1). Two common haplotypes of the serine protease inhibitor Kazal type 1 (SPINK1) gene have been shown to increase the

EPZ-6438 datasheet risk for CP. A haplotype comprising the c.101A > G (p.N34S) missense variant and four intronic alterations have been found worldwide. In a recent study, a second haplotype consisting of the c.−215G > A promoter variant and the c.194 + 2T > C intronic alteration has also been observed.17 Other safety mechanisms which inhibit the trypsin that leaks into the interstitial space around the pancreas are trypsin inhibitors, including α1-antitrypsin and β2-microglobulin.16 It has also been hypothesized that the mechanism to prevent trypsin injury inside the acinar cell is to maintain calcium at low levels.18 Trypsinogen activation and trypsin survival are known to be regulated by calcium. Once trypsinogen is secreted into the duct, the calcium-dependent mechanisms utilized by the acinar cell for protection from trypsin PD-0332991 manufacturer are rendered ineffective due to the high level of calcium present in the duct. The duct is, however, protected by maintenance of an alkaline pH and rapid flushing of the zymogens and prematurely activated enzymes

out of the pancreas into the duodenum.19 There are extensive genetic studies on SPINK1, which is thought to be a candidate gene for pancreatitis. Forty variants have been reported so far, 14 of which were exclusively found in CP patients but not in controls. This clearly demonstrated the loss-of-function mutations. These findings support the hypothesis that pancreatic secretory trypsin inhibitor (PSTI) is a key negative regulator of prematurely activated trypsin within the pancreatic acinar cells.20 An A > G transition at 101 nucleotide position in the SPINK1 gene leading to substitution of asparagine by serine at codon 34 (N34S) has been reported with its highest frequency (approximately 46%) in an Indian population.21 However, N34S is shown to be in complete linkage disequilibrium with four intronic variants such as, 56 − 37T > C, 87 + 268A > g, 195 − 604G > A, 195–66_-65insTTTT. In spite medchemexpress of being

the strongest predictor and an important risk factor in the pathogenesis of TCP, the mechanism of N34S SPINK1mutations contributing to disease phenotype still remains elusive.22 Rosendahl et al.23 identified chymotrypsin C (CTRC, OMIM 601405) as a new pancreatitis-associated gene and discovered that loss-of-function alterations in CTRC gene predispose to pancreatitis by retreating its protective trypsin-degrading activity. The same was shown to be true in TCP patients. A recent study concluded that pancreatitis-associated CTRC mutations can markedly increase the propensity of CTRC to elicit endoplasmic recticulum (ER) stress in pancreatic acinar cells. Thus, carriers of CTRC mutations may be at a higher risk of developing ER stress in the exocrine pancreas, which may contribute to parenchymal damage through acinar cell apoptosis.