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Schedel, M.* ; Pinto, LA.* ; Schaub, B.* ; Rosenstiel, P.* ; Cherkasov, D.* ; Cameron, L.* ; Klopp, N. ; Illig, T. ; Vogelberg, C.* ; Weiland, S.K.* ; von Mutius, E.* ; Lohoff, M.* ; Kabesch, M.*

IRF-1 gene variations influence IgE regulation and atopy.

Am. J. Respir. Crit. Care Med. 177, 613-621 (2008)
DOI
Open Access Green as soon as Postprint is submitted to ZB.
The development of atopic diseases is characterized by skewed immune responses to common allergens. Only recently, interferons have been identified to play a crucial role in these mechanisms. OBJECTIVES: Because interferon regulatory factor (IRF)-1 is critical for interferon expression, we tested the hypotheses that genetic changes in this essential transcription factor may have consequences for the development of atopy. METHODS: The IRF-1 gene locus was resequenced in 80 human chromosomes. Association and haplotype analyses were performed in a cross-sectional study population of German children from Dresden (n = 1,940), and results were replicated in a second population sample from Munich (n = 1,159), both part of the ISAAC (International Study of Asthma and Allergy in Childhood) phase II. Promoter polymorphism effects were studied using electrophoretic mobility shift assay and colorimetric binding assays. Allele-specific IRF-1 gene expression was studied in vitro using luciferase reporter assays, whereas we assessed ex vivo expression of IRF-1 by real-time polymerase chain reaction and IFN-gamma protein by Luminex technology (Bio-Rad, Hercules, CA). Statistical analyses were performed using SAS/Genetics (SAS 9.1.3; SAS Institute, Cary, NC). MEASUREMENTS AND MAIN RESULTS: By resequencing, 49 polymorphisms were identified within the IRF-1 gene. Four blocks containing 11 polymorphisms were significantly associated with atopy, total IgE levels, or specific IgE levels in both populations (P < 0.05). Two polymorphisms changed transcription factor binding of nuclear factor (NF)-kappaB and EGR1 (early growth response 1) to the IRF-1 promoter, altered gene expression in vitro (P = 0.0004), and altered IRF-1 mRNA and IFN-gamma protein expression ex vivo. CONCLUSIONS: Our results suggest that functionally relevant IRF-1 polymorphisms influence atopy risk, potentially by altering transcription factor binding, IRF-1 gene expression, and IFN-gamma regulation.
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Publication type Article: Journal article
Document type Scientific Article
Keywords asthma; genes; interferons; IRF-1 transcription factor; genetic polymorphism
ISSN (print) / ISBN 1073-449X
e-ISSN 1535-4970
Journal American Journal of Respiratory and Critical Care Medicine
Quellenangaben Volume: 177, Issue: 6, Pages: 613-621 Article Number: , Supplement: ,
Publisher American Thoracic Society
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology (EPI)