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CC BY 4.0 · Glob Med Genet 2023; 10(04): 324-334
DOI: 10.1055/s-0043-1776981
Review Article

Genetics and Genomics of Chronic Pancreatitis with a Focus on Disease Biology and Molecular Pathogenesis

Erum Khan
1   Department of Neurology, Alzheimer's Disease Research Center, The university of Alabama at Birmingham, Birmingham, United States
,
Soura Chakrabarty
2   Department of Pathology, University of Cambridge, Cambridge, United Kingdom
,
Sanobar Shariff
3   Yerevan State Medical University, Yerevan, Armenia
,
Mainak Bardhan
4   Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, Florida, United States
› Author Affiliations Funding None.
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Abstract

Chronic pancreatitis is a long-term fibroinflammatory condition of the pancreas with varying incidences across countries. The recent increase in its occurrence implies the involvement of genetic, hereditary, and unconventional risk factors. However, there is a lack of updated literature on recent advances in genetic polymorphisms of chronic pancreatitis. Therefore, this review aims to present recent findings on the genetic implications of chronic pancreatitis based on individual gene mechanisms and to discuss epigenetics and epistasis involved in the disease. Four mechanisms have been implicated in the pathogenesis of chronic pancreatitis, including premature activation of proteases, endoplasmic reticulum stress, ductal pathway dysfunction, and inflammatory pathway dysfunction. These mechanisms involve genes such as PRSS1, PRSS2, SPINK, CEL, PNLIP, PNLIPRP2, CFTR, CaSR, CLDN2, Alpha 1 antitrypsin, and GGT1. Studying genetic polymorphisms on the basis of altered genes and their products may aid clinicians in identifying predispositions in patients with and without common risk factors. Further research may also identify associations between genetic predispositions and disease staging or prognosis, leading to personalized treatment protocols and precision medicine.

Keywords

pancreatitis - chronic pancreatitis - genetics - genomics


Publication History

Article published online:
22 November 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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  • References

  • 1 Gullo L, Migliori M, Oláh A. et al. Acute pancreatitis in five European countries: etiology and mortality. Pancreas 2002; 24 (03) 223-227
    CrossrefPubMedGoogle Scholar
  • 2 Kleeff J, Whitcomb DC, Shimosegawa T. et al. Chronic pancreatitis. Nat Rev Dis Primers 2017; 3: 17060
    CrossrefPubMedGoogle Scholar
  • 3 Balazs EA, Davies JV, Phillips GO, Scheufele DS. Ppolyanions and their complexes. 3. Reactions of heparin, hyaluronic acid, sodium poly(ethylenesulphonate), sodium poly(styrenesulphonate), and sodium carboxymethylcellulose with hydroxyl radicals and hydrated electrons. J Chem Soc, Perkin Trans 1 1968; 12: 1420-1423
    PubMedGoogle Scholar
  • 4 Yadav D, Timmons L, Benson JT, Dierkhising RA, Chari ST. Incidence, prevalence, and survival of chronic pancreatitis: a population-based study. Am J Gastroenterol 2011; 106 (12) 2192-2199
    CrossrefPubMedGoogle Scholar
  • 5 Spanier B, Bruno MJ, Dijkgraaf MG. Incidence and mortality of acute and chronic pancreatitis in the Netherlands: a nationwide record-linked cohort study for the years 1995-2005. World J Gastroenterol 2013; 19 (20) 3018-3026
    CrossrefPubMedGoogle Scholar
