Genes that determine immunology and inflammation modify the basic defect of impaired ion conductance in cystic fibrosis epithelia.
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.
Stanke
Frauke
F
Department of Pediatrics, Hannover Medical School, Germany. mekus.frauke@mh-hannover.de
Becker
Tim
T
Kumar
Vinod
V
Hedtfeld
Silke
S
Becker
Christian
C
Cuppens
Harry
H
Tamm
Stephanie
S
Yarden
Jennifer
J
Laabs
Ulrike
U
Siebert
Benny
B
Fernandez
Luis
L
Macek
Milan
M
Radojkovic
Dragica
D
Ballmann
Manfred
M
Greipel
Joachim
J
Cassiman
Jean-Jacques
JJ
Wienker
Thomas F
TF
Tümmler
Burkhard
B
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
C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator