Genes that determine immunology and inflammation modify the basic defect of impaired ion conductance in cystic fibrosis epithelia

Frauke Stanke (1) , Tim Becker (2) , Vinod Kumar (1) , Silke Hedtfeld (1) , Christian Becker (1) , Harry Cuppens (3) , Stephanie Tamm (1) , Jennifer Yarden (3) , Ulrike Laabs (1) , Benny Siebert (1) , Luis Fernandez (1) , Milan Macek (4) , Dragica Radojkovic (5) , Manfred Ballmann (1) , Joachim Greipel (6) , Jean-Jaques Cassiman (3) , Thomas F Wienker (2) , Burkhard Tümmler (1)

1 Department of Pediatrics, Hannover Medical School, Hannover, Germany
2 Department of Biomedicine and the Centre for Integrative Sequencing
3 Department of Human Genetics, University of Leuven, Leuven, Belgium
4 UK - Univerzita Karlova [Praha, Česká republika] = Charles University [Prague, Czech Republic]
5 IMGGE - Institute of Molecular Genetics and Genetic Engineering [Belgrade]
6 Department of Biophysical Chemistry, Hannover Medical School, Hannover, Germany

Background The 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. We performed a candidate gene based association study of 52 genes on 16 different chromosomes with a total of 182 genetic markers. Differences in haplotype and/or diplotype distribution between case and reference CF subpopulations were analyzed. Results Variants at immunologically relevant genes were associated with the manifestation of the CF basic defect (0.01 < Praw < 0.0001 at IL1B, TLR9, TNFĄ, 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. We conclude that awareness of non-genetic factors such as improvement of patient care over time is crucial for the interpretation of CF modifier studies.

Mots clés: Genetics; Immunology (including allergy); Infectious Diseases; Cystic fibrosis; Epidemiology

Frauke Stanke, Tim Becker, Vinod Kumar, Silke Hedtfeld, Christian Becker, et al.. Genes that determine immunology and inflammation modify the basic defect of impaired ion conductance in cystic fibrosis epithelia. Journal of Medical Genetics, 2010, 48 (1), pp.24. ⟨10.1136/jmg.2010.080937⟩. ⟨hal-00565395⟩