title: CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated?
abstract: OBJECTIVE
  In chronic pancreatitis (CP), alterations in several genes have so far been described, but only small cohorts have been extensively investigated for all predisposing genes.
  
  
  METHODS
  660 patients with idiopathic or hereditary CP and up to 1758 controls were enrolled. PRSS1, SPINK1 and CTRC were analysed by DNA sequencing, and cystic fibrosis transmembrane conductance regulator (CFTR) by melting curve analysis.
  
  
  RESULTS
  Frequencies of CFTR variants p.R75Q, p.I148T, 5T-allele and p.E528E were comparable in patients and controls. We identified 103 CFTR variants, which represents a 2.7-fold risk increase (p<0.0001). Severe cystic fibrosis (CF)-causing variants increased the risk of developing CP 2.9-fold, and mild CF-causing variants 4.5-fold (p<0.0001 for both). Combined CF-causing variants increased CP risk 3.4-fold (p<0.0001), while non-CF-causing variants displayed a 1.5-fold over-representation in patients (p=0.14). CFTR compound heterozygous status with variant classes CF-causing severe and mild represented an OR of 16.1 (p<0.0001). Notably, only 9/660 (1.4%) patients were compound heterozygotes in this category. Trans-heterozygosity increased CP risk, with an OR of 38.7, with 43/660 (6.5%) patients and 3/1667 (0.2%) controls being trans-heterozygous (p<0.0001).
  
  
  CONCLUSIONS
  Accumulation of CFTR variants in CP is less pronounced than reported previously, with ORs between 2.7 and 4.5. Only CF-causing variants reached statistical significance. Compound and trans-heterozygosity is an overt risk factor for the development of CP, but the number of CFTR compound heterozygotes in particular is rather low. In summary, the study demonstrates the complexity of genetic interactions in CP and a minor influence of CFTR alterations in CP development.
authors.affiliation: Department for Paediatrics & Else Kröner-Fresenius-Zentrum (EKFZ), Technical University Munich (TUM), Gregor-Mendel-Str. 2, 85350 Freising, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Rosendahl
authors.forename: Olfert
authors.initials: O
authors.lastname: Landt
authors.forename: Jana
authors.initials: J
authors.lastname: Bernadova
authors.forename: Peter
authors.initials: P
authors.lastname: Kovacs
authors.forename: Niels
authors.initials: N
authors.lastname: Teich
authors.forename: Hans
authors.initials: H
authors.lastname: Bödeker
authors.forename: Volker
authors.initials: V
authors.lastname: Keim
authors.forename: Claudia
authors.initials: C
authors.lastname: Ruffert
authors.forename: Joachim
authors.initials: J
authors.lastname: Mössner
authors.forename: Andreas
authors.initials: A
authors.lastname: Kage
authors.forename: Michael
authors.initials: M
authors.lastname: Stumvoll
authors.forename: David
authors.initials: D
authors.lastname: Groneberg
authors.forename: Renate
authors.initials: R
authors.lastname: Krüger
authors.forename: Werner
authors.initials: W
authors.lastname: Luck
authors.forename: Matthias
authors.initials: M
authors.lastname: Treiber
authors.forename: Michael
authors.initials: M
authors.lastname: Becker
authors.forename: Heiko
authors.initials: H
authors.lastname: Witt
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002918:Chymotrypsin / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D050500:Pancreatitis, Chronic / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D014357:Trypsin / Q000235:genetics*; D014359:Trypsin Inhibitor, Kazal Pancreatic
chemical_list: D002352:Carrier Proteins; C486642:SPINK1 protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D014359:Trypsin Inhibitor, Kazal Pancreatic; D002918:Chymotrypsin; C117569:chymotrypsin C; C489303:PRSS1 protein, human; D014357:Trypsin