Genetics of pancreatitis

Current Opinion in Gastroenterology

Volumn 27, Issue 5, 2011, Pages 467-474

  Larusch, Jessica ^a   Whitcomb, David C ^a,b  

^a Hepatology and Nutrition   (United States)

^b UNIVERSITY OF PITTSBURGH   (United States)

Author keywords

CASR; CFTR; CTRC; cystic fibrosis; epistasis; pancreas; PRSS1; SPINK1; trypsin; trypsinogen

Indexed keywords

CHYMOTRYPSIN C; G PROTEIN COUPLED RECEPTOR; PROTEIN CASR; PROTEIN PRSS1; SERINE PROTEASE INHIBITOR KAZAL 1; SERINE PROTEINASE INHIBITOR; TRANSMEMBRANE CONDUCTANCE REGULATOR; TRYPSIN; UNCLASSIFIED DRUG;

ACUTE PANCREATITIS; CHRONIC PANCREATITIS; ENVIRONMENTAL FACTOR; GENE; GENE INTERACTION; GENE MUTATION; GENETIC EPISTASIS; GENETIC RISK; GENETIC SUSCEPTIBILITY; HEREDITY; HUMAN; RECURRENT DISEASE; REVIEW;

CARRIER PROTEINS; CHYMOTRYPSIN; CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR; EPISTASIS, GENETIC; GENETIC PREDISPOSITION TO DISEASE; HUMANS; PANCREATITIS, CHRONIC; RECEPTORS, CALCIUM-SENSING; RECURRENCE; TRYPSIN;

EID: 80051775848     PISSN: 02671379     EISSN: 15317056     Source Type: Journal    
DOI: 10.1097/MOG.0b013e328349e2f8     Document Type: Review

References (49)

