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Chronic Pancreatitis pp 63–77Cite as

Pathogenetics of Chronic Pancreatitis

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Abstract

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-of-function 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 variants in 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.

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Abbreviations

CEL:

Carboxyl ester lipase

CFTR:

Cystic fibrosis transmembrane conductance regulator

CLDN2:

Claudin-2

CPA1:

Carboxypeptidase A1

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

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Acknowledgments

The work was supported by the Conseil Régional de Bretagne, the Association des Pancréatites Chroniques Héréditaires, the Association de Transfusion Sanguine et de Biogénétique Gaetan Saleun, and the Institut National de la Santé et de la Recherche Médicale (INSERM), France; and the National Natural Science Foundation of China (81470884 and 81422010 to ZL), the Shuguang Program of Shanghai Education Development Foundation and Shanghai Municipal Education Commission (15SG33 to ZL) and the Chang Jiang Scholars Program of Ministry of Education (Q2015190 to ZL), China.

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Authors and Affiliations

  1. Department of Gastroenterology, Changhai Hospital, the Second Military Medical University, Shanghai, China

    Zhuan Liao & Zhao-Shen Li

  2. Shanghai Institute of Pancreatic Diseases, Shanghai, China

    Zhuan Liao & Zhao-Shen Li

  3. Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, UK

    David N. Cooper

  4. Institut National de la Santé et de la Recherche Médicale (INSERM), Brest, U1078, France

    Claude Férec & Jian-Min Chen M.D., Ph.D.

  5. Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale (UBO), Brest, France

    Claude Férec & Jian-Min Chen M.D., Ph.D.

  6. Etablissement Français du Sang (EFS)—Bretagne, Brest, France

    Claude Férec & Jian-Min Chen M.D., Ph.D.

  7. Laboratoire de Génétique Moléculaire et d’Histocompatibilité, Centre Hospitalier Universitaire (CHU) Brest, Hôpital Morvan, Brest, France

    Claude Férec

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  1. Zhuan Liao
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  2. Zhao-Shen Li
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  3. David N. Cooper
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  4. Claude Férec
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  5. Jian-Min Chen M.D., Ph.D.
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Correspondence to Jian-Min Chen M.D., Ph.D. .

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Editors and Affiliations

  1. Department of Gastroenterology, Changhai Hospital, Shanghai, China

    Zhao-Shen Li

  2. Changhai Hospital, Department of Gastroenterology, Shanghai, China

    Zhuan Liao

  3. INSERM, Brest, France

    Jian-Min Chen

  4. INSERM UMR 1078, Brest, France

    Claude Férec

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Liao, Z., Li, ZS., Cooper, D.N., Férec, C., Chen, JM. (2017). Pathogenetics of Chronic Pancreatitis. In: Li, ZS., Liao, Z., Chen, JM., Férec, C. (eds) Chronic Pancreatitis. Springer, Singapore. https://doi.org/10.1007/978-981-10-4515-8_6

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