mutations in the cationic trypsinogen gene and evidence for genetic heterogeneity in hereditary pancreatitis. J Med Genet. 1999;36:228–32.PubMedPubMedCentralGoogle Scholar
  22. Fjeld K, Weiss FU, Lasher D, Rosendahl J, Chen JM, Johansson BB, Kirsten H, Ruffert C, Masson E, Steine SJ, Bugert P, Cnop M, Grutzmann R, Mayerle J, Mossner J, Ringdal M, Schulz HU, Sendler M, Simon P, Sztromwasser P, Torsvik J, Scholz M, Tjora E, Férec C, Witt H, Lerch MM, Njolstad PR, Johansson S, Molven A. A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis. Nat Genet. 2015;47:518–22.CrossRefPubMedPubMedCentralGoogle Scholar
  23. Forrest AR, Kawaji H, Rehli M, Baillie JK, de Hoon MJ, Haberle V, Lassmann T, Kulakovskiy IV, Lizio M, Itoh M, Andersson R, Mungall CJ, Meehan TF, Schmeier S, Bertin N, Jorgensen M, Dimont E, Arner E, Schmidl C, Schaefer U, Medvedeva YA, Plessy C, Vitezic M, Severin J, Semple C, Ishizu Y, Young RS, Francescatto M, Alam I, Albanese D, Altschuler GM, Arakawa T, Archer JA, Arner P, Babina M, Rennie S, Balwierz PJ, Beckhouse AG, Pradhan-Bhatt S, Blake JA, Blumenthal A, Bodega B, Bonetti A, Briggs J, Brombacher F, Burroughs AM, Califano A, Cannistraci CV, Carbajo D, Chen Y, Chierici M, Ciani Y, Clevers HC, Dalla E, Davis CA, Detmar M, Diehl AD, Dohi T, Drablos F, Edge AS, Edinger M, Ekwall K, Endoh M, Enomoto H, Fagiolini M, Fairbairn L, Fang H, Farach-Carson MC, Faulkner GJ, Favorov AV, Fisher ME, Frith MC, Fujita R, Fukuda S, Furlanello C, Furino M, Furusawa J, Geijtenbeek TB, Gibson AP, Gingeras T, Goldowitz D, Gough J, Guhl S, Guler R, Gustincich S, Ha TJ, Hamaguchi M, Hara M, Harbers M, Harshbarger J, Hasegawa A, Hasegawa Y, Hashimoto T, Herlyn M, Hitchens KJ, Ho Sui SJ, Hofmann OM, Hoof I, Hori F, Huminiecki L, Iida K, Ikawa T, Jankovic BR, Jia H, Joshi A, Jurman G, Kaczkowski B, Kai C, Kaida K, Kaiho A, Kajiyama K, Kanamori-Katayama M, Kasianov AS, Kasukawa T, Katayama S, Kato S, Kawaguchi S, Kawamoto H, Kawamura YI, Kawashima T, Kempfle JS, Kenna TJ, Kere J, Khachigian LM, Kitamura T, Klinken SP, Knox AJ, Kojima M, Kojima S, Kondo N, Koseki H, Koyasu S, Krampitz S, Kubosaki A, Kwon AT, Laros JF, Lee W, Lennartsson A, Li K, Lilje B, Lipovich L, Mackay-Sim A, Manabe R, Mar JC, Marchand B, Mathelier A, Mejhert N, Meynert A, Mizuno Y, de Lima Morais DA, Morikawa H, Morimoto M, Moro K, Motakis E, Motohashi H, Mummery CL, Murata M, Nagao-Sato S, Nakachi Y, Nakahara F, Nakamura T, Nakamura Y, Nakazato K, van Nimwegen E, Ninomiya N, Nishiyori H, Noma S, Noazaki T, Ogishima S, Ohkura N, Ohimiya H, Ohno H, Ohshima M, Okada-Hatakeyama M, Okazaki Y, Orlando V, Ovchinnikov DA, Pain A, Passier R, Patrikakis M, Persson H, Piazza S, Prendergast JG, Rackham OJ, Ramilowski JA, Rashid M, Ravasi T, Rizzu P, Roncador M, Roy S, Rye MB, Saijyo E, Sajantila A, Saka A, Sakaguchi S, Sakai M, Sato H, Savvi S, Saxena A, Schneider C, Schultes EA, Schulze-Tanzil GG, Schwegmann A, Sengstag T, Sheng G, Shimoji H, Shimoni Y, Shin JW, Simon C, Sugiyama D, Sugiyama T, Suzuki M, Suzuki N, Swoboda RK, t Hoen PA, Tagami M, Takahashi N, Takai J, Tanaka H, Tatsukawa H, Tatum Z, Thompson M, Toyodo H, Toyoda T, Valen E, van de Wetering M, van den Berg LM, Verado R, Vijayan D, Vorontsov IE, Wasserman WW, Watanabe S, Wells CA, Winteringham LN, Wolvetang E, Wood EJ, Yamaguchi Y, Yamamoto M, Yoneda M, Yonekura Y, Yoshida S, Zabierowski SE, Zhang PG, Zhao X, Zucchelli S, Summers KM, Suzuki H, Daub CO, Kawai J, Heutink P, Hide W, Freeman TC, Lenhard B, Bajic VB, Taylor MS, Makeev VJ, Sandelin A, Hume DA, Carninci P, Hayashizaki Y. A promoter-level mammalian expression atlas. Nature. 2014;507:462–70.CrossRefPubMedGoogle Scholar
