Chymotrypsinogen C Genetic Variants, Including c.180TT, Are Strongly Associated With Chronic Pancreatitis in Pediatric Patients

J Pediatr Gastroenterol Nutr. 2017 Dec;65(6):652-657. doi: 10.1097/MPG.0000000000001767.

Abstract

Objectives: Genetic studies in adults/adolescent patients with chronic pancreatitis (CP) identified chymotrypsinogen C (CTRC) genetic variants but their association with CP risk has been difficult to replicate. To evaluate the risk of CP associated with CTRC variants in CP pediatric patients-control study.

Methods: The distribution of CTRC variants in CP pediatric cohort (n = 136, median age at CP onset 8 years) with no history of alcohol/smoking abuse was compared with controls (n = 401, median age 45).

Results: We showed that p.Arg254Trp (4.6%) and p.Lys247_Arg254del (5.3%) heterozygous mutations are frequent and significantly associated with CP risk in pediatric patients (odds ratio [OR] = 19.1; 95% CI 2.8-160; P = 0.001 and OR = 5.5; 95% CI 1.6-19.4; P = 0.001, respectively). For the first time, we demonstrated that the c.180TT genotype of common p.Gly60Gly variant is strong, an independent CP risk factor (OR = 23; 95% CI 7.7-70; P < 0.001) with effect size comparable to p.Arg254Trp mutation. The other novel observation is that common c.493+51C>A variant, both CA and AA genotype, is significantly underrepresented in CP compared with controls (15% vs 35%; OR = 0.33; 95% CI 0.19-0.59; P < 0.001 and 2.8% vs 11%; OR = 0.24; 95% CI 0.06-0.85; P = 0.027, respectively).

Conclusions: Our study provides evidence that CTRC variants, including c.180TT (p.Gly60Gly) are strong CP risk factors. The c.493+51C>A variant may play a protective role against CP development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Child
  • Chymotrypsinogen / genetics*
  • Female
  • Genetic Predisposition to Disease*
  • Genetic Variation
  • Genotype
  • Humans
  • Male
  • Pancreatitis, Chronic / diagnosis
  • Pancreatitis, Chronic / genetics*
  • Risk Factors
  • Serine Endopeptidases / genetics*
  • Trypsin Inhibitor, Kazal Pancreatic / genetics

Substances

  • SPINK1 protein, human
  • chymotrypsinogen C
  • Trypsin Inhibitor, Kazal Pancreatic
  • Chymotrypsinogen
  • Serine Endopeptidases