title: Genes that determine immunology and inflammation modify the basic defect of impaired ion conductance in cystic fibrosis epithelia.
abstract: BACKGROUND
  The cystic fibrosis (CF) basic defect, caused by dysfunction of the apical chloride channel CFTR in the gastrointestinal and respiratory tract epithelia, has not been employed so far to support the role of CF modifier genes.
  
  
  METHODS
  Patients were selected from 101 families with a total of 171 F508del-CFTR homozygous CF patients to identify CF modifying genes. A candidate gene based association study of 52 genes on 16 different chromosomes with a total of 182 genetic markers was performed. Differences in haplotype and/or diplotype distribution between case and reference CF subpopulations were analysed.
  
  
  RESULTS
  Variants at immunologically relevant genes were associated with the manifestation of the CF basic defect (0.01<Praw<0.0001 at IL1B, TLR9, TNFα, CD95, STAT3 and TNFR). The intragenic background of F508del-CFTR chromosomes determined disease severity and manifestation of the basic defect (Praw=0.0009). Allele distributions comparing transmitted and non-transmitted alleles were distorted at several loci unlinked to CFTR.
  
  
  CONCLUSIONS
  The inherited capabilities of the innate and adaptive immune system determine the manifestation of the CF basic defect. Variants on F508del-CFTR chromosomes contribute to the observed patient-to-patient variability among F508del-CFTR homozygotes. A survivor effect, manifesting as a transmission disequilibrium at many loci, is consistent with the improvement of clinical care over the last decades, resulting in a depletion of risk alleles at modifier genes. Awareness of non-genetic factors such as improvement of patient care over time is crucial for the interpretation of CF modifier studies.
authors.affiliation: Department of Pediatrics, Hannover Medical School, Germany. mekus.frauke@mh-hannover.de
authors.forename: Frauke
authors.initials: F
authors.lastname: Stanke
authors.forename: Tim
authors.initials: T
authors.lastname: Becker
authors.forename: Vinod
authors.initials: V
authors.lastname: Kumar
authors.forename: Silke
authors.initials: S
authors.lastname: Hedtfeld
authors.forename: Christian
authors.initials: C
authors.lastname: Becker
authors.forename: Harry
authors.initials: H
authors.lastname: Cuppens
authors.forename: Stephanie
authors.initials: S
authors.lastname: Tamm
authors.forename: Jennifer
authors.initials: J
authors.lastname: Yarden
authors.forename: Ulrike
authors.initials: U
authors.lastname: Laabs
authors.forename: Benny
authors.initials: B
authors.lastname: Siebert
authors.forename: Luis
authors.initials: L
authors.lastname: Fernandez
authors.forename: Milan
authors.initials: M
authors.lastname: Macek
authors.forename: Dragica
authors.initials: D
authors.lastname: Radojkovic
authors.forename: Manfred
authors.initials: M
authors.lastname: Ballmann
authors.forename: Joachim
authors.initials: J
authors.lastname: Greipel
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Cassiman
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Wienker
authors.forename: Burkhard
authors.initials: B
authors.lastname: Tümmler
mesh_terms: D000483:Alleles; D003550:Cystic Fibrosis / Q000235:genetics* / Q000276:immunology* / Q000503:physiopathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D004777:Environment; D004847:Epithelial Cells / Q000276:immunology* / Q000473:pathology*; D056726:Genetic Association Studies; D018740:Genetic Heterogeneity; D006720:Homozygote; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000276:immunology*; D040582:Inheritance Patterns / Q000235:genetics; D015640:Ion Channel Gating / Q000502:physiology*; D017136:Ion Transport; D018895:Microsatellite Repeats / Q000235:genetics; D008957:Models, Genetic
chemical_list: C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator