Genetics of Pancreatitis: The 2014 Update

Abstract

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.

Establishing a Clinic-Based Pancreatic Cancer and Periampullary Tumour Research Registry in Quebec

“…Although our cohort is small, those observations are consistent with the results of a pooled case-control analysis showing that 6.2% of pdac patients have a history of pancreatitis 29 . Younger patients (<65 years of age) with a history of pancreatitis could be at increased risk for a genetic predisposition to pdac, including hereditary pancreatitis 30 . Several studies have shown that an increased body mass index (bmi) is associated with pdac risk 31 .…”

Functional significance of SPINK1 promoter variants in chronic pancreatitis

“…Even though p.N34S was presumed to cause a loss of function, the exact mechanism of action has never been identified, as no functional defect was demonstrated for p.N34S or any of the four intronic variants associated with this haplotype (5,7,19,20,24,26). In contrast, an unambiguous loss-of-function phenotype was evident for variant c.194ϩ2TϾC (28,35,39, and references therein), the second most frequent SPINK1 mutation that affects a splice site in intron-3 and causes exon skipping with markedly reduced SPINK1 mRNA expression (19,23). This intronic mutation is in complete linkage disequilibrium (i.e., found together) with the promoter variant c.-215GϾA.…”

Micronutrient ('Antioxidant') Therapy for Chronic Pancreatitis: Basis and Clinical Experience

“…The exocrine pancreas with its huge rate of protein synthesis is particularly vulnerable when subjected to congestion in the busy proteintrafficking lanesan inevitable consequence of pancreastasis episodes, despite the acinar cell's best efforts to compensate by endocrine rerouting of newly synthesised enzymes; removal of zymogen granules via the three-pronged strategy of centripetal dissolution, crinophagy and basolateral redirection; and down-regulation of enzyme synthesis (19,30,34,52). The close integration between oxidative, electrophilic, ER, and inflammation stress is now regarded as the basis for many chronic diseases (177) and, increasingly, for chronic pancreatitis (97,112,123).…”

“…The 1998 version (24) views the acinar cell as the site of mounting electrophilic stress that steadily erodes methyl (CH 3 ) and thiol (SH) -principally glutathione (GSH ) -moieties, as a result of CYP induction, concurrent exposure to a toxicant that yields RXS, and insufficiency of refurbishing micronutrients (Figure 1). A fourth factor must now be built into the equation, namely, gene mutations that might favour the cytoplasmic presence of trypsin (97): the enzyme, as also chymotrysin, is readily inhibited by GSH via SH-SS exchange (24) should it break loose of constraint by SPINK1 (serine protease inhibitor Kazal type 1) (118), but less GSH is then available for control of electrophilic / oxidative stress and other vital roles (24,30,162). The qualifying clauses help to explain why patients on CYP-inducing anticonvulsant drugs rarely develop chronic pancreatitis, or why profound electrophilic / oxidative stress but with low CYP activity in children with kwashiorkor results in painless loss of acini, not chronic pancreatitis (64).…”

“…This is not the position depicted in Figure 1, which instead seeks to understand the increased frequency of CFTR mutation(s), with or without mutation in SPINK1, among patients with idiopathic chronic pancreatitis (97), especially the tropical variant (102).…”