IL-12B Promoter Polymorphism Associated with Asthma and IL-12B Transcriptional Activity

Abstract

Background: The interleukin-12B gene (IL-12B) encodes the p40 chain of interleukin-12 (IL-12), which promotes cell-mediated Th1 responses and the production of interferon-gamma (IFN-γ) that downregulates IgE production. Chromosome 5q31-q33 near the IL-12B locus is significantly linked to asthma, as determined by a genome-wide search in the Japanese population. Methods: We sequenced exons 1–8 including parts of the introns and promoter region of IL-12B in asthmatic patients and healthy controls. We examined plasma IL-12 concentrations, IL-12 production by Derf1-stimulated peripheral blood mononuclear cells (PBMCs) and the IL-12B transcriptional activity. Results: IL-12B promoter polymorphism existed as −2703CTCTAA/GC and −2403T/C alleles, which were linked to each other. Homozygosity for haplotype 1 (−2703CTCTAA /−2403T) was associated with asthma susceptibility in Japanese children (P < 0.001). Both plasma IL-12 concentrations and IL-12 production by Derf1-stimulated PBMCs in the subjects with homozygotes for haplotype 1 were lower than those with homozygotes for haplotype 2 (−2703GC /−2403C) (P < 0.001). The transcriptional activity of the construct with haplotype 1 was lower than that of the construct with haplotype 2, and the IL-12B transcriptional activity was influenced by the −2403T/ C allele rather than by the −2403CTCTAA/GC allele. Conclusions: Homozygosity for haplotype 1, which is associated with reduced IL-12B transcriptional activity and reduced IL-12 production, is a predisposing factor for asthma susceptibility in Japanese children.

Keywords

• asthma
• IgE
• interferon-gamma
• interleukin-12B promoter polymorphism