  24. Giri AK, Midha S, Banerjee P, Agrawal A, Mehdi SJ, Dhingra R, Kaur I, Ramesh Kumar G, Lakhotia R, Ghosh S, Das K, Mohindra S, Rana S, Bhasin DK, Garg PK, Bharadwaj D. Common variants in CLDN2 and MORC4 genes confer disease susceptibility in patients with chronic pancreatitis. PLoS One. 2016;11:e0147345.CrossRefPubMedPubMedCentralGoogle Scholar
  25. Gukovskaya AS, Gukovsky I. Autophagy and pancreatitis. Am J Physiol Gastrointest Liver Physiol. 2012;303:G993–G1003.CrossRefPubMedPubMedCentralGoogle Scholar
  26. Holmes RS, Cox LA. Comparative structures and evolution of vertebrate carboxyl ester lipase (CEL) genes and proteins with a major role in reverse cholesterol transport. Cholesterol. 2011;2011:781643.CrossRefPubMedPubMedCentralGoogle Scholar
  27. Idris MM, Bhaskar S, Reddy DN, Mani KR, Rao GV, Singh L, Chandak GR. Mutations in anionic trypsinogen gene are not associated with tropical calcific pancreatitis. Gut. 2005;54:728–9.CrossRefPubMedPubMedCentralGoogle Scholar
  28. Jancso Z, Sahin-Tóth M. Tighter control by chymotrypsin C (CTRC) explains lack of association between human anionic trypsinogen and hereditary pancreatitis. J Biol Chem. 2016;291:12897–905.CrossRefPubMedPubMedCentralGoogle Scholar
  29. Karam R, Wengrod J, Gardner LB, Wilkinson MF. Regulation of nonsense-mediated mRNA decay: implications for physiology and disease. Biochim Biophys Acta. 2013;1829:624–33.CrossRefPubMedPubMedCentralGoogle Scholar
  30. Kereszturi E, Szmola R, Kukor Z, Simon P, Weiss FU, Lerch MM, Sahin-Tóth M. Hereditary pancreatitis caused by mutation-induced misfolding of human cationic trypsinogen: a novel disease mechanism. Hum Mutat. 2009a;30:575–82.CrossRefPubMedPubMedCentralGoogle Scholar
  31. Kereszturi E, Kiraly O, Sahin-Tóth M. Minigene analysis of intronic variants in common SPINK1 haplotypes associated with chronic pancreatitis. Gut. 2009b;58:545–9.CrossRefPubMedGoogle Scholar
  32. Kirsten H, Scholz M, Kovacs P, Grallert H, Peters A, Strauch K, Frank J, Rietschel M, Nothen MM, Witt H, Rosendahl J. Genetic variants of lipase activity in chronic pancreatitis. Gut. 2016;65:184–5.CrossRefPubMedGoogle Scholar
  33. Klionsky DJ. Autophagy revisited: a conversation with Christian de Duve. Autophagy. 2008;4:740–3.CrossRefPubMedGoogle Scholar
  34. LaRusch J, Jung J, General IJ, Lewis MD, Park HW, Brand RE, Gelrud A, Anderson MA, Banks PA, Conwell D, Lawrence C, Romagnuolo J, Baillie J, Alkaade S, Cote G, Gardner TB, Amann ST, Slivka A, Sandhu B, Aloe A, Kienholz ML, Yadav D, Barmada MM, Bahar I, Lee MG, Whitcomb DC. Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis. PLoS Genet. 2014;10:e1004376.CrossRefPubMedPubMedCentralGoogle Scholar
