title: Association of rare chymotrypsinogen C (CTRC) gene variations in patients with idiopathic chronic pancreatitis.
abstract: Extensive genetic studies of chronic pancreatitis over the past decade have highlighted the importance of a tightly regulated balance between activation and inactivation of trypsin within the pancreas to disease susceptibility and resistance. The recent identification of chymotrypsin C (CTRC) as enzyme Y, which was proposed to protect the pancreas by degrading prematurely activated trypsinogen within the pancreas 20 years ago, made CTRC an excellent candidate gene for disease-association studies. Here, we analyzed all eight exons of the CTRC gene for conventional genetic variants and copy number variations (CNVs) by direct sequencing and quantitative fluorescent multiplex PCR, respectively, in a total of 287 French white patients (idiopathic x 216; familial x 42; hereditary x 29). While no CNVs were found in any of the 287 subjects, 20 conventional variations including a nonsense mutation (p.W55X), a microdeletion mutation (p.K247_R254del) and nine missense mutations were found in the 216 patients with idiopathic chronic pancreatitis (ICP). Except for two common polymorphisms, all the remaining 18 mutational events represent rare variations, with a minor allele frequency of 0-0.3% in the control population. All these rare variants were always found more frequently in the ICP patients than in the controls, and their combined frequency in the ICP patients (26/216; 12.0%) is significantly different from that in the controls (4/350; 1.1%) (OR = 11.8 [3.9-40.6]), chi (2) = 31.58, P < 10(-6)). This genetic finding, when considered in the perceived role of CTRC in eliminating prematurely activated trypsin, indicated that CTRC is a new pancreatitis susceptibility gene.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U613, 29220, Brest, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Masson
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Chen
authors.forename: Virginie
authors.initials: V
authors.lastname: Scotet
authors.forename: Cédric
authors.initials: C
authors.lastname: Le Maréchal
authors.forename: Claude
authors.initials: C
authors.lastname: Férec
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002851:Chromatography, High Pressure Liquid; D002908:Chronic Disease; D002919:Chymotrypsinogen / Q000737:chemistry / Q000235:genetics*; D017931:DNA Primers; D020022:Genetic Predisposition to Disease; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010195:Pancreatitis / Q000235:genetics*; D016133:Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics*
chemical_list: D017931:DNA Primers; C096020:chymotrypsinogen C; D002919:Chymotrypsinogen; D012697:Serine Endopeptidases