1. WhitcombDC,GorryMC, PrestonRA, et al.Hereditarypancreatitis iscaused by a mutation in the cationic trypsinogen gene. Nature Genet 1996; 14:141-145.
2. Whitcomb DC. Hereditary pancreatitis: New insights into acute and chronic pancreatitis. Gut 1999; 45:317-322.
3. Gorry MC, Gabbaizedeh D, Furey W, et al. Mutations in the cationic trypsinogen gene are associated with recurrent acute and chronic pancreatitis. Gastroenterology 1997; 113:1063-1068.
4. Grocock CJ, Rebours V, Delhaye MN, et al. The variable phenotype of the p.A16 V mutation of cationic trypsinogen (PRSS1) in pancreatitis families. Gut 2010; 59:357-363. Ten European families with pancreatic disease and the rare PRSS1 mutation A16V were analyzed in this study. Whereas there were no identified mutations in known modifying genes (SPINK1, CFTR, CTRC) the penetrance and clinical consequence of this trypsin mutation varied widely between families, suggesting that A16VPRSS1 may contribute to disease in a multigenic fashion, as opposed to autosomal dominance, by which other trypsin mutations (i.e. R122H) are known to act.
5. 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; 25:213-216.
6. Pfutzer RH, Barmada MM, Brunskill AP, et al. SPINK1/PSTI polymorphisms act as disease modifiers in familial and idiopathic chronic pancreatitis. Gastroenterology 2000; 119:615-623.
7. Khalid A, Finkelstein S, Thompson B, et al. A 93 year old man with the PRSS1 R122H mutation, low SPINK1 expression, and no pancreatitis: Insights into phenotypic nonpenetrance. Gut 2006; 55:728-731.
8. 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; 50:675-681.
9. 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 metaanalysis. PLoS One 2008; 3:e2003.
10. Kiraly O, Boulling A, Witt H, et al. Signal peptide variants that impair secretion of pancreatic secretory trypsin inhibitor (SPINK1) cause autosomal dominant hereditary pancreatitis. Hum Mutat 2007; 28:469-476.
11. Kiraly O, Wartmann T, Sahin-Toth M. Missense mutations in pancreatic secretory trypsin inhibitor (SPINK1) cause intracellular retention and degradation. Gut 2007; 56:1433-1438.
12. Kereszturi E, Kiraly O, Sahin-Toth M. Minigene analysis of intronic variants in common SPINK1 haplotypes associated with chronic pancreatitis. Gut 2009; 58:545-549.
13. Sharer N, Schwarz M, Malone G, et al. Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. N Engl J Med 1998; 339:645-652.
14. Cohn JA, Friedman KJ, Noone PG, et al. Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. N Engl J Med 1998; 339:653-658.
15. Park HW, Nam JH, Kim JY, et al. Dynamic regulation of CFTR bicarbonate permeability by [Cl-]i and its role in pancreatic bicarbonate secretion. Gastroenterology 2010; 139:620-631. Park et al. demonstrated that a dynamic increase in the CFTR HCO3 permeability by intracellular Cl concentration sensitive mechanisms plays a pivotal role in pancreatic HCO3 secretion and is regulated by the WNK1-OSR1/SPAK pathway.
16. Ravnik-Glavac M, Glavac D, di Sant Agnese P, et al. Cystic fibrosis gene mutations detected in hereditary pancreatitis. Pflugers Arch Eur J Physiol 1996; 431 (6 Suppl 2):R191-R192.
17. Cohn JA, Bornstein JD, Jowell PJ, et al. Molecular pathogenesis of chronic pancreatitis associated with abnormal CFTR genotypes. Gastroenterology 2000; 118:A159.
18. Schneider A, Larusch J, Sun X, et al. Combined bicarbonate conductanceimpairing variants in CFTR and SPINK1 variants are associated with chronic pancreatitis in patients without cystic fibrosis. Gastroenterology 2011; 140:162-171. SPINK1 and CFTR sequence analysis of familial and idiopathic chronic pancreatitis patients revealed that transheterozygous inheritance of SPINK1 and CFTR mutations were frequent in chronic pancreatitis and rarely found in healthy controls. Moreover, the R75Q variant of CFTR was identified to be overrepresented in patients, previously thought to be a benign variant, it displayed reduced bicarbonate conductance but normal chloride conductance, the first and only functional evidence for a pancreatic specific CFTR mutation.
19. Collawn JF, Fu L, Bebok Z. Targets for cystic fibrosis therapy: Proteomic analysis and correction of mutant cystic fibrosis transmembrane conductance regulator. Expert Rev Proteomics 2010; 7:495-506.
20. Szmola R, Sahin-Toth M. Chymotrypsin C (caldecrin) promotes degradation of human cationic trypsin: Identity with Rinderknecht's enzyme Y. Proc Natl Acad Sci USA 2007; 104:11227-11232.
21. 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.
22. Masson E, Chen JM, Scotet V, et al. Association of rare chymotrypsinogen C (CTRC) gene variations in patients with idiopathic chronic pancreatitis. Hum Genet 2008; 123:83-91.
23. Riccardi D, Brown EM. Physiology and pathophysiology of the calciumsensing receptor in the kidney. Am J Physiol Renal Physiol 2010; 298: F485-F499.
24. Bruce JI, Yang X, Ferguson CJ, et al. Molecular, functional identification of a Ca2+(polyvalent cation)-sensing receptor in rat pancreas. J Biol Chem 1999; 274:20561-20568.