  35. LaRusch J, Lozano-Leon A, Stello K, Moore A, Muddana V, O’Connell M, Diergaarde B, Yadav D, Whitcomb DC. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  36. Le Bodic L, Bignon JD, Raguénès O, Mercier B, Georgelin T, Schnee M, Soulard F, Gagne K, Bonneville F, Muller JY, Bachner L, Férec C. The hereditary pancreatitis gene maps to long arm of chromosome 7. Hum Mol Genet. 1996;5:549–54.CrossRefPubMedGoogle Scholar
  37. Le Maréchal C, Masson E, Chen JM, Morel F, Ruszniewski P, Levy P, Férec C. Hereditary pancreatitis caused by triplication of the trypsinogen locus. Nat Genet. 2006;38:1372–4.CrossRefPubMedGoogle Scholar
  38. Lindquist S, Blackberg L, Hernell O. Human bile salt-stimulated lipase has a high frequency of size variation due to a hypervariable region in exon 11. Eur J Biochem. 2002;269:759–67.CrossRefPubMedGoogle Scholar
  39. MacArthur DG, Manolio TA, Dimmock DP, Rehm HL, Shendure J, Abecasis GR, Adams DR, Altman RB, Antonarakis SE, Ashley EA, Barrett JC, Biesecker LG, Conrad DF, Cooper GM, Cox NJ, Daly MJ, Gerstein MB, Goldstein DB, Hirschhorn JN, Leal SM, Pennacchio LA, Stamatoyannopoulos JA, Sunyaev SR, Valle D, Voight BF, Winckler W, Gunter C. Guidelines for investigating causality of sequence variants in human disease. Nature. 2014;508:469–76.CrossRefPubMedPubMedCentralGoogle Scholar
  40. Majumder S, Chari ST. Chronic pancreatitis. Lancet. 2016;387:1957–66.CrossRefPubMedGoogle Scholar
  41. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, McCarthy MI, Ramos EM, Cardon LR, Chakravarti A, Cho JH, Guttmacher AE, Kong A, Kruglyak L, Mardis E, Rotimi CN, Slatkin M, Valle D, Whittemore AS, Boehnke M, Clark AG, Eichler EE, Gibson G, Haines JL, Mackay TF, McCarroll SA, Visscher PM. Finding the missing heritability of complex diseases. Nature. 2009;461:747–53.CrossRefPubMedPubMedCentralGoogle Scholar
  42. Masamune A. Genetics of pancreatitis: the 2014 update. Tohoku J Exp Med. 2014;232:69–77.CrossRefPubMedGoogle Scholar
  43. Masamune A, Nakano E, Hamada S, Kakuta Y, Kume K, Shimosegawa T. Common variants at PRSS1-PRSS2 and CLDN2-MORC4 loci associate with chronic pancreatitis in Japan. Gut. 2015;64:1345–6.CrossRefPubMedGoogle Scholar
  44. Masson E, Le Maréchal C, Chandak GR, Lamoril J, Bezieau S, Mahurkar S, Bhaskar S, Reddy DN, Chen JM, Férec C. Trypsinogen copy number mutations in patients with idiopathic chronic pancreatitis. Clin Gastroenterol Hepatol. 2008a;6:82–8.CrossRefPubMedGoogle Scholar
  45. Masson E, Chen JM, Scotet V, Le Maréchal C, Férec C. Association of rare chymotrypsinogen C (CTRC) gene variations in patients with idiopathic chronic pancreatitis. Hum Genet. 2008b;123:83–91.CrossRefPubMedGoogle Scholar
  46. Masson E, Chen JM, Audrezet MP, Cooper DN, Férec C. A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. PLoS One. 2013;8:e73522.CrossRefPubMedPubMedCentralGoogle Scholar
  47. Molven A, Fjeld K, Lowe ME. Lipase genetic variants in chronic pancreatitis: when the end is wrong, all’s not well. Gastroenterology. 2016;150:1515–8.CrossRefPubMedGoogle Scholar
  48. Mounzer R, Whitcomb DC. Genetics of acute and chronic pancreatitis. Curr Opin Gastroenterol. 2013;29:544–51.CrossRefPubMedPubMedCentralGoogle Scholar