  • 6 Lowenfels AB, Maisonneuve P, Cavallini G. et al; International Pancreatitis Study Group. Pancreatitis and the risk of pancreatic cancer. N Engl J Med 1993; 328 (20) 1433-1437
    CrossrefPubMedGoogle Scholar
  • 7 Etemad B, Whitcomb DC. Chronic pancreatitis: diagnosis, classification, and new genetic developments. Gastroenterology 2001; 120 (03) 682-707
    CrossrefPubMedGoogle Scholar
  • 8 Frulloni L, Gabbrielli A, Pezzilli R. et al; PanCroInfAISP Study Group. Chronic pancreatitis: report from a multicenter Italian survey (PanCroInfAISP) on 893 patients. Dig Liver Dis 2009; 41 (04) 311-317
    CrossrefPubMedGoogle Scholar
  • 9 Coté GA, Yadav D, Slivka A. et al; North American Pancreatitis Study Group. Alcohol and smoking as risk factors in an epidemiology study of patients with chronic pancreatitis. Clin Gastroenterol Hepatol 2011; 9 (03) 266-273 , quiz e27
    CrossrefPubMedGoogle Scholar
  • 10 Whitcomb DC, LaRusch J, Krasinskas AM. et al; Alzheimer's Disease Genetics Consortium. Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis. Nat Genet 2012; 44 (12) 1349-1354
    CrossrefPubMedGoogle Scholar
  • 11 Andriulli A, Botteri E, Almasio PL, Vantini I, Uomo G, Maisonneuve P. ad hoc Committee of the Italian Association for the Study of the Pancreas. Smoking as a cofactor for causation of chronic pancreatitis: a meta-analysis. Pancreas 2010; 39 (08) 1205-1210
    CrossrefPubMedGoogle Scholar
  • 12 Yadav D, Hawes RH, Brand RE. et al; North American Pancreatic Study Group. Alcohol consumption, cigarette smoking, and the risk of recurrent acute and chronic pancreatitis. Arch Intern Med 2009; 169 (11) 1035-1045
    CrossrefPubMedGoogle Scholar
  • 13 Warshaw AL, Richter JM, Schapiro RH. The cause and treatment of pancreatitis associated with pancreas divisum. Ann Surg 1983; 198 (04) 443-452
    CrossrefPubMedGoogle Scholar
  • 14 Bertin C, Pelletier AL, Vullierme MP. et al. Pancreas divisum is not a cause of pancreatitis by itself but acts as a partner of genetic mutations. Am J Gastroenterol 2012; 107 (02) 311-317
    CrossrefPubMedGoogle Scholar
  • 15 Whitcomb DC. North American Pancreatitis Study Group. Pancreatitis: TIGAR-O version 2 risk/etiology checklist with topic reviews, updates, and use primers. Clin Transl Gastroenterol 2019; 10 (06) e00027
    CrossrefPubMedGoogle Scholar
  • 16 Kimura W, Mössner J. Role of hypertriglyceridemia in the pathogenesis of experimental acute pancreatitis in rats. Int J Pancreatol 1996; 20 (03) 177-184
    CrossrefPubMedGoogle Scholar
  • 17 Aseervatham GS, Sivasudha T, Jeyadevi R, Arul Ananth D. Environmental factors and unhealthy lifestyle influence oxidative stress in humans: an overview. Environ Sci Pollut Res Int 2013; 20 (07) 4356-4369
    CrossrefPubMedGoogle Scholar
  • 18 Chen QY, DesMarais T, Costa M. Metals and mechanisms of carcinogenesis. Annu Rev Pharmacol Toxicol 2019; 59: 537-554
    CrossrefPubMedGoogle Scholar
  • 19 Weizman Z, Picard E, Barki Y, Moses S. Wilson's disease associated with pancreatitis. J Pediatr Gastroenterol Nutr 1988; 7 (06) 931-933
    CrossrefPubMedGoogle Scholar
  • 20 Kikuchi M, Hasegawa K, Handa I, Watabe M, Narisawa K, Tada K. Chronic pancreatitis in a child with glycogen storage disease type 1. Eur J Pediatr 1991; 150 (12) 852-853
    CrossrefPubMedGoogle Scholar
  • 21 Witt H, Luck W, Becker M. A signal peptide cleavage site mutation in the cationic trypsinogen gene is strongly associated with chronic pancreatitis. Gastroenterology 1999; 117 (01) 7-10