25. Varghese J, Rich T, Jimenez C. Benign familial hypocalciuric hypercalcemia. Endocr Pract 2011; 1-16.
26. 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; 71:1155-1162.
27. Racz GZ, Kittel A, Riccardi D, et al. Extracellular calcium sensing receptor in human pancreatic cells. Gut 2002; 51:705-711.
28. Pidasheva S, D'Souza-Li L, Canaff L, et al. CASRdb: Calcium-sensing receptor locus-specific database for mutations causing familial (benign) hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. Hum Mutat 2004; 24:107-111.
29. Falchetti A, Marini F, Giusti F, et al. DNA-based test: When and why to apply it to primary hyperparathyroidism clinical phenotypes. J Intern Med 2009; 266:69-83.
30. Felderbauer P, Karakas E, Fendrich V, et al. Pancreatitis in primary hyperparathyroidism- related hypercalcaemia is not associated with mutations in the CASR gene. Exp Clin Endocrinol Diabetes 2007; 115:527-529.
31. Felderbauer P, Hoffmann P, Einwachter H, et al. A novel mutation of the calcium sensing receptor gene is associated with chronic pancreatitis in a family with heterozygous SPINK1 mutations. BMC Gastroenterol 2003; 3:34.
32. Baudry C, Rebours V, Houillier P, et al. Recurrent acute pancreatitis caused by association of a novel mutation of the calcium-sensing receptor gene and a heterozygous mutation of the SPINK1 gene. Pancreas 2010; 39:420-421. Baudry et al. describe a case of a recurrent acute pancreatitis patient with temporal hypercalcemia and transheterozygous mutations in SPINK1 (IVS3+2TtoC) and CASR (P682L).
33. Felderbauer P, Klein W, Bulut K, et al. Mutations in the calcium-sensing receptor: A new genetic risk factor for chronic pancreatitis? Scand J Gastroenterol 2006; 41:343-348.
34. Muddana V, Lamb J, Greer JB, et al. Association between calcium sensing receptor gene polymorphisms, chronic pancreatitis in a US population: Role of serine protease inhibitor Kazal 1 type, alcohol. World J Gastroenterol 2008; 14:4486-4491.
35. Murugaian EE, Premkumar RM, Radhakrishnan L, Vallath B. Novel mutations in the calcium sensing receptor gene in tropical chronic pancreatitis in India. Scand J Gastroenterol 2008; 43:117-121.
36. Scillitani A, Guarnieri V, De Geronimo S, et al. Blood ionized calcium is associated with clustered polymorphisms in the carboxyl-terminal tail of the calcium-sensing receptor. J Clin Endocrinol Metab 2004; 89:5634-5638.
37. Yamauchi M, Sugimoto T, Yamaguchi T, et al. Association of polymorphic alleles of the calcium-sensing receptor gene with the clinical severity of primary hyperparathyroidism. Clin Endocrinol (Oxf) 2001; 55:373-379.
38. Vezzoli G, Tanini A, Ferrucci L, et al. Influence of calcium-sensing receptor gene on urinary calcium excretion in stone-forming patients. J Am Soc Nephrol 2002; 13:2517-2523.
39. Yadav D, Hawes RH, Brand RE, et al. Alcohol consumption, cigarette smoking, and the risk of recurrent acute and chronic pancreatitis. Arch Intern Med 2009; 169:1035-1045.
40. Stepanchick A, McKenna J, McGovern O, et al. Calcium sensing receptor mutations implicated in pancreatitis and idiopathic epilepsy syndrome disrupt an arginine-rich retention motif. Cell Physiol Biochem 2010; 26:363-374. Stepanchick et al. determined the biological consequence of pancreatitis associated CaSR mutations in arginine rich regions to be increased targeting of the protein to the plasma membrane and subsequent altered calcium signaling.
41. 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; 90:1565-1572.
42. Noone PG, Zhou Z, Silverman LM, et al. Cystic fibrosis gene mutations and pancreatitis risk: Relation to epithelial ion transport and trypsin inhibitor gene mutations. Gastroenterology 2001; 121:1310-1319.
43. da Costa MZ, Guarita DR, Ono-Nita SK, et al. CFTR polymorphisms in patients with alcoholic chronic pancreatitis. Pancreatology 2009; 9:173-181.
44. 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 1):S34-S38.
45. Kitahara K, Kawa S, Katsuyama Y, et al. Microsatellite scan identifies new candidate genes for susceptibility to alcoholic chronic pancreatitis in Japanese patients. Dis Markers 2008; 25:175-180.
46. Cichoz-Lach H, Partycka J, Nesina I, et al. Genetic polymorphism of alcohol dehydrogenase 3 in alcohol liver cirrhosis and in alcohol chronic pancreatitis. Alcohol Alcohol 2006; 41:14-17.
47. Shimosegawa T, Kume K, Masamune A. SPINK1, ADH2, and ALDH2 gene variants and alcoholic chronic pancreatitis in Japan. J Gastroenterol Hepatol 2008; 23 (Suppl 1):S82-S86.
48. McWilliams RR, Petersen GM, Rabe KG, et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations and risk for pancreatic adenocarcinoma. Cancer 2010; 116:203-209.
49. Yadav D, Slivka A, Sherman S, et al. Smoking is underrecognized as a risk factor for chronic pancreatitis. Pancreatology 2011; 10:713-719. The North American Pancreatitis Study reports that although smoking is a recognized risk factor for pancreatitis, the reporting of smoking as a risk factor by physicians is highly variable and as low as 10% even for patients who self-report as current smokers.