Variants in CPA1 are strongly associated with early onset chronic pancreatitis
Heiko Witt,Sebastian Beer,Jonas Rosendahl,Jian-Min Chen,Jian-Min Chen,Giriraj R. Chandak,Atsushi Masamune,Melinda Bence,Richárd Szmola,Richárd Szmola,Grzegorz Oracz,Milan Macek,Eesh Bhatia,Sandra Steigenberger,Denise Lasher,Florence Bühler,Catherine Delaporte,Johanna Tebbing,Maren Ludwig,Claudia Pilsak,Karolin Saum,Peter Bugert,Emmanuelle Masson,Emmanuelle Masson,Sumit Paliwal,Seema Bhaskar,Agnieszka Sobczynska-Tomaszewska,Daniel Bak,Ivan Balascak,Gourdas Choudhuri,D. Nageshwar Reddy,G Venkat Rao,Varghese Thomas,Kiyoshi Kume,Eriko Nakano,Yoichi Kakuta,Tooru Shimosegawa,Lukasz Durko,András Szabó,Andrea Schnúr,Andrea Schnúr,Péter Hegyi,Zoltán Rakonczay,Roland H. Pfützer,Alexander Schneider,David A. Groneberg,Markus Braun,Hartmut Schmidt,Ulrike Witt,Helmut Friess,Hana Algül,Olfert Landt,Markus Schuelke,Renate Krüger,Bertram Wiedenmann,Frank Schmidt,Klaus Peter Zimmer,Peter Kovacs,Michael Stumvoll,Matthias Blüher,Thomas Müller,Andreas R. Janecke,Niels Teich,Robert Grützmann,Hans Ulrich Schulz,Joachim Mössner,Volker Keim,Matthias Löhr,Claude Férec,Claude Férec,Miklós Sahin-Tóth +70 more
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TLDR
The mechanism by which CPA1 variants confer increased pancreatitis risk may involve misfolding-induced endoplasmic reticulum stress rather than elevated trypsin activity, as is seen with other genetic risk factors for this disease.Abstract:
Chronic pancreatitis is an inflammatory disorder of the pancreas. We analyzed CPA1, encoding carboxypeptidase A1, in subjects with nonalcoholic chronic pancreatitis (cases) and controls in a German discovery set and three replication sets. Functionally impaired variants were present in 29/944 (3.1%) German cases and 5/3,938 (0.1%) controls (odds ratio (OR) = 24.9, P = 1.5 × 10(-16)). The association was strongest in subjects aged ≤ 10 years (9.7%; OR = 84.0, P = 4.1 × 10(-24)). In the replication sets, defective CPA1 variants were present in 8/600 (1.3%) cases and 9/2,432 (0.4%) controls from Europe (P = 0.01), 5/230 (2.2%) cases and 0/264 controls from India (P = 0.02) and 5/247 (2.0%) cases and 0/341 controls from Japan (P = 0.013). The mechanism by which CPA1 variants confer increased pancreatitis risk may involve misfolding-induced endoplasmic reticulum stress rather than elevated trypsin activity, as is seen with other genetic risk factors for this disease.read more
Citations
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Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium
Michael Goggins,Kasper A. Overbeek,Randall E. Brand,Sapna Syngal,Marco Del Chiaro,Detlef K. Bartsch,Claudio Bassi,Alfredo Carrato,James J. Farrell,Elliot K. Fishman,Paul Fockens,Thomas M. Gress,Jeanin E. van Hooft,Ralph H. Hruban,Fay Kastrinos,Fay Kastrinos,Allison Klein,Anne Marie Lennon,Aimee L. Lucas,Walter G. Park,Anil K. Rustgi,Diane M. Simeone,Elena M. Stoffel,Hans F. A. Vasen,Djuna L. Cahen,Marcia I. Canto,Marco J. Bruno +26 more
TL;DR: Pancreatic surveillance is recommended for selected high-risk individuals to detect early pancreatic cancer and its high-grade precursors, but should be performed in a research setting by multidisciplinary teams in centres with appropriate expertise.
