Insights into the Genetic Risk Factors for the Development of Pancreatic Disease

Overview

Journal Therap Adv Gastroenterol

Publisher Sage Publications

Specialty Gastroenterology

Date 2017 Mar 2

PMID 28246549

Citations 10

Authors

Zachary Zator

David C Whitcomb

Affiliations

Soon will be listed here.

Abstract

Diseases of the exocrine pancreas such as recurrent acute pancreatitis (RAP), chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC) represent syndromes defined according to traditional clinicopathologic criteria. The failure of traditional approaches to identify primary mechanisms underlying these progressive disorders illustrates a greater problem of failure of the germ theory of disease for complex disorders. Multiple genetic discoveries and new complex disease models force consideration of a new paradigm of 'precision medicine', requiring a new mechanistic definition of CP. Recognizing the advances in understanding complex gene and environment interactions, as well as the development of new strategies that limit or prevent the development of devastating end-stage diseases of the pancreas may lead to substantial improvements in patient care.

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References

Whitcomb D, LaRusch J, Krasinskas A, Klei L, Smith J, Brand R . Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis. Nat Genet. 2012; 44(12):1349-54. PMC: 3510344. DOI: 10.1038/ng.2466. View

Sarner M, Cotton P . Classification of pancreatitis. Gut. 1984; 25(7):756-9. PMC: 1432589. DOI: 10.1136/gut.25.7.756. View

Fortunato F, Deng X, Gates L, McClain C, Bimmler D, Graf R . Pancreatic response to endotoxin after chronic alcohol exposure: switch from apoptosis to necrosis?. Am J Physiol Gastrointest Liver Physiol. 2005; 290(2):G232-41. DOI: 10.1152/ajpgi.00040.2005. View

Ammann R, Heitz P, Kloppel G . Course of alcoholic chronic pancreatitis: a prospective clinicomorphological long-term study. Gastroenterology. 1996; 111(1):224-31. DOI: 10.1053/gast.1996.v111.pm8698203. View

Park H, Nam J, Kim J, Namkung W, Yoon J, Lee J . Dynamic regulation of CFTR bicarbonate permeability by [Cl-]i and its role in pancreatic bicarbonate secretion. Gastroenterology. 2010; 139(2):620-31. DOI: 10.1053/j.gastro.2010.04.004. View

Lin Y, Tamakoshi A, Hayakawa T, Ogawa M, Ohno Y . Cigarette smoking as a risk factor for chronic pancreatitis: a case-control study in Japan. Research Committee on Intractable Pancreatic Diseases. Pancreas. 2000; 21(2):109-14. DOI: 10.1097/00006676-200008000-00001. View

Sharma A, Tao X, Gopal A, Ligon B, Andrade-Gordon P, Steer M . Protection against acute pancreatitis by activation of protease-activated receptor-2. Am J Physiol Gastrointest Liver Physiol. 2004; 288(2):G388-95. DOI: 10.1152/ajpgi.00341.2004. View

Brand R, Lerch M, Rubinstein W, Neoptolemos J, Whitcomb D, Hruban R . Advances in counselling and surveillance of patients at risk for pancreatic cancer. Gut. 2007; 56(10):1460-9. PMC: 2000231. DOI: 10.1136/gut.2006.108456. View

Shelton C, Whitcomb D . Genetics and treatment options for recurrent acute and chronic pancreatitis. Curr Treat Options Gastroenterol. 2014; 12(3):359-71. PMC: 4246502. DOI: 10.1007/s11938-014-0022-y. View

10.

Yadav D, Eigenbrodt M, Briggs M, Williams D, Wiseman E . Pancreatitis: prevalence and risk factors among male veterans in a detoxification program. Pancreas. 2007; 34(4):390-8. DOI: 10.1097/mpa.0b013e318040b332. View

11.

Witt H, Luck W, Hennies H, Classen M, Kage A, Lass U . Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat Genet. 2000; 25(2):213-6. DOI: 10.1038/76088. View

12.

Paliwal S, Bhaskar S, Mani K, Reddy D, Venkat Rao G, Singh S . Comprehensive screening of chymotrypsin C (CTRC) gene in tropical calcific pancreatitis identifies novel variants. Gut. 2012; 62(11):1602-6. DOI: 10.1136/gutjnl-2012-302448. View

13.

Syngal S, Brand R, Church J, Giardiello F, Hampel H, Burt R . ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 2015; 110(2):223-62. PMC: 4695986. DOI: 10.1038/ajg.2014.435. View

14.

Talamini G, Bassi C, Falconi M, Sartori N, Salvia R, Rigo L . Alcohol and smoking as risk factors in chronic pancreatitis and pancreatic cancer. Dig Dis Sci. 1999; 44(7):1303-11. DOI: 10.1023/a:1026670911955. View

15.

Nordback I, Pelli H, Lappalainen-Lehto R, Sand J . Is it long-term continuous drinking or the post-drinking withdrawal period that triggers the first acute alcoholic pancreatitis?. Scand J Gastroenterol. 2005; 40(10):1235-9. DOI: 10.1080/00365520510023413. View

16.

Raeder H, Johansson S, Holm P, Haldorsen I, Mas E, Sbarra V . Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction. Nat Genet. 2005; 38(1):54-62. DOI: 10.1038/ng1708. View

17.

Talamini G, Bassi C, Falconi M, Sartori N, Vaona B, Bovo P . Smoking cessation at the clinical onset of chronic pancreatitis and risk of pancreatic calcifications. Pancreas. 2007; 35(4):320-6. DOI: 10.1097/mpa.0b013e31812e965e. View

18.

Whitcomb D, Frulloni L, Garg P, Greer J, Schneider A, Yadav D . Chronic pancreatitis: An international draft consensus proposal for a new mechanistic definition. Pancreatology. 2016; 16(2):218-24. PMC: 6042966. DOI: 10.1016/j.pan.2016.02.001. View

19.

Giri A, Midha S, Banerjee P, Agrawal A, Mehdi S, Dhingra R . Common Variants in CLDN2 and MORC4 Genes Confer Disease Susceptibility in Patients with Chronic Pancreatitis. PLoS One. 2016; 11(1):e0147345. PMC: 4731142. DOI: 10.1371/journal.pone.0147345. View

20.

Kereszturi E, Szmola R, Kukor Z, Simon P, Weiss F, Lerch M . Hereditary pancreatitis caused by mutation-induced misfolding of human cationic trypsinogen: a novel disease mechanism. Hum Mutat. 2009; 30(4):575-82. PMC: 2663013. DOI: 10.1002/humu.20853. View