  49. Nakano E, Geisz A, Masamune A, Niihori T, Hamada S, Kume K, Kakuta Y, Aoki Y, Matsubara Y, Ebert K, Ludwig M, Braun M, Groneberg DA, Shimosegawa T, Sahin-Tóth M, Witt H. Variants in pancreatic carboxypeptidase genes CPA2 and CPB1 are not associated with chronic pancreatitis. Am J Physiol Gastrointest Liver Physiol. 2015;309:G688–94.CrossRefPubMedPubMedCentralGoogle Scholar
  50. Nemeth BC, Sahin-Tóth M. Human cationic trypsinogen (PRSS1) variants and chronic pancreatitis. Am J Physiol Gastrointest Liver Physiol. 2014;306:G466–73.CrossRefPubMedPubMedCentralGoogle Scholar
  51. Nyaruhucha CN, Kito M, Fukuoka SI. Identification and expression of the cDNA-encoding human mesotrypsin (ogen), an isoform of trypsin with inhibitor resistance. J Biol Chem. 1997;272:10573–8.CrossRefPubMedGoogle Scholar
  52. Oakes SA, Papa FR. The role of endoplasmic reticulum stress in human pathology. Annu Rev Pathol. 2015;10:173–94.CrossRefPubMedGoogle Scholar
  53. Ooi CY, Dorfman R, Cipolli M, Gonska T, Castellani C, Keenan K, Freedman SD, Zielenski J, Berthiaume Y, Corey M, Schibli S, Tullis E, Durie PR. Type of CFTR mutation determines risk of pancreatitis in patients with cystic fibrosis. Gastroenterology. 2011;140:153–61.CrossRefPubMedGoogle Scholar
  54. Paliwal S, Bhaskar S, Mani KR, Reddy DN, Rao GV, Singh SP, Thomas V, Chandak GR. Comprehensive screening of chymotrypsin C (CTRC) gene in tropical calcific pancreatitis identifies novel variants. Gut. 2013;62:1602–6.CrossRefPubMedGoogle Scholar
  55. Paliwal S, Bhaskar S, Chandak GR. Genetic and phenotypic heterogeneity in tropical calcific pancreatitis. World J Gastroenterol. 2014;20:17314–23.CrossRefPubMedPubMedCentralGoogle Scholar
  56. Paliwal S, Bhaskar S, Nageshwar Reddy D, Rao GV, Thomas V, Singh SP, Chandak GR. Association analysis of PRSS1-PRSS2 and CLDN2-MORC4 variants in nonalcoholic chronic pancreatitis using tropical calcific pancreatitis as model. Pancreas. 2016;45:1153–7.CrossRefPubMedGoogle Scholar
  57. Pandya A, Blanton SH, Landa B, Javaheri R, Melvin E, Nance WE, Markello T. Linkage studies in a large kindred with hereditary pancreatitis confirms mapping of the gene to a 16-cM region on 7q. Genomics. 1996;38:227–30.CrossRefPubMedGoogle Scholar
  58. Pereverzev AP, Gurskaya NG, Ermakova GV, Kudryavtseva EI, Markina NM, Kotlobay AA, Lukyanov SA, Zaraisky AG, Lukyanov KA. Method for quantitative analysis of nonsense-mediated mRNA decay at the single cell level. Sci Rep. 2015;5:7729.CrossRefPubMedPubMedCentralGoogle Scholar
  59. Raeder H, Johansson S, Holm PI, Haldorsen IS, Mas E, Sbarra V, Nermoen I, Eide SA, Grevle L, Bjorkhaug L, Sagen JV, Aksnes L, Sovik O, Lombardo D, Molven A, Njolstad PR. Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction. Nat Genet. 2006;38:54–62.CrossRefPubMedGoogle Scholar
  60. Ravi Kanth V, Nageshwar Reddy D. Genetics of acute and chronic pancreatitis: an update. World J Gastrointest Pathophysiol. 2014;5:427–37.CrossRefPubMedPubMedCentralGoogle Scholar
  61. Rinderknecht H, Renner IG, Abramson SB, Carmack C. Mesotrypsin: a new inhibitor-resistant protease from a zymogen in human pancreatic tissue and fluid. Gastroenterology. 1984;86:681–92.PubMedGoogle Scholar