Journal ArticleDOI
Whole genome sequencing defines the genetic heterogeneity of familial pancreatic cancer
Nicholas J. Roberts,Alexis L. Norris,Gloria M. Petersen,Melissa L. Bondy,Randall E. Brand,Steven Gallinger,Robert C. Kurtz,Sara H. Olson,Anil K. Rustgi,Ann G. Schwartz,Elena M. Stoffel,Sapna Syngal,George Zogopoulos,Syed Z. Ali,Jennifer E. Axilbund,Kari G. Chaffee,Yun-Ching Chen,Michele L. Cote,Erica J. Childs,Christopher Douville,Fernando S. Goes,Joseph M. Herman,Christine A. Iacobuzio-Donahue,Melissa Kramer,Alvin Makohon-Moore,Richard W. McCombie,K. Wyatt McMahon,Noushin Niknafs,Jennifer Parla,Mehdi Pirooznia,James B. Potash,Andrew D. Rhim,Andrew D. Rhim,Alyssa L. Smith,Yuxuan Wang,Christopher L. Wolfgang,Laura D. Wood,Peter P. Zandi,Michael Goggins,Rachel Karchin,James R. Eshleman,Nickolas Papadopoulos,Kenneth W. Kinzler,Bert Vogelstein,Ralph H. Hruban,Alison P. Klein +45 more
TL;DR: It is demonstrated that the genetic underpinning of inherited pancreatic cancer is highly heterogeneous, which has significant implications for the management of patients with familial Pancreatic cancer and for the identification of susceptibility genes in other common cancer types.
Journal ArticleDOI
Diagnosis and Management of Chronic Pancreatitis: A Review.
TL;DR: Treatment consists primarily of alcohol and smoking cessation, pain control, replacement of pancreatic insufficiency, or mechanical drainage of obstructed pancreatic ducts for some patients, which may provide better pain relief among people who do not respond to endoscopic therapy.
Journal ArticleDOI
Risk Factors Associated With Pediatric Acute Recurrent and Chronic Pancreatitis: Lessons From INSPPIRE.
Soma Kumar,Chee Y. Ooi,Steven L. Werlin,Maisam Abu-El-Haija,Bradley A. Barth,Melena D. Bellin,Peter R. Durie,Douglas S. Fishman,Steven D. Freedman,Cheryl E. Gariepy,Matthew J. Giefer,Tanja Gonska,Melvin B. Heyman,Ryan Himes,Sohail Z. Husain,Tom K. Lin,Mark E. Lowe,Veronique D. Morinville,Joseph J. Palermo,John F. Pohl,Sarah Jane Schwarzenberg,David M. Troendle,Michael Wilschanski,M. Bridget Zimmerman,Aliye Uc +24 more
TL;DR: The high disease burden in pediatric CP underscores the importance of identifying predisposing factors for progression of ARP to CP in children.
Journal ArticleDOI
A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis
Karianne Fjeld,Frank Ulrich Weiss,Denise Lasher,Jonas Rosendahl,Jian-Min Chen,Jian-Min Chen,Bente B. Johansson,Bente B. Johansson,Holger Kirsten,Claudia Ruffert,Emmanuelle Masson,Solrun J. Steine,Peter Bugert,Miriam Cnop,Robert Grützmann,Julia Mayerle,Joachim Mössner,Monika Ringdal,Monika Ringdal,Hans-Ulrich Schulz,Matthias Sendler,Peter Simon,Paweł Sztromwasser,Paweł Sztromwasser,Janniche Torsvik,Janniche Torsvik,Markus Scholz,Erling Tjora,Erling Tjora,Claude Férec,Heiko Witt,Markus M. Lerch,Pål R. Njølstad,Pål R. Njølstad,Stefan Johansson,Stefan Johansson,Anders Molven,Anders Molven +37 more
TL;DR: A hybrid allele (CEL-HYB) originating from a crossover between CEL and its neighboring pseudogene, CELP is described, implicate a new pathway distinct from the protease-antiprotease system of pancreatic acinar cells in chronic pancreatitis.
