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 (nâ=â136, median age at CP onset 8 years) with no history of alcohol/smoking abuse was compared with controls (nâ=â401, 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]â=â19.1; 95% CI 2.8-160; Pâ=â0.001 and ORâ=â5.5; 95% CI 1.6-19.4; Pâ=â0.001, respectively). For the first time, we demonstrated that the c.180TT genotype of common p.Gly60Gly variant is strong, an independent CP risk factor (ORâ=â23; 95% CI 7.7-70; Pâ<â0.001) 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%; ORâ=â0.33; 95% CI 0.19-0.59; Pâ<â0.001 and 2.8% vs 11%; ORâ=â0.24; 95% CI 0.06-0.85; Pâ=â0.027, 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.
Subject(s)
Chymotrypsinogen/genetics , Genetic Predisposition to Disease , Pancreatitis, Chronic/genetics , Serine Endopeptidases/genetics , Adult , Child , Female , Genetic Variation , Genotype , Humans , Male , Pancreatitis, Chronic/diagnosis , Risk Factors , Trypsin Inhibitor, Kazal Pancreatic/geneticsABSTRACT
BACKGROUND: Available data from adult patients do not reflect natural course of hereditary pancreatitis (HP) in children. To date, no study has assessed the clinical course of HP in children. OBJECTIVE: To investigate the clinical course of HP in children and compare it to non-HP group with chronic pancreatitis (CP). METHODS: A group of 265 children with CP, hospitalized from 1988 to 2014, were enrolled in the study. Medical records of those patients were reviewed for data on presentation, diagnostic findings and treatment. All children were screened for mutations in major pancreatitis-associated genes, i.e. PRSS1, SPINK1, and CFTR. RESULTS: HP was diagnosed in 41 children (15.5%). Family history was positive in 88% of children with HP. Mutations of PRSS1 gene were found in 80% (33/41) of HP patients. We detected p.R122H, p.R122C, p.N29I, and p.E79K mutation in 34% (14/41), 27% (11/41), 12% (5/41), and 7% (3/41) of HP patients, respectively. Patients with paternal inheritance had first symptoms earlier than those with maternal inheritance (5.9 vs. 9.1 years; P < 0.05). Children with HP showed more severe changes in ERCP then those from non-HP group (2.05 Cambridge grade, vs. 1.6°; P < 0.05). ESWL was performed more frequently in HP group (12.2% vs. 3.1%; P < 0.05). There was no difference in age of disease onset (7.98 vs. 8.9 years; NS), pancreatic duct stenting (46.3% vs. 33%; NS), or number of surgical interventions (12.2% vs. 14.3%; NS) between both groups. CONCLUSIONS: Children with HP reveal significantly more severe clinical presentation of the disease than non-HP patients, despite the same age of onset.
