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IRF-1 Gene Variations Influence IgE Regulation and Atopy

Michaela Schedel^1,*, Leonardo A. Pinto^1,*, Bianca Schaub¹, Philip Rosenstiel², Dmitry Cherkasov³, Lisa Cameron¹, Norman Klopp⁴, Thomas Illig⁴, Christian Vogelberg⁵, Stephan K. Weiland^6,, Erika von Mutius¹, Michael Lohoff^3,* and Michael Kabesch^1,*

¹ University Children's Hospital, Ludwig Maximilian's University Munich, Munich, Germany; ² Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; ³ Institute of Microbiology, University of Marburg, Marburg, Germany; ⁴ Institute of Epidemiology, GSF–Research Centre for Environment and Health, Neuherberg, Germany; ⁵ University Children's Hospital, Dresden, Germany; and ⁶ Institute of Epidemiology, Ulm University, Ulm, Germany

Correspondence and requests for reprints should be addressed to Michael Kabesch, M.D., University Children's Hospital, Ludwig Maximilian's University Munich, Lindwurmstrasse 4, D-80337 München, Germany. E-mail: michael.kabesch{at}med.uni-muenchen.de

Rationale: 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- 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)-B 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- 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- regulation.

Key Words: asthma • genes • interferons • IRF-1 transcription factor • genetic polymorphism

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Interferon regulatory factor (IRF)-1 is critical for interferon expression. However, little is known concerning the influence of genetic changes in this essential transcription factor on the development of atopic diseases. What This Study Adds to the Field Our results suggest that functionally relevant IRF-1 polymorphisms influence atopy risk, potentially by altering transcription factor binding, IRF-1 gene expression, and IFN- regulation.