  62. Rosendahl J, Witt H, Szmola R, Bhatia E, Ozsvari B, Landt O, Schulz HU, Gress TM, Pfutzer R, Lohr M, Kovacs P, Bluher M, Stumvoll M, Choudhuri G, Hegyi P, te Morsche RH, Drenth JP, Truninger K, Macek M Jr, Puhl G, Witt U, Schmidt H, Buning C, Ockenga J, Kage A, Groneberg DA, Nickel R, Berg T, Wiedenmann B, Bodeker H, Keim V, Mossner J, Teich N, Sahin-Tóth M. Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. Nat Genet. 2008;40:78–82.CrossRefPubMedGoogle Scholar
  63. Rowen L, Williams E, Glusman G, Linardopoulou E, Friedman C, Ahearn ME, Seto J, Boysen C, Qin S, Wang K, Kaur A, Bloom S, Hood L, Trask BJ. Interchromosomal segmental duplications explain the unusual structure of PRSS3, the gene for an inhibitor-resistant trypsinogen. Mol Biol Evol. 2005;22:1712–20.CrossRefPubMedGoogle Scholar
  64. Rygiel AM, Beer S, Simon P, Wertheim-Tysarowska K, Oracz G, Kucharzik T, Tysarowski A, Niepokoj K, Kierkus J, Jurek M, Gawlinski P, Poznanski J, Bal J, Lerch MM, Sahin-Tóth M, Weiss FU. Gene conversion between cationic trypsinogen (PRSS1) and the pseudogene trypsinogen 6 (PRSS3P2) in patients with chronic pancreatitis. Hum Mutat. 2015;36:350–6.CrossRefPubMedPubMedCentralGoogle Scholar
  65. Scheele G, Bartelt D, Bieger W. Characterization of human exocrine pancreatic proteins by two-dimensional isoelectric focusing/sodium dodecyl sulfate gel electrophoresis. Gastroenterology. 1981;80:461–73.PubMedGoogle Scholar
  66. Schnúr A, Beer S, Witt H, Hegyi P, Sahin-Tóth M. Functional effects of 13 rare PRSS1 variants presumed to cause chronic pancreatitis. Gut. 2014;63:337–43.CrossRefPubMedGoogle Scholar
  67. Szabó A, Ludwig M, Hegyi E, Szépeová R, Witt H, Sahin-Tóth M. Mesotrypsin signature mutation in a chymotrypsin C (CTRC) variant associated with chronic pancreatitis. J Biol Chem. 2015a;290:17282–92.CrossRefPubMedPubMedCentralGoogle Scholar
  68. Szabó A, Xiao X, Haughney M, Spector A, Sahin-Tóth M, Lowe ME. A novel mutation in PNLIP causes pancreatic triglyceride lipase deficiency through protein misfolding. Biochim Biophys Acta. 2015b;1852:1372–9.CrossRefPubMedPubMedCentralGoogle Scholar
  69. Szmola R, Sahin-Tóth M. Chymotrypsin C (caldecrin) promotes degradation of human cationic trypsin: identity with Rinderknecht’s enzyme Y. Proc Natl Acad Sci U S A. 2007;104:11227–32.CrossRefPubMedPubMedCentralGoogle Scholar
  70. Szmola R, Kukor Z, Sahin-Tóth M. Human mesotrypsin is a unique digestive protease specialized for the degradation of trypsin inhibitors. J Biol Chem. 2003;278:48580–9.CrossRefPubMedPubMedCentralGoogle Scholar
  71. Teich N, Nemoda Z, Kohler H, Heinritz W, Mossner J, Keim V, Sahin-Tóth M. Gene conversion between functional trypsinogen genes PRSS1 and PRSS2 associated with chronic pancreatitis in a six-year-old girl. Hum Mutat. 2005;25:343–7.CrossRefPubMedPubMedCentralGoogle Scholar
  72. Tennessen JA, Bigham AW, O’Connor TD, Fu W, Kenny EE, Gravel S, McGee S, Do R, Liu X, Jun G, Kang HM, Jordan D, Leal SM, Gabriel S, Rieder MJ, Abecasis G, Altshuler D, Nickerson DA, Boerwinkle E, Sunyaev S, Bustamante CD, Bamshad MJ, Akey JM. Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science. 2012;337:64–9.CrossRefPubMedPubMedCentralGoogle Scholar
