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  • Title: IL-4/IL-13 pathway genetics strongly influence serum IgE levels and childhood asthma.
    Author: Kabesch M, Schedel M, Carr D, Woitsch B, Fritzsch C, Weiland SK, von Mutius E.
    Journal: J Allergy Clin Immunol; 2006 Feb; 117(2):269-74. PubMed ID: 16461126.
    Abstract:
    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). CONCLUSION: 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.
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