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Comprehensive screening of chymotrypsin C (CTRC) gene in tropical calcific pancreatitis identifies novel variants
  1. Sumit Paliwal1,
  2. Seema Bhaskar1,
  3. K Radha Mani1,
  4. D Nageshwar Reddy2,
  5. G Venkat Rao2,
  6. Shivaram Prasad Singh3,
  7. Varghese Thomas4,
  8. Giriraj Ratan Chandak1
  1. 1Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research, Hyderabad, India
  2. 2Asian Healthcare Foundation, Asian Institute of Gastroenterology, Hyderabad, India
  3. 3Department of Gastroenterology, SCB Medical College, Cuttack, India
  4. 4Department of Gastroenterology, Medical College, Calicut, India
  1. Correspondence to Dr Giriraj Ratan Chandak, Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research, Uppal Road, Habsiguda, Hyderabad 500007, India; chandakgrc{at}


Objective In a previous study, the authors have shown that rather than variants in trypsinogen gene(s), mutations in pancreatic secretory trypsin inhibitor (encoded by SPINK1) and cathepsin B (CTSB) are associated with tropical calcific pancreatitis (TCP). Recently, chymotrypsin C (CTRC) variants that diminish its activity or secretion were found to predict susceptibility to chronic pancreatitis (CP). The authors analysed CTRC variants in a large, ethnically matched case-control TCP cohort.

Design The authors sequenced all eight exons and flanking regions in CTRC in 584 CP patients (497 TCP, 87 idiopathic CP) and 598 normal subjects and analysed the significance of association using χ2 test. The authors also investigated interaction of CTRC variants with p.N34S SPINK1 and p.L26V CTSB mutations.

Results The authors identified 14 variants in CTRC, of which non-synonymous variants were detected in 71/584 CP patients (12.2%) and 22/598 controls (3.7%; OR 3.62, 95% CI 2.21 to 5.93; p=6.2×10−8). Rather than the commonly reported p.K247_R254del variant in Caucasians, p.V235I was the most common mutation in Indian CP patients (28/575 (4.9%); OR 7.60, 95% CI 2.52 to 25.71; p=1.01×10−5). Another pathogenic variant, p.A73T was identified in 3.1% (18/584) patients compared with 0.3% (2/598) in controls (OR=9.48, 95% CI 2.19 to 41.03, p=2.5×10−4). The authors also observed significant association for the synonymous variant c.180C>T (p.(=)) with CP (OR 2.71, 95% CI 1.79 to 4.12, p=5.3×10−7). Two novel nonsense mutations, p.G242AfsX9 and p.W113X were also identified exclusively in CP patients. No interaction between CTRC variants and p.N34S SPINK1 or p.L26V CTSB mutations was observed.

Conclusion This study on a large cohort of TCP patients provides evidence of allelic heterogeneity and confirms that CTRC variants play a significant role in its pathogenesis.

  • Chymotrypsin C
  • mutations
  • chronic pancreatitis
  • SPINK1
  • cathepsin B
  • gene-gene interaction
  • pancreatitis
  • hepatitis B
  • hepatocellular carcinoma
  • nonalcoholic steatohepatitis
  • non-ulcer dyspepsia
  • tropical gastroenterology
  • IBD—genetics
  • homocysteine
  • genetics
  • micronutrients
  • molecular genetics

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  • Funding This research received a specific funding from Council of Scientific and Industrial Research (NWP0032).

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Ethics approval was provided by the Institutional Ethics Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.