Tohoku J. Exp. Med., 2014 February, 232(2)

Invited Review

Genetics of Pancreatitis: The 2014 Update

ATSUSHI MASAMUNE1

1Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan

Chronic pancreatitis is a progressive inflammatory disease in which pancreatic secretory parenchyma is destroyed and replaced by fibrous tissue, eventually leading to malnutrition and diabetes. Alcohol is the leading cause in Western countries, but genetic factors are also implicated. Since the identification of mutations in the cationic trypsinogen (PRSS1) gene as a cause of hereditary pancreatitis in 1996, we have seen great progress in our understanding of the genetics of pancreatitis. It has been established that mutations in the genes related to the activation and inactivation of trypsin(ogen) such as PRSS1, serine protease inhibitor Kazal type 1 (SPINK1) and chymotrypsin C (CTRC) genes are associated with pancreatitis. In 2013, carboxypeptidase A1 (CPA1) was identified as a novel pancreatitis susceptibility gene. Endoplasmic reticulum stress in pancreatic acinar cells resulting from the mis-folding of mutated pancreatic enzymes has been shown to act as a novel mechanism underlying the susceptibility to pancreatitis. In Japan, the nationwide survey revealed 171 patients (96 males and 75 females) with hereditary pancreatitis in 59 families based on the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer criteria. Because about 30% of families with hereditary pancreatitis do not carry mutations in any of the known pancreatitis susceptibility genes, other yet unidentified genes might be involved. Next generation sequencers can perform billions of sequencing reactions with a read length of 150-250 nucleotides. Comprehensive analysis using next generation sequencers will be a promising strategy to identify novel pancreatitis-associated genes and further clarify the pathogenesis of pancreatitis.

Key words —— carboxypeptidase; endoplasmic reticulum stress; next generation sequencer; trypsin; whole-exome sequencing

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Tohoku J. Exp. Med., 2014, 232, 69-77

Correspondence: Atsushi Masamune, M.D., Ph.D., Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.

e-mail: amasamune@med.tohoku.ac.jp