Association of cathepsin B gene polymorphisms with tropical calcific pancreatitis

Abstract

Background and aims: Tropical calcific pancreatitis (TCP) is a type of chronic pancreatitis unique to countries in the tropics. Mutations in pancreatic secretory trypsin inhibitor (SPINK1) rather than cationic trypsinogen (PRSS1) explain the disease in only 50% of TCP patients. As cathepsin B (CTSB) is known to activate cationic trypsinogen, we attempted to understand the role of CTSB mutations in TCP. Evidence of epistatic interaction was investigated with the previously associated N34S SPINK1 allele, a variant considered to be a modifier rather than a true susceptibility allele. Subjects and methods: We sequenced the coding region of CTSB gene in 51 TCP patients and 25 controls and further genotyped 89 patients and 130 controls from the same cohort for Leu26Val, C595T, T663C, and Ser53Gly polymorphisms. The positive findings observed in the earlier cohort were re-examined in an ethnically matched replication cohort comprising 166 patients and 175 controls. Appropriate statistical analyses were performed and Bonferroni correction for multiple testing was applied. Results: We found a statistically significant association of the Val26 allele at Leu26Val polymorphism with an odds ratio (OR) of 2.15 (95% confidence interval (CI) 1.60-2.90 (p = 0.009)), after Bonferroni correction (corrected p value = 0.025). This significant association of Leu26Val with TCP was replicated in another cohort (OR 2.10 (95% CI 1.56-2.84); p = 0.013). Val26 allele also showed significantly higher frequency in N34S positive and N34S negative patients than in controls (p = 0.019 and 0.013, respectively). We also found significant differences in the mutant allele frequencies at Ser53Gly and C595T single nucleotide polymorphisms between N34S positive patients and controls (p = 0.008 and 0.001, respectively). Although haplotype analysis did not complement the results of allelic association, it did uncover a unique haplotype protective for TCP (p = 0.0035). Conclusion: Our study suggests for the first time that CTSB polymorphisms are associated with TCP. As PRSS1 mutations are absent in TCP and the N34S SPINK1 mutation is proposed to play a modifier role, these variants may be critical as a trigger for cationic trypsinogen activation.

Extensive Molecular Analysis Suggested the Strong Genetic Heterogeneity of Idiopathic Chronic Pancreatitis

“…Such genes were selected among the genes annotated in the "Pancreatic Secretion Pathway" (map04972), available in the KEGG database (22). The 70 genes selected were classified into six groups according to the activity of the encoded protein or their role in the pathogenesis of pancreatitis: (i) genes encoding proteins potentially involved in premature intrapancreatic activation of trypsin (CFTR, PRSS1, PRSS2, SPINK1, CTRC, CTSB, KRT8 and CASR) (23)(24)(25)(26)(27)(28)(29)(30); (ii) CF modifier genes the risk increases for patients with residual pancreatic function (about 10% of cases). However, also excluding all such causes, about one-third of recurrent/ chronic pancreatitis remains idiopathic, and this number is higher in children, who seldom report the classical risk factors observed in adults (8).…”

Is the profile of chronic pancreatitis in India changing?

“…SPINK1 gene mutations have been reported to be common in Indian patients with TCP [4,10,20,21]. In fact, one study found that 42 % of these patients had SPINK1 mutation, 9 % had CFTR gene mutation, and 41 % had CFTR gene polymorphisms [4,10].…”

Human trypsinogens in the pancreas and in cancer

“…This suggests that the premature intracellular activation of trypsinogen in acute pancreatitis might be initiated by the action of CTSB on trypsinogen-3 leading to degradation of PSTI, which contributes to the development of human pancreatitis. Furthermore, the Lys26Val mutation in the CTSB propeptide region is associated with tropical calcific pancreatitis (TCP) (Mahurkar et al, 2006). This mutation could affect CTSB trafficing and sorting to a lysosome or a zymogen granule.…”