    CrossrefPubMedGoogle Scholar
  • 22 Chen JM, Kukor Z, Le Maréchal C. et al. Evolution of trypsinogen activation peptides. Mol Biol Evol 2003; 20 (11) 1767-1777
    CrossrefPubMedGoogle Scholar
  • 23 Geisz A, Hegyi P, Sahin-Tóth M. Robust autoactivation, chymotrypsin C independence and diminished secretion define a subset of hereditary pancreatitis-associated cationic trypsinogen mutants. FEBS J 2013; 280 (12) 2888-2899
    CrossrefPubMedGoogle Scholar
  • 24 Joergensen MT, Geisz A, Brusgaard K. et al. Intragenic duplication: a novel mutational mechanism in hereditary pancreatitis. Pancreas 2011; 40 (04) 540-546
    CrossrefPubMedGoogle Scholar
  • 25 Kereszturi E, Sahin-Tóth M. Intracellular autoactivation of human cationic trypsinogen mutants causes reduced trypsinogen secretion and acinar cell death. J Biol Chem 2009; 284 (48) 33392-33399
    CrossrefPubMedGoogle Scholar
  • 26 Chen JM, Raguenes O, Ferec C, Deprez PH, Verellen-Dumoulin C, Andriulli A. The A16V signal peptide cleavage site mutation in the cationic trypsinogen gene and chronic pancreatitis. Gastroenterology 1999; 117 (06) 1508-1509
    CrossrefPubMedGoogle Scholar
  • 27 Shibata T, Ogawa M, Matsuda K, Miyauchi K, Yamamoto T, Mori T. Purification and characterization of pancreatic secretory trypsin inhibitor in human gastric mucosa. Clin Chim Acta 1986; 159 (01) 27-36
    CrossrefPubMedGoogle Scholar
  • 28 Barkin JS, Fayne SD. Chronic pancreatitis: update 1986. Mt Sinai J Med 1986; 53 (05) 404-408
    PubMedGoogle Scholar
  • 29 Durbec JP, Sarles H. Multicenter survey of the etiology of pancreatic diseases. Relationship between the relative risk of developing chronic pancreaitis and alcohol, protein and lipid consumption. Digestion 1978; 18 (5–6): 337-350
    CrossrefPubMedGoogle Scholar
  • 30 Cheng SH, Gregory RJ, Marshall J. et al. Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis. Cell 1990; 63 (04) 827-834
    CrossrefPubMedGoogle Scholar
  • 31 Primhak RA, Tanner MS. Alpha-1 antitrypsin deficiency. Arch Dis Child 2001; 85 (01) 2-5
    CrossrefPubMedGoogle Scholar
  • 32 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 (02) 213-216
    CrossrefPubMedGoogle Scholar
  • 33 Witt H, Becker M. Genetics of chronic pancreatitis. J Pediatr Gastroenterol Nutr 2002; 34 (02) 125-136
    CrossrefPubMedGoogle Scholar
  • 34 Zhou J, Sahin-Tóth M. Chymotrypsin C mutations in chronic pancreatitis. J Gastroenterol Hepatol 2011; 26 (08) 1238-1246
    CrossrefPubMedGoogle Scholar
  • 35 Mayerle J, Sendler M, Hegyi E, Beyer G, Lerch MM, Sahin-Tóth M. Genetics, cell biology, and pathophysiology of pancreatitis. Gastroenterology 2019; 156 (07) 1951-1968.e1
    CrossrefPubMedGoogle Scholar
  • 36 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 (01) 78-82
    CrossrefPubMedGoogle Scholar
  • 37 Felderbauer P, Karakas E, Fendrich V, Lebert R, Bartsch DK, Bulut K. Multifactorial genesis of pancreatitis in primary hyperparathyroidism: evidence for “protective” (PRSS2) and “destructive” (CTRC) genetic factors. Exp Clin Endocrinol Diabetes 2011; 119 (01) 26-29
    Article in Thieme ConnectPubMedGoogle Scholar
  • 38 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 (08) 889-894
    CrossrefPubMedGoogle Scholar
  • 39 Sahin-Tóth M. Genetic risk in chronic pancreatitis: the misfolding-dependent pathway. Curr Opin Gastroenterol 2017; 33 (05) 390-395
    CrossrefPubMedGoogle Scholar