  73. Vesterhus M, Raeder H, Kurpad AJ, Kawamori D, Molven A, Kulkarni RN, Kahn CR, Njolstad PR. Pancreatic function in carboxyl-ester lipase knockout mice. Pancreatology. 2010;10:467–76.CrossRefPubMedPubMedCentralGoogle Scholar
  74. Wang M, Kaufman RJ. Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature. 2016;529:326–35.CrossRefPubMedGoogle Scholar
  75. Weiss FU, Schurmann C, Guenther A, Ernst F, Teumer A, Mayerle J, Simon P, Volzke H, Radke D, Greinacher A, Kuehn JP, Zenker M, Volker U, Homuth G, Lerch MM. 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.CrossRefPubMedGoogle Scholar
  76. Weiss FU, Schurmann C, Teumer A, Mayerle J, Simon P, Volzke H, Greinacher A, Kuehn JP, Zenker M, Volker U, Homuth G, Lerch MM. ABO blood type B and fucosyltransferase 2 non-secretor status as genetic risk factors for chronic pancreatitis. Gut. 2016;65:353–4.CrossRefPubMedGoogle Scholar
  77. Whitcomb DC, Gorry MC, Preston RA, Furey W, Sossenheimer MJ, Ulrich CD, Martin SP, Gates LK Jr, 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. 1996a;14:141–5.CrossRefPubMedGoogle Scholar
  78. Whitcomb DC, Preston RA, Aston CE, Sossenheimer MJ, Barua PS, Zhang Y, Wong-Chong A, White GJ, Wood PG, Gates LK Jr, Ulrich C, Martin SP, Post JC, Ehrlich GD. A gene for hereditary pancreatitis maps to chromosome 7q35. Gastroenterology. 1996b;110:1975–80.CrossRefPubMedGoogle Scholar
  79. Whitcomb DC, LaRusch J, Krasinskas AM, Klei L, Smith JP, Brand RE, Neoptolemos JP, Lerch MM, Tector M, Sandhu BS, Guda NM, Orlichenko L, Alkaade S, Amann ST, Anderson MA, Baillie J, Banks PA, Conwell D, Cote GA, Cotton PB, DiSario J, Farrer LA, Forsmark CE, Johnstone M, Gardner TB, Gelrud A, Greenhalf W, Haines JL, Hartman DJ, Hawes RA, Lawrence C, Lewis M, Mayerle J, Mayeux R, Melhem NM, Money ME, Muniraj T, Papachristou GI, Pericak-Vance MA, Romagnuolo J, Schellenberg GD, Sherman S, Simon P, Singh VP, Slivka A, Stolz D, Sutton R, Weiss FU, Wilcox CM, Zarnescu NO, Wisniewski SR, O’Connell MR, Kienholz ML, Roeder K, Barmada MM, Yadav D, Devlin B. Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis. Nat Genet. 2012;44:1349–54.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 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. 2000;25:213–6.CrossRefPubMedGoogle Scholar
  81. Witt H, Sahin-Tóth M, Landt O, Chen JM, Kahne T, Drenth JP, Kukor Z, Szepessy E, Halangk W, Dahm S, Rohde K, Schulz HU, Le Marechal C, Akar N, Ammann RW, Truninger K, Bargetzi M, Bhatia E, Castellani C, Cavestro GM, Cerny M, Destro-Bisol G, Spedini G, Eiberg H, Jansen JB, Koudova M, Rausova E, Macek M Jr, Malats N, Real FX, Menzel HJ, Moral P, Galavotti R, Pignatti PF, Rickards O, Spicak J, Zarnescu NO, Bock W, Gress TM, Friess H, Ockenga J, Schmidt H, Pfutzer R, Lohr M, Simon P, Weiss FU, Lerch MM, Teich N, Keim V, Berg T, Wiedenmann B, Luck W, Groneberg DA, Becker M, Keil T, Kage A, Bernardova J, Braun M, Guldner C, Halangk J, Rosendahl J, Witt U, Treiber M, Nickel R, Férec C. A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis. Nat Genet. 2006;38:668–73.CrossRefPubMedPubMedCentralGoogle Scholar