References
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Journal ArticleDOI
Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene.
David C. Whitcomb,Michael C. Gorry,Preston Ra,William Furey,Michael Sossenheimer,Charles D. Ulrich,Stephen P. Martin,Lawrence K. Gates,Stephen T. Amann,Phillip P. Toskes,Roger A. Liddle,Kevin McGrath,Generoso Uomo,James Christopher Post,James Christopher Post,Garth D. Ehrlich +15 more
TL;DR: X-ray crystal structure analysis, molecular modelling, and protein digest data indicate that the Arg 117 residue is a trypsin-sensitive site, and that loss of this cleavage site would permit autodigestion resulting in pancreatitis.
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Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis
Heiko Witt,W Luck,Hans Christian Hennies,M Classen,A. Kage,U Lass,Olfert Landt,Michael Becker +7 more
TL;DR: Analysis of the gene encoding the serine protease inhibitor, Kazal type 1, a pancreatic trypsin inhibitor, indicates that mutations in SPINK1 are associated with chronic pancreatitis.
Journal ArticleDOI
Chronic Pancreatitis: Challenges and Advances in Pathogenesis, Genetics, Diagnosis, and Therapy
TL;DR: The pancreatic stellate cells are now established as key cells in fibrogenesis, particularly when activated either directly by toxic factors associated with pancreatitis or by cytokines released during pancreatic necroinflammation.
Journal ArticleDOI
Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis.
Jonas Rosendahl,Heiko Witt,Richárd Szmola,Eesh Bhatia,Béla Ózsvári,Béla Ózsvári,Olfert Landt,Hans Ulrich Schulz,Thomas M. Gress,Roland H. Pfützer,Matthias Löhr,Peter Kovacs,Matthias Blüher,Michael Stumvoll,Gourdas Choudhuri,Péter Hegyi,Rene H. M. te Morsche,Joost P.H. Drenth,Kaspar Truninger,Milan Macek,Gero Puhl,Ulrike Witt,Hartmut Schmidt,Carsten Büning,Johann Ockenga,Andreas Kage,David A. Groneberg,Renate Nickel,Thomas Berg,Bertram Wiedenmann,Hans Bödeker,Volker Keim,Joachim Mössner,Niels Teich,Miklós Sahin-Tóth +34 more
TL;DR: The results indicate that loss-of-function alterations in CTRC predispose to pancreatitis by diminishing its protective trypsin-degrading activity.
Journal ArticleDOI
Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis
David C. Whitcomb,Jessica LaRusch,Alyssa M. Krasinskas,Lambertus Klei,Jill P. Smith,Randall E. Brand,John P. Neoptolemos,Markus M. Lerch,Matt Tector,Bimaljit S. Sandhu,Nalini M. Guda,Lidiya Orlichenko,Samer Alkaade,Stephen T. Amann,Michelle A. Anderson,John Baillie,Peter A. Banks,Darwin L. Conwell,Gregory A. Cote,Peter B. Cotton,James A. DiSario,Lindsay A. Farrer,Chris E. Forsmark,Marianne Johnstone,Timothy B. Gardner,Andres Gelrud,William Greenhalf,Jonathan L. Haines,Douglas J. Hartman,Robert A. Hawes,Christopher Lawrence,Michele D. Lewis,Julia Mayerle,Richard Mayeux,Nadine M. Melhem,Mary E. Money,Thiruvengadam Muniraj,Georgios I. Papachristou,Margaret A. Pericak-Vance,Joseph