Pathogenetics of Chronic Pancreatitis
Zhuan Liao，Zhao-Shen Li，David N.Cooper，Claude Férec，and Jian-Min Chen
Z.Liao·Z.-S.Li
Department of Gastroenterology，Changhai Hospital，the Second Military Medical University，Shanghai，China
Shanghai Institute of Pancreatic Diseases，Shanghai，China
D.N.Cooper
Institute of Medical Genetics，School of Medicine，Cardiff University，Cardiff，UK
C.Férec
Institut National de la Santé et de la Recherche Médicale（INSERM），Brest U1078，France
Faculté de Médecine et des Sciences de la Santé，Université de Bretagne Occidentale（UBO），Brest，France
Etablissement Français du Sang（EFS）—Bretagne，Brest，France
Laboratoire de Génétique Moléculaire et d'Histocompatibilité，Centre Hospitalier Universitaire（CHU）Brest，Hôpital Morvan，Brest，France
J.-M.Chen，M.D.，Ph.D.（✉）
Institut National de la Santé et de la Recherche Médicale（INSERM），Brest U1078，France
Faculté de Médecine et des Sciences de la Santé，Université de Bretagne Occidentale（UBO），Brest，France
Etablissement Français du Sang（EFS）—Bretagne，Brest，France
e-mail:Jian-Min.Chen@univ-brest.fr
© Springer Nature Singapore Pte Ltd.and Shanghai Scientific and Technical Publishers 2017
Z.-S.Li et al.（eds.），Chronic Pancreatitis，DOI 10.1007/978-981-10-4515-8_6
Abbreviations
CEL Carboxyl ester lipase(https://www.daowen.com)
CFTR Cystic fibrosis transmembrane conductance regulator
CLDN2 Claudin-2
CPA1 Carboxypeptidase Al
CTRC Chymotrypsin C
ERS Endoplasmic reticulum stress
FUT2 Fucosyltransferase 2
GWAS Genome-wide association study
ICP Idiopathic chronic pancreatitis
MODY Maturity-onset diabetes of the young
NACP Nonalcoholic chronic pancreatitis
NAHR Non-allelic homologous recombination
NMD Nonsense-mediated mRNA decay
OR Odds ratio
PCR Polymerase chain reaction
RAP Recurrent acute pancreatitis
RT-PCR Reverse transcription polymerase chain reaction
SNP Single nucleotide polymorphism
VNTR Variable number tandem repeat
Chronic pancreatitis is a condition that is associated with the progressive inflammation of the pancreas which over time gives rise to irreversible morphological changes accompanied by impairment of both exocrine and endocrine functions（Majumder and Chari 2016）.Over the last 20 years，molecular genetics has played an increasingly important role in elucidating the aetiology of chronic pancreatitis.The dawn of the new era in the genetic analysis of autosomal dominant hereditary pancreatitis（OMIM#167800）was heralded by the mapping of a disease locus to the long arm of chromosome 7（Le Bodic et al.1996；Pandya et al.1996；Whitcomb et al.1996b）and the subsequent identification of a gain-offunction missense mutation（i.e.，p.Arg122His）in the cationic trypsinogen gene（PRSS1；OMIM#276000）（Whitcomb et al.1996a）.Thereafter，a steady stream of chronic pancreatitis susceptibility（or protective）variants in different genes has been reported.The analysis of variantsin four specific genes，all highly expressed in human pancreatic acinar cells［PRSS1，PRSS2（encoding anionic trypsinogen；OMIM#601564），SPINK1（encoding pancreatic secretory trypsin inhibitor；OMIM#167790）and CTRC（encoding chymotrypsin C，which specifically degrades all human trypsinogen/trypsin isoforms（OMIM#601405）（Szmola and Sahin-Tóth 2007））］has firmly established the importance of a homeostatic balance between the activation and inactivation of trypsinogen within the pancreas，thereby defining a trypsin-dependent pathway in the pathogenesis of chronic pancreatitis.Whereas gain-of-function missense mutations and copy number variants in PRSS1（Le Maréchal et al.2006；Whitcomb et al.1996a）and loss-of-function variants in SPINK1（Witt et al.2000）and CTRC（Masson et al.2008b；Rosendahl et al.2008）predispose to chronic pancreatitis，loss-of-function variants in PRSS1（Boulling et al.2015；Chen et al.2003；Derikx et al.2015；Whitcomb et al.2012）and PRSS2（Witt et al.2006）protect against the disease.
In past years，we have comprehensively reviewed the genetics and pathogenesis of chronic pancreatitis（Chen and Férec 2009，2012）.Herein we summarize the main developments of the last 5 years，focusing on（ⅰ）the conservative assessment of the major genetic causes of idiopathic chronic pancreatitis（ICP），（ⅱ）the emerging pathway of misfolding-induced endoplasmic reticulum stress（ERS）in the aetiology of chronic pancreatitis，（ⅲ）new findings from the first genome-wide association study（GWAS）performed on chronic pancreatitis，（ⅳ）the association of rare functional CPA1 variants with chronic pancreatitis，（ⅴ）the involvement of CEL-HYB alleles in chronic pancreatitis，and（ⅵ）some other recent developments.The interested reader is invited to consult several other recent review articles that provide slightly different perspectives（Aghdassi et al.2015；Masamune 2014；Mounzer and Whitcomb 2013；Paliwal et al.2014；Ravi Kanth and Nageshwar Reddy 2014）.