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© Borgis - Postępy Nauk Medycznych 3/2011, s. 186-192
*Jonas Rosendahl, Joachim Mössner
Genetyka przewlekłego zapalenia trzustki – Nowe aspekty?
Genetics of Chronic Pancreatitis – New Aspects?
Department for Internal Medicine, Neurology and Dermatology, Division of Gastroenterology and Rheumatology, Universitätsklinikum Leipzig AöR
Head of Department: prof. Joachim Mössner
Streszczenie
Piętnaście lat temu, odkrycie mutacji genu trypsynogenu kationowego (PRSS1) u pacjentów z dziedzicznym przewlekłym zapaleniem trzustki poparło hipotezę Hansa Chiari sugerującą, że przewlekłe zapalenie trzustki jest wynikiem samotrawienia trzustki oraz stworzyło fundament pod przyszłe badania naukowe tego zagadnienia. Podejrzenie istnienia genetycznego podłoża przewlekłego zapalenia trzustki zostało zasugerowane w 1952 roku przez Comfort i Steinberg, lecz dopiero po 44. latach zidentyfikowano pierwsze powiązanie genetyczne w tej chorobie. Następnie, badania koncentrowały się na proteazach i antyproteazach funkcjonujących w kaskadzie enzymów trawiennych, co doprowadziło do zidentyfikowania inhibitora proteaz serynowych (Kazal type 1, SPINK1) jako kolejnego genu związanego z zapaleniem trzustki. Obok kaskady enzymów trawiennych, gen regulatorowy odpowiedzialny za mukowiscydozę (transmembrane conductance regulator gene, CFTR) badany był przez dwie grupy badaczy, które stwierdziły częstsze występowanie mutacji genu CFTR u pacjentów z przewlekłym zapaleniem trzustki. Stymulacją do tych badań była mukowiscydoza, w której 1-2% pacjentów towarzyszy przewlekłe zapalenie trzustki. W ciągu ostatnich pięciu lat pojawiły się nowe aspekty w dziedzinie genetyki przewlekłego zapalenia trzustki. Warianty receptora rozpoznającego wapń (calcium sensing receptor, CASR) wydają się mieć znaczenie w patogenezie przewlekłego zapalenia trzustki u nosicieli SPINK1 p.N34S. Tryplikacja i duplikacja locus genu trypsynogenu jest zupełnie nowym mechanizmem wywołującym chorobę, predysponującym do przewlekłego zapalenia trzustki poprzez tzw. efekt dawkowania genu. Identyfikacja chymotrypsyny C (CTRC) jako zagadkowego Enzymu Y, opisanego przez Rinderknechta ponad 20 lat temu, wskazała kolejny gen kandydujący. Badania CTRC wykazały małą penetrację wariantów z utratą funkcji, które zmniejszają wydzielanie lub aktywność CTRC i przez to przyczyniają się do rozwoju choroby. Podsumowując, wyniki ostatnich badań dodatkowo wspierają znaczenie równowagi w kaskadzie enzymów trawiennych, z trypsyną odgrywającą kluczową rolę. Dalsze badania w tej dziedzinie, stymulowane hipotezami oraz niezwiązane z hipotezami, wyłonią dodatkowe geny skojarzone z przewlekłym zapaleniem trzustki.
Summary
Fifteen years ago the discovery of a mutation of the cationic trypsinogen gene (PRSS1) in patients with hereditary chronic pancreatitis supported Hans Chiari’s theory that chronic pancreatitis is the result of autodigestion of the pancreas and depicted the fundament for further research in this field. A genetic basis for chronic pancreatitis had to be assumed in a pedigree described by Comfort and Steinberg already in 1952 it needed additional 44 years to identify this first genetic association. Thereafter, research had its focus on proteases and anti-proteases that are assembled in the digestive enzyme cascade, an approach that identified serine protease inhibitor, Kazal type 1 (SPINK1) as another pancreatitis gene. Aside the digestive enzyme cascade, the cystic fibrosis transmembrane conductance regulator gene (CFTR) that is responsible for Cystic Fibrosis, was investigated by two groups and both found an enrichment of CFTR variants in patients with chronic pancreatitis. Support for this investigation came from Cystic Fibrosis, where 1-2% of patients suffer from chronic pancreatitis. New aspects in the field of genetics in chronic pancreatitis emerged in the last five years. A variant of anionic trypsinogen (PRSS2) was found to be overrepresented in controls and protects against chronic pancreatitis. Additionally, variants of the calcium sensing receptor (CASR) seem to influence the pathogenesis of chronic pancreatitis in SPINK1 p.N34S carriers. Triplication and duplication of the trypsinogen locus represents a completely new disease causing mechanism that predisposes to chronic pancreatitis by a so-called gene dosage effect. Identification of chymotrypsin C (CTRC) as the enigmatic Enzyme Y described by Rinderknecht over 20 years ago displayed another reasonable candidate gene. Investigations of CTRC found low penetrance loss of function variants that diminish secretion and/or activity of CTRC and thereby contribute to the development of the disease. Taken together recent data further support the importance of a balanced digestive enzyme cascade in that trypsin captures a key role. Further research in this field will yield additional associated genes by hypothesis-driven and hypothesis free approaches.



