Abstract for presentation at 11th International Congress of Human Genetics

Association of Cathepsin B Gene Polymorphisms with Tropical Calcific Pancreatitis: A New Candidate Gene

  • Ms Swapna Mahurkar, Centre for Cellular and Molecular Biology, Hyderabad, India
  • Ms Seema Bhaskar, Centre for Cellular and Molecular Biology, Hyderabad, India
  • Dr Nageshwar Reddy, Asian Institute of Gasteroenterology, Hyderabad, India
  • Mr Mohammed Idris, Centre for Cellular and Molecular Biology, Hyderabad, India
  • Dr G Rao, Asian Institute of Gasteroenterology, Hyderabad, India
  • Dr Varghese Thomas, Department of Gasteroenterology, Calicut Medical College, Calicut, India
  • Dr Giriraj Chandak, Centre for Cellular and Molecular Biology, Hyderabad

    • Purpose: Tropical calcific pancreatitis (TCP) is a type of chronic pancreatitis unique to 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.
    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 Val26 allele at Leu26Val polymorphism with an OR of 2.15 (95%CI=1.60-2.90, p=0.009, after Bonferroni correction, pcorr=0.025), which 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 controls (p=0.019 and 0.013, respectively). We also found significant differences in the mutant allele frequencies at Ser53Gly and C595T SNPs between N34S positive patients and controls (p=0.008 and 0.001, respectively). Haplotype analysis discovered a unique haplotype protective for TCP (p=0.0035).
    Conclusion: Our study for the first time suggests that CTSB polymorphisms are associated with TCP. Since PRSS1 mutations are absent in TCP and N34S SPINK1 mutation proposed to play a modifier role, CTSB variants may act as trigger for cationic trypsinogen activation.

    Conference Organiser - ICMS Pty Ltd