IL-4/IL-13 pathway genetics strongly influence serum IgE levels and childhood asthma.
BACKGROUND
IgE production, a hallmark of asthma and atopic disease, may be under genetic control. Genes of the IL-4 and IL-13 pathway, central for IgE regulation, have so far only been assessed in studies of single gene effects.


OBJECTIVE
Here we analyzed combined extended haplotypes involving IL-4, IL-13, their shared receptor chain IL-4Ralpha, and the intracellular signal transducer and activator of transcription, STAT6, to assess the combined effect of single nucleotide polymorphisms in this important immunological signaling pathway.


METHODS
We genotyped a large cross-sectional population of 1120 children age 9 to 11 years for 18 polymorphisms in the respective genes of the IL-4/IL-13 pathway. One polymorphism per gene was selected because of its putative functional role, and extended haplotypes were built in a stepwise procedure where gene-by-gene interactions were assessed by using a Cordell model.


RESULTS
Combining polymorphisms in all 4 major pathway genes in a stepwise procedure, the risk for high serum IgE levels increased 10.8-fold (P = .02) and the risk for the development of asthma increased by a factor of 16.8-fold (P = .005) compared with the maximum effect of any single polymorphism. Significant interactions in a model with additive and dominant effects, for both pair and triplet combinations for asthma (lowest P = .005), and for pairs of polymorphisms in IgE regulation were observed (lowest P = .054).


CONCLUSIONS
These data indicate that only the combined analyses of genetic alterations in the IL-4/IL-13 pathway reveal its actual significance to the development of atopy and childhood asthma.
Kabesch
Michael
M
University Children's Hospital Munich, Germany. Michael.Kabesch@med.uni-muenchen.de
Schedel
Michaela
M
Carr
David
D
Woitsch
Bernd
B
Fritzsch
Christian
C
Weiland
Stephan K
SK
von Mutius
Erika
E
D001249:Asthma / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood*; D018793:Interleukin-13 / Q000235:genetics* / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D019948:Receptors, Interleukin-4 / Q000235:genetics / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism
D018793:Interleukin-13; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015847:Interleukin-4; D007073:Immunoglobulin E