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

Stanke, F., Becker, T., Kumar, V., Hedtfeld, S., Becker, C., Cuppens, H., et al. (2011). Genes that determine immunology and inflammation modify the basic defect of impaired ion conductance in cystic fibrosis epithelia. J Med Genet, 48(1), 24-31. Retrieved from http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20837493 http://jmg.bmj.com/content/48/1/24.full.pdf.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-7954-C Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-7955-A
Genre: Journal Article

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 Creators:
Stanke, F., Author
Becker, T., Author
Kumar, V., Author
Hedtfeld, S., Author
Becker, C., Author
Cuppens, H., Author
Tamm, S.1, Author              
Yarden, J., Author
Laabs, U., Author
Siebert, B., Author
Fernandez, L., Author
Macek, M., Author
Radojkovic, D., Author
Ballmann, M., Author
Greipel, J., Author
Cassiman, J. J., Author
Wienker, T. F.2, Author              
Tummler, B., Author
Affiliations:
1Human Chromosome 21 (Marie-Laure Yaspo), Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479652              
2Clinical Genetics (Thomas F. Wienker), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479643              

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Free keywords: Alleles; Cystic Fibrosis/*genetics/*immunology/physiopathology; Cystic Fibrosis Transmembrane Conductance Regulator/genetics; Environment; Epithelial Cells/*immunology/*pathology; Genetic Association Studies; Genetic Heterogeneity; Homozygote; Humans; Inflammation/*genetics/*immunology; Inheritance Patterns/genetics; Ion Channel Gating/*physiology; Ion Transport; Microsatellite Repeats/genetics; Models, Genetic
 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, TNFalpha, 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.

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 Dates: 2011
 Publication Status: Published in print
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Title: J Med Genet
Source Genre: Journal
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Pages: - Volume / Issue: 48 (1) Sequence Number: - Start / End Page: 24 - 31 Identifier: ISSN: 1468-6244 (Electronic) 0022-2593 (Linking)