Introduction
Chronic Pancreatitis (CP) is a progressive inflammatory disease of the pancreas leading to permanent impairment of pancreatic exocrine and endocrine function that can result in maldigestion and diabetes mellitus (1). Certainly, one of the most displeasing characteristics of CP are recurring attacks of acute abdominal pain that in some patients pass into a state of chronic pain often hindering patients to participate in a normal working life (2). In the western world the most predominant underlying cause is chronic alcohol abuse. Notably, only about five percent of chronic alcoholics develop CP. Aside chronic alcohol abuse several other factors such as nicotine, hypercalcemia, drugs, trauma and genetic alterations underlie CP. Over a century ago Hans Chiari postulated that chronic pancreatitis is the result of autodigestion of the pancreas, a thesis that is now again supported by genetic studies and functional analyses of genetic variants conducted within the last fifteen years (3). The first pedigree of a family with inherited CP was described in 1952 by Comfort and Steinberg illustrating the influence of genetic alterations that may contribute to the pathogenesis of CP (4). Thereafter, in the end 44 years were necessary until the p.R122H variant of the cationic trypsinogen (PRSS1) was identified in patients with hereditary CP (5). This finding was fundamental for a search for further genetic alterations in CP and also highlighted the importance of a balanced digestive enzyme cascade. In the following years research focused on proteases and anti-proteases that participate in this digestive enzyme cascade as well as on the CFTR gene whose major genetic alterations are responsible for Cystic Fibrosis. Further, “milder” genetic alterations of CFTR were associated with CP. In this rather compact review our we focus on the latest findings in the field of genetics in CP and former findings like association of PRSS1, CFTR and SPINK1 variants are only briefly discussed.
Cationic Trypsinogen (PRSS1) and Hereditary Chronic Pancreatitis
Hereditary CP, an autosomal dominant disease with a clinical penetrance rate of about 60-70% is a very rare form of chronic pancreatitis. The clinical course is different from that in alcoholic CP, since it encompasses an earlier onset and has a slower progression. However, morphological features and laboratory findings do not differ as well as given treatment opportunities. After the first description of the p.R122H variant several other rare variants were found in the PRSS1 gene (6 and references within). Most of the variants seem to cause premature trypsinogen activation in vitro with the consequence of an overweight of proteases since trypsin is able to activate the digestive enzyme cascade. This ssumption was further supported by transgenic animal models that express R122H mutated trypsinogen, because in these animal models elevated serum levels of lipase and amylase were observed (7, 8). However, definite histological changes resembling CP in humans were only found after repetitive supramaximal stimulations with caerulein. However, taken together, functional data in vitro and in vivo support the theory that a disarrangement of the balance between trypsin and its inhibitors in favour of more protease activity is responsible for the development of CP. An important question for the clinician as well as for the patient is whether patients with hereditary CP have a higher risk for the development of pancreatic cancer. Compared to patients with alcoholic CP who have a 20-fold increased lifetime risk of pancreatic cancer the lifetime risk is about 50-fold in patients with hereditary CP (9, 10). In our cohort from Leipzig 3 out of 101 patients with hereditary CP (carrier of the p.R122H mutation) developed pancreatic cancer and this corresponds to a rate of about 1 per 1200 person years among carriers of this mutation (11). In conclusion, the risk to develop pancreatic cancer is elevated in patients with hereditary CP, but the relative risk increase is not unambigously defined so far. Since cigarette smoking is a further evident risk factor for the development of pancreatic cancer, patients with hereditary CP should be strongly encouraged not to smoke (12).
CFTR variants in Chronic Pancreatitis
The role of CFTR variants in CP seems to be the most complex chapter of genetics in CP. This is on the one hand due to the variety of described CFTR variants and on the other hand due to the multifaceted functional consequences of some variants that in many cases are poorly understood so far. Moreover, it seems reasonable that CFTR variants alone will not lead to the development of CP. However, a rather complex interaction of variants in previously described genes and so far unkown low-risk genes will predispose to CP. Noteworthy, it seems appropriate to characterize patients with two CFTR variants without other unequivocal aspects of CF as patients with an “atypical” form of CF or as a CFTR-related disorder and this complex issue was profoundly discussed in a recent consensus conference (13).
Cystic fibrosis is an autosomal recessive disorder with an incidence in Caucasians of approximately 1 in 2500 live births. In 1989, CFTR was identified as the underlying gene. Since 1-2% of patients with CF suffer from CP it was a logical step to investigate CFTR in CP and in 1998 Sharer and colleagues and Cohn and colleagues were able to show an association of CFTR variants with CP that was replicated thereafter (14-23). According to their effect CFTR variants are divided in five or six classes (I-V/VI) (24, 25). In cystic fibrosis, the most common mutation is F508del, accounting for approximately 66% of all mutated alleles (26). In CP the distribution of CFTR variants does not resemble the distribution found in CF. Most of all rare and mild CFTR variants (class IV-VI) that are found in CP are only seldomly described in CF or congenital aplasia of the vas deferens (CBAVD). Consequently, it was postulated that compound heterozygous CFTR carriers have a distinct elevated risk for the development of chronic pancreatitis, which is even higher when an additional SPINK1 variant is present (27, 28).
SPINK1 variants in Chronic Pancreatitis

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otrzymano: 2011-01-10
zaakceptowano do druku: 2011-02-22

Adres do korespondencji:
*Jonas Rosendahl
University of Leipzig
Department for Internal Medicine, Neurology and Dermatology
Division of Gastroenterology and Rheumatology
Universitätsklinikum Leipzig AöR
Liebigstrasse 20, D-04103 Leipzig, Germany
tel.: +49-341-9713223, fax: +49-341-9712209
e-mail: jonas.rosendahl@medizin.uni-leipzig.de

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