Gleiche Varianten, unterschiedlicher Verlauf: Genetik der chronischen Pankreatitis

Abstract

Multiple genetic associations with chronic pancreatitis have been identified. In cases with hereditary pancreatitis family history is reported and mostly distinct causative variants in cationic trypsinogen (PRSS1) are identified. Furthermore, variants in other genes of proteases and anti-proteases of the digestive enzyme cascade (SPINK1, CTRC, CPA1), are also associated with chronic pancreatitis. Interestingly, penetrance of associated variants as well as the disease course are variable. As such environmental factors like smoking may play an important role. Patients with chronic pancreatitis of unknown etiology should be offered genetic testing after referral to a pancreatic center.

Für die chronische Pankreatitis sind verschiedene genetische Assoziationen beschrieben. Bei der hereditären Pankreatitis liegen eine positive Familienanamnese und am häufigsten kausale Varianten im kationischen Trysinogen (PRSS1) vor. Neben diesen wurden weitere genetische Veränderungen in Proteasen und Anti-Proteasen (SPINK1, CTRC, CPA1) der Verdauungsenzymkaskade bei Patienten mit chronischer Pankreatitis als assoziiert beschrieben. Die Penetranz der genetischen Veränderungen, das heißt der klinische Verlauf der chronischen Pankreatitis ist variabel. Umweltfaktoren, wie zum Beispiel das Rauchen sind hierbei von Bedeutung. Bei Diagnosestellung einer chronischen Pankreatitis ungeklärter Ätiologie kann den Patienten eine genetische Analyse nach Vorstellung in einem Pankreaszentrum angeboten werden.

Schlüsselwörter

Chronische Pankreatitis - Genetik - hereditäre Pankreatitis - Varianten - PRSS1

Key words

chronic pancreatitis - genetics - hereditary pancreatitis - variants - PRSS1

• Literatur

• 1 Löhr M. Besselink M. Haas S. et al. UEG Evidence-based guidelines for the diagnosis and therapy of chronic pancreatitis: Harmonising pancreatitis across Europe (HaPanEU). United Europ Gastroenterol J 2017; . Online First January 16
• 2 Maisonneuve P. Lowenfels AB. Mullhaupt B. et al. Cigarette smoking accelerates progression of alcoholic chronic pancreatitis. Gut 2005; 54: 510-514
• 3 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: 582-592
• 4 Hoffmeister A. Mayerle J. Beglinger C. et al. S3–Consensus guidelines on definition, etiology, diagnosis and medical, endoscopic and surgical management of chronic pancreatitis German Society of Digestive and Metabolic Diseases (DGVS). Z Gastroenterol 2012; 50: 1176-1224
• 5 Szabó A. Sahin-Tóth M. Increased activation of hereditary pancreatitis-associated human cationic trypsinogen mutants in presence of chymotrypsin C. J Chem Biol 2012; 287: 20701-20710
• 6 Grocock CJ. Rebours V. Myriam N. et al. The variable phenotype of the p.A16V mutation of cationic trypsinogen (PRSS1) in pancreatitis families. Gut 2010; 59: 357363
• 7 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. Nature Genet 2012; 44: 1349-1354
• 8 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 Translat Gastroenterol 2015; 6: e68
• 9 Howes N. Greenhalf W. Stocken DD. et al. Cationic trypsinogen mutations and pancreatitis. Clin Lab Med 2005; 25: 39-59
• 10 Maisonneuve P. Lowenfels AB. Chronic pancreatitis and pancreatic cancer. Dig Dis 2002; 20: 32-37
• 11 Frøkjær JB. Olesen SS. Drewes AM. Fibrosis, atrophy, and ductal pathology in chronic pancreatitis are associated with pancreatic function but independent of symptoms. Pancreas 2013; 42: 1182-1187
• 12 Rosendahl J. Witt H. Szmola R. et al. Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. Nature Genet 2008; 40: 78-82
• 13 Witt H. Beer S. Rosendahl J. et al. Variants in CPA1 are strongly associated with early onset chronic pancreatitis. Nature Genet 2013; 45: 1216-1220
• 14 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. Nature Genet 2015; 47: 518-522