  • 40 Witt H, Beer S, Rosendahl J. et al. Variants in CPA1 are strongly associated with early onset chronic pancreatitis. Nat Genet 2013; 45 (10) 1216-1220
    CrossrefPubMedGoogle Scholar
  • 41 Nilsson J, Bläckberg L, Carlsson P, Enerbäck S, Hernell O, Bjursell G. cDNA cloning of human-milk bile-salt-stimulated lipase and evidence for its identity to pancreatic carboxylic ester hydrolase. Eur J Biochem 1990; 192 (02) 543-550
    CrossrefPubMedGoogle Scholar
  • 42 Lombardo D. Bile salt-dependent lipase: its pathophysiological implications. Biochim Biophys Acta 2001; 1533 (01) 1-28
    CrossrefPubMedGoogle Scholar
  • 43 Dalva M, El Jellas K, Steine SJ. et al. Copy number variants and VNTR length polymorphisms of the carboxyl-ester lipase (CEL) gene as risk factors in pancreatic cancer. Pancreatology 2017; 17 (01) 83-88
    CrossrefPubMedGoogle Scholar
  • 44 Fjeld K, Weiss FU, Lasher D. et al. A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis. Nat Genet 2015; 47 (05) 518-522
    CrossrefPubMedGoogle Scholar
  • 45 Van Itallie CM, Holmes J, Bridges A. et al. The density of small tight junction pores varies among cell types and is increased by expression of claudin-2. J Cell Sci 2008; 121 (Pt 3): 298-305
    CrossrefPubMedGoogle Scholar
  • 46 Meriläinen S, Mäkelä J, Anttila V. et al. Acute edematous and necrotic pancreatitis in a porcine model. Scand J Gastroenterol 2008; 43 (10) 1259-1268
    CrossrefPubMedGoogle Scholar
  • 47 Vezzoli G, Terranegra A, Arcidiacono T. et al. R990G polymorphism of calcium-sensing receptor does produce a gain-of-function and predispose to primary hypercalciuria. Kidney Int 2007; 71 (11) 1155-1162
    CrossrefPubMedGoogle Scholar
  • 48 Novis BH, Young GO, Bank S, Marks IN. Chronic pancreatitis and alpha-1-antitrypsin. Lancet 1975; 2 (7938): 748-749
    CrossrefPubMedGoogle Scholar
  • 49 Mihas AA, Hirschowitz BI. Alpha-antitrypsin and chronic pancreatitis. Lancet 1976; 2 (7993): 1032-1033
    CrossrefPubMedGoogle Scholar
  • 50 Haber PS, Wilson JS, McGarity BH, Hall W, Thomas MC, Pirola RC. Alpha 1 antitrypsin phenotypes and alcoholic pancreatitis. Gut 1991; 32 (08) 945-948
    CrossrefPubMedGoogle Scholar
  • 51 Busslinger M, Moschonas N, Flavell RA. Beta + thalassemia: aberrant splicing results from a single point mutation in an intron. Cell 1981; 27 (2, Pt 1): 289-298
    CrossrefPubMedGoogle Scholar
  • 52 Piperno A, Sampietro M, Pietrangelo A. et al. Heterogeneity of hemochromatosis in Italy. Gastroenterology 1998; 114 (05) 996-1002
    CrossrefPubMedGoogle Scholar
  • 53 Camaschella C, Roetto A, Calì A. et al. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet 2000; 25 (01) 14-15
    CrossrefPubMedGoogle Scholar
  • 54 del Rosario JF, Putnam PE, Orenstein DM. Chronic pancreatitis in a patient with cystic fibrosis and clinical pancreatic insufficiency. J Pediatr 1995; 126 (06) 951-952
    CrossrefPubMedGoogle Scholar
  • 55 Vassalli P. The pathophysiology of tumor necrosis factors. Annu Rev Immunol 1992; 10: 411-452
    CrossrefPubMedGoogle Scholar
  • 56 Yang Y, Wang X, Moore DR, Lightfoot SA, Huycke MM. TNF-α mediates macrophage-induced bystander effects through Netrin-1. Cancer Res 2012; 72 (20) 5219-5229
    CrossrefPubMedGoogle Scholar
  • 57 Liu Y, Ho RC, Mak A. Interleukin (IL)-6, tumour necrosis factor alpha (TNF-α) and soluble interleukin-2 receptors (sIL-2R) are elevated in patients with major depressive disorder: a meta-analysis and meta-regression. J Affect Disord 2012; 139 (03) 230-239