Romagnuolo,Gerard D. Schellenberg,Stuart Sherman,Peter Simon,Vijay P. Singh,Adam Slivka,Donna B. Stolz,Robert Sutton,Frank Ulrich Weiss,C. Mel Wilcox,Narcis O. Zarnescu,Stephen R. Wisniewski,Michael R. O'Connell,Michelle L. Kienholz,Kathryn Roeder,M. Michael Barmada,Dhiraj Yadav,Bernie Devlin,Marilyn S. Albert,Roger L. Albin,Roger L. Albin,Liana G. Apostolova,Steven E. Arnold,Clinton T. Baldwin,Robert Barber,Lisa L. Barnes,Thomas G. Beach,Gary W. Beecham,Duane Beekly,David A. Bennett,Eileen H. Bigio,Thomas D. Bird,Deborah Blacker,Adam L. Boxer,James R. Burke,Joseph D. Buxbaum,Nigel J. Cairns,Laura B. Cantwell,Chuanhai Cao,Regina M. Carney,Steven L. Carroll,Helena C. Chui,David G. Clark,David H. Cribbs,Elizabeth Crocco,Carlos Cruchaga,Charles DeCarli,F. Yesim Demirci,Malcolm B. Dick,Dennis W. Dickson,Ranjan Duara,Nilufer Ertekin-Taner,Kelley Faber,Kenneth B. Fallon,Martin R. Farlow,Steven H. Ferris,Tatiana Foroud,Matthew P. Frosch,Douglas Galasko,Mary Ganguli,Marla Gearing,Daniel H. Geschwind,Bernardino Ghetti,John R. Gilbert,Sid Gilman,Jonathan D. Glass,Alison Goate,Neill R. Graff-Radford,Robert C. Green,John H. Growdon,Hakon Hakonarson,Kara L. Hamilton-Nelson,Ronald L. Hamilton,Lindy E. Harrell,Elizabeth Head,Lawrence S. Honig,Christine M. Hulette,Bradley T. Hyman,Gregory A. Jicha,Lee-Way Jin,Gyungah Jun,M. Ilyas Kamboh,Anna Karydas,Jeffrey Kaye,Jeffrey Kaye,Ronald C. Kim,Edward H. Koo,Neil W. Kowall,Joel H. Kramer,Patricia L. Kramer,Walter A. Kukul,Frank M. LaFerla,James J. Lah,James B. Leverenz,Allan I. Levey,Ge Li,Chiao-Feng Lin,Andrew P. Lieberman,Oscar L. Lopez,Kathryn L. Lunetta,Constantine G. Lyketsos,Wendy J. Mack,Daniel C. Marson,Eden R. Martin,Frank Martiniuk,Deborah C. Mash,Eliezer Masliah,Ann C. McKee,M.-Marsel Mesulam,Bruce L. Miller,Carol A. Miller,Joshua W. Miller,Thomas J. Montine,John C. Morris,Jill R. Murrel,Adam C. Naj,Adam C. Naj,John M Olichney,Joseph E. Parisi,Elaine R. Peskind,Ronald C. Petersen,Aimee Pierce,Wayne W. Poon,Huntington Potter,Joseph F. Quinn,Ashok Raj,Murray A. Raskind,Eric M. Reiman,Barry Reisberg,Christiane Reitz,John M. Ringman,Erik D. Roberson,Howard J. Rosen,Roger N. Rosenberg,Mary Sano,Andrew J. Saykin,Julie A. Schneider,Lon S. Schneider,William W. Seeley,Amanda Smith,Joshua A. Sonnen,Salvatore Spina,Robert S. Stern,Rudolph E. Tanzi,John Q. Trojanowski,Juan C. Troncoso,Juan C. Troncoso,Debby W. Tsuang,Otto Valladares,Vivianna M. Van Deerlin,Linda J. Van Eldik,Badri N. Vardarajan,Harry V. Vinters,Jean Paul Vonsatte,Li-San Wang,Sandra Weintraub,Kathleen A. Welsh-Bohmer,Jennifer Williamson,Randall L. Woltjer,Clinton B. Wright,Steven G. Younkin,Chang En Yu,Lei Yu +201 more
TL;DR: Two associations at genome-wide significance identified and replicated at PRSS1-PRSS2 and X-linked CLDN2 are reported and could partially explain the high frequency of alcohol-related pancreatitis in men.
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