Genetic mechanisms underlying the pathogenesis of tropical calcific pancreatitis.
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ABSTRACT:
SUBMITTER: Mahurkar S
PROVIDER: S-EPMC2653322 | biostudies-literature | 2009 Jan
REPOSITORIES: biostudies-literature
Publications
Genetic mechanisms underlying the pathogenesis of tropical calcific pancreatitis.
Mahurkar Swapna S Reddy D Nageshwar DN Rao G Venkat GV Chandak Giriraj Ratan GR
World journal of gastroenterology 20090101 3
Chronic pancreatitis is known to be a heterogeneous disease with varied etiologies. Tropical calcific pancreatitis (TCP) is a severe form of chronic pancreatitis unique to developing countries. With growing evidence of genetic factors contributing to the pathogenesis of TCP, this review is aimed at compiling the available information in this field. We also propose a two hit model to explain the sequence of events in the pathogenesis of TCP. ...[more]
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Project description:Tropical calcific pancreatitis (TCP) is a form of chronic non-alcoholic pancreatitis initially reported in the developing parts of the tropical world. The clinical phenotype of TCP has undergone marked changes since its first description in 1968. The disease is now seen in relatively older people with less severe symptoms. In addition, there are varying reports on the proportion of cases presenting with imaging abnormalities like calcification, ductal dilation, and glandular atrophy. Significant progress has also been made in understanding the etiopathology of TCP. The role of malnutrition and cassava toxicity in its pathogenesis is disproven and few studies have focused on the role of micronutrient deficiency and oxidative stress in the etiopathogenesis of TCP. Emerging evidence support an important role for genetic risk factors in TCP. Several studies have shown that, rather than mutations in trypsinogens, variants in serine protease inhibitor kazal type 1, cathepsin B, chymotrypsin C, cystic fibrosis transmembrane regulator, and carboxypeptidase A1, predict risk of TCP. These studies also provided evidence of mutational heterogeneity between TCP and chronic pancreatitis in Western populations. The current review summarizes recent advances that have implications in the understanding of the pathophysiology and thus, heterogeneity in genotype-phenotype correlations in TCP.
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Project description:Background and aimsTropical 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 methodsWe 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.ResultsWe 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).ConclusionOur 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.
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