IRF-1 gene variations influence IgE regulation and atopy.
BACKGROUND
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.


OBJECTIVE
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).


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.
Schedel
Michaela
M
University Children's Hospital, Ludwig Maximilian's University Munich, Lindwurmstrasse 4, D-80337 München, Germany.
Pinto
Leonardo A
LA
Schaub
Bianca
B
Rosenstiel
Philip
P
Cherkasov
Dmitry
D
Cameron
Lisa
L
Klopp
Norman
N
Illig
Thomas
T
Vogelberg
Christian
C
Weiland
Stephan K
SK
von Mutius
Erika
E
Lohoff
Michael
M
Kabesch
Michael
M
D000328:Adult; D016022:Case-Control Studies; D002648:Child; D003430:Cross-Sectional Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005858:Germany; D006801:Humans; D006967:Hypersensitivity / Q000235:genetics*; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D050856:Interferon Regulatory Factor-1 / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012882:Skin Tests
D050856:Interferon Regulatory Factor-1; D007073:Immunoglobulin E