    CrossrefPubMedGoogle Scholar
  • 58 Iwamoto S, Iwai S, Tsujiyama K. et al. TNF-alpha drives human CD14+ monocytes to differentiate into CD70+ dendritic cells evoking Th1 and Th17 responses. J Immunol 2007; 179 (03) 1449-1457
    CrossrefPubMedGoogle Scholar
  • 59 Talar-Wojnarowska R, Gasiorowska A, Smolarz B, Romanowicz-Makowska H, Kulig A, Malecka-Panas E. Tumor necrosis factor alpha and interferon gamma genes polymorphisms and serum levels in pancreatic adenocarcinoma. Neoplasma 2009; 56 (01) 56-62
    CrossrefPubMedGoogle Scholar
  • 60 Zhong Y, Zou R, Cao J, Peng M. Glutathione S-transferase M1 and glutathione S-transferase T1 genotype in chronic pancreatitis: a meta-analysis. J Int Med Res 2015; 43 (01) 9-16
    CrossrefPubMedGoogle Scholar
  • 61 Manjari KS, Jyothy A, Kumar PS, Prabhakar B, Nallari P, Venkateshwari A. Association of matrix metalloproteinase-7 (-181A/G) promoter polymorphism in chronic pancreatitis. Indian J Med Res 2014; 140 (05) 609-615
    PubMedGoogle Scholar
  • 62 Shrikhande SV, Martignoni ME, Shrikhande M. et al. Comparison of histological features and inflammatory cell reaction in alcoholic, idiopathic and tropical chronic pancreatitis. Br J Surg 2003; 90 (12) 1565-1572
    CrossrefPubMedGoogle Scholar
  • 63 Noone PG, Zhou Z, Silverman LM, Jowell PS, Knowles MR, Cohn JA. Cystic fibrosis gene mutations and pancreatitis risk: relation to epithelial ion transport and trypsin inhibitor gene mutations. Gastroenterology 2001; 121 (06) 1310-1319
    CrossrefPubMedGoogle Scholar
  • 64 Schneider A, Larusch J, Sun X. et al. Combined bicarbonate conductance-impairing variants in CFTR and SPINK1 variants are associated with chronic pancreatitis in patients without cystic fibrosis. Gastroenterology 2011; 140 (01) 162-171
    CrossrefPubMedGoogle Scholar
  • 65 Maruyama K, Harada S, Yokoyama A. et al. Association analyses of genetic polymorphisms of GSTM1, GSTT1, NQO1, NAT2, LPL, PRSS1, PSTI, and CFTR with chronic alcoholic pancreatitis in Japan. Alcohol Clin Exp Res 2010; 34 (Suppl. 01) S34-S38
    PubMedGoogle Scholar
  • 66 Nencioni L, Pizza M, Bugnoli M. et al. Characterization of genetically inactivated pertussis toxin mutants: candidates for a new vaccine against whooping cough. Infect Immun 1990; 58 (05) 1308-1315
    CrossrefPubMedGoogle Scholar
  • 67 Zhong Y, Dong G, Luo H. et al. Induction of brain CYP2E1 by chronic ethanol treatment and related oxidative stress in hippocampus, cerebellum, and brainstem. Toxicology 2012; 302 (2–3): 275-284
    CrossrefPubMedGoogle Scholar
  • 68 Zhong Y, Cao J, Zou R, Peng M. Genetic polymorphisms in alcohol dehydrogenase, aldehyde dehydrogenase and alcoholic chronic pancreatitis susceptibility: a meta-analysis. Gastroenterol Hepatol 2015; 38 (07) 417-425
    PubMedGoogle Scholar
  • 69 Foster JR, Idle JR, Hardwick JP, Bars R, Scott P, Braganza JM. Induction of drug-metabolizing enzymes in human pancreatic cancer and chronic pancreatitis. J Pathol 1993; 169 (04) 457-463
    CrossrefPubMedGoogle Scholar
  • 70 Stamatoyannopoulos G, Chen SH, Fukui M. Liver alcohol dehydrogenase in Japanese: high population frequency of atypical form and its possible role in alcohol sensitivity. Am J Hum Genet 1975; 27 (06) 789-796
    PubMedGoogle Scholar
  • 71 Aguilar JS, Ochoa EL, De Robertis E. Reconstitution of solubilized atrial cholinergic muscarinic receptors in liposomes. Neurochem Res 1987; 12 (01) 83-91
    CrossrefPubMedGoogle Scholar