  82. Witt H, Beer S, Rosendahl J, Chen JM, Chandak GR, Masamune A, Bence M, Szmola R, Oracz G, Macek M Jr, Bhatia E, Steigenberger S, Lasher D, Buhler F, Delaporte C, Tebbing J, Ludwig M, Pilsak C, Saum K, Bugert P, Masson E, Paliwal S, Bhaskar S, Sobczynska-Tomaszewska A, Bak D, Balascak I, Choudhuri G, Nageshwar Reddy D, Rao GV, Thomas V, Kume K, Nakano E, Kakuta Y, Shimosegawa T, Durko L, Szabo A, Schnur A, Hegyi P, Rakonczay Z Jr, Pfutzer R, Schneider A, Groneberg DA, Braun M, Schmidt H, Witt U, Friess H, Algul H, Landt O, Schuelke M, Kruger R, Wiedenmann B, Schmidt F, Zimmer KP, Kovacs P, Stumvoll M, Bluher M, Muller T, Janecke A, Teich N, Grutzmann R, Schulz HU, Mossner J, Keim V, Lohr M, Férec C, Sahin-Tóth M. Variants in CPA1 are strongly associated with early onset chronic pancreatitis. Nat Genet. 2013;45:1216–20.CrossRefPubMedPubMedCentralGoogle Scholar
  83. Yadav D. Recent advances in the epidemiology of alcoholic pancreatitis. Curr Gastroenterol Rep. 2011;13:157–65.CrossRefPubMedGoogle Scholar
  84. Yadav D, Lowenfels AB. The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology. 2013;144:1252–61.CrossRefPubMedPubMedCentralGoogle Scholar
  85. Yadav D, O’Connell M, Papachristou GI. Natural history following the first attack of acute pancreatitis. Am J Gastroenterol. 2012;107:1096–103.CrossRefPubMedGoogle Scholar
  86. Zhang X, Bailey SD, Lupien M. Laying a solid foundation for Manhattan—‘setting the functional basis for the post-GWAS era’. Trends Genet. 2014;30:140–9.CrossRefPubMedPubMedCentralGoogle Scholar
  87. Zou WB, Boulling A, Masson E, Cooper DN, Liao Z, Li ZS, Férec C, Chen JM. Clarifying the clinical relevance of SPINK1 intronic variants in chronic pancreatitis. Gut. 2016a;65:884–6.CrossRefPubMedGoogle Scholar
  88. Zou WB, Masson E, Boulling A, Cooper DN, Li ZS, Liao Z, Férec C, Chen JM. Digging deeper into the intronic sequences of the SPINK1 gene. Gut. 2016b;65:1055–6.CrossRefPubMedGoogle Scholar
  89. Zou WB, Boulling A, Masamune A, Issarapu P, Masson E, Wu H, Sun XT, Hu LH, Zhou DZ, He L, Fichou Y, Nakano E, Hamada S, Kakuta Y, Kume K, Isayama H, Paliwal S, Mani KR, Bhaskar S, Cooper DN, Férec C, Shimosegawa T, Chandak GR, Chen JM, Li ZS, Liao Z. No association between CEL-HYB hybrid allele and chronic pancreatitis in Asian populations. Gastroenterology. 2016c;150:1558–60. e5CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. and Shanghai Scientific and Technical Publishers 2017

Authors and Affiliations

  • Zhuan Liao
    • 1
    • 2
  • Zhao-Shen Li
    • 1
    • 2
  • David N. Cooper
    • 3
  • Claude Férec
    • 4
    • 5
    • 6
    • 7
  • Jian-Min Chen
    • 4
    • 5
    • 6
  1. 1.Department of GastroenterologyChanghai Hospital, the Second Military Medical UniversityShanghaiChina
  2. 2.Shanghai Institute of Pancreatic DiseasesShanghaiChina
  3. 3.Institute of Medical Genetics, School of MedicineCardiff UniversityCardiffUK
  4. 4.Institut National de la Santé et de la Recherche Médicale (INSERM)BrestFrance
  5. 5.Faculté de Médecine et des Sciences de la SantéUniversité de Bretagne Occidentale (UBO)BrestFrance
  6. 6.Etablissement Français du Sang (EFS)—BretagneBrestFrance
  7. 7.Laboratoire de Génétique Moléculaire et d’HistocompatibilitéCentre Hospitalier Universitaire (CHU) Brest, Hôpital MorvanBrestFrance

Personalised recommendations