Asthma is a familial inflammatory disease of the airways of the lung. Microbial exposures in childhood protect against asthma through unknown mechanisms. The innate immune system is able to identify microbial components through a variety of pattern-recognition receptors (PRRs). NOD1 is an intracellular PRR that initiates inflammation in response to bacterial diaminopimelic acid (iE-DAP). The NOD1 gene is on chromosome 7p14, in a region that has been genetically linked to asthma. We carried out a systematic search for polymorphism in the gene. We found an insertion-deletion polymorphism (ND(1)+32656) near the beginning of intron IX that accounted for approximately 7% of the variation in IgE in two panels of families (P<0.0005 in each). Allele*2 (the insertion) was associated with high IgE levels. The same allele was strongly associated with asthma in an independent study of 600 asthmatic children and 1194 super-normal controls [odds ratio (OR) 6.3; 95% confidence interval (CI) 1.4-28.3, dominant model]. Differential binding of the two ND(1)+32656 alleles was observed to a protein from nuclei of the Calu 3 epithelial cell line. In an accompanying study, the deletion allele (ND(1)+32656*1) was found to be associated with inflammatory bowel disease. The results indicate that intracellular recognition of specific bacterial products affects the presence of childhood asthma.

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The first genome wide association study (GWAS) for childhood asthma identified a novel major susceptibility locus on chromosome 17q21 harboring the ORMDL3 gene, but the role of previous asthma candidate genes was not specifically analyzed in this GWAS. We systematically identified 89 SNPs in 14 candidate genes previously associated with asthma in >3 independent study populations. We re-genotyped 39 SNPs in these genes not covered by GWAS performed in 703 asthmatics and 658 reference children. Genotyping data were compared to imputation data derived from Illumina HumanHap300 chip genotyping. Results were combined to analyze 566 SNPs covering all 14 candidate gene loci. Genotyped polymorphisms in ADAM33, GSTP1 and VDR showed effects with p-values <0.0035 (corrected for multiple testing). Combining genotyping and imputation, polymorphisms in DPP10, EDN1, IL12B, IL13, IL4, IL4R and TNF showed associations at a significance level between p = 0.05 and p = 0.0035. These data indicate that (a) GWAS coverage is insufficient for many asthma candidate genes, (b) imputation based on these data is reliable but incomplete, and (c) SNPs in three previously identified asthma candidate genes replicate in our GWAS population with significance after correction for multiple testing in 14 genes.

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Background: Several studies have shown linkage of chromosome 12q 13-24 with atopy related phenotypes. Among candidate genes in this region is STAT6 (signal transducer and activator of transcription), which is essential for Th2 cell differentiation, recruitment, and effector function. Methods: We evaluated six polymorphisms of STAT6 for evidence of associations with serum IgE levels and atopic diseases in a population based cross sectional cohort of 1407 German adults. Genotyping was performed using the matrix assisted laser desorption ionisation-time of flight mass spectrometry method. Haplotypes were estimated using the SAS/Genetics module, and population-derived IgE percentiles (50% IgE.53 kU/l, 66% IgE.99 kU/l and 90% IgE.307 kU/l) were modelled as outcome variables in haplotype trend regression analysis. Results: All polymorphisms were genotyped successfully. Haplotype reconstruction revealed 8/64 possible haplotypes, reaching estimated frequencies of 1% or more. One polymorphism in intron 2 (rs324011) showed a significant association with total serum IgE (p = 0.015). A STAT6 risk haplotype for elevated IgE showing odds ratios of 1.7 (p = 0.015) for IgE cut-off 100 kU/l, and 1.54 (p = 0.032), 1.6 (p = 0.025), and 2.54 (p = 0.007) for IgE percentiles 50%, 66%, and 90%, respectively was detected. The increased risk of this haplotype was confirmed by linear haplotype trend regression on log transformed IgE values (p = 0.007). Analysis further revealed a risk haplotype for specific sensitisation and a risk haplotype for asthma. Conclusion:The data indicate that genetic variants within STAT6 contribute significantly to IgE regulation and manifestation of atopic diseases.

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Background T regulatory cells attenuate development of asthma in wild-type (WT) mice with both naturally occurring (nTregs) and inducible T regulatory cells (iTregs) exhibiting suppressive activity. When transferred into CD8-deficient (CD8−/−) recipients, both cell types enhanced development of allergen-induced airway hyperresponsiveness (AHR). Objective To determine if the pathways leading to enhancement of lung allergic responses by transferred nTregs and iTregs differed. Methods nTregs (CD4+CD25+) were isolated from WT mice and iTregs were generated from WT CD4+CD25− T cells following activation in the presence of TGF-β and transferred into sensitized CD8−/− recipients prior to challenge. Development of AHR, cytokine levels, and airway inflammation were monitored. Results Transfer of nTregs enhanced lung allergic responses as did transfer of iTregs. While anti-IL-13 reduced nTreg-mediated enhancement, it was ineffective in iTreg-mediated enhancement; conversely, anti-IL-17 but not anti-IL-13 attenuated the enhancement by iTregs. Recovered iTregs from the lungs of CD8−/− recipients were capable of IL-17 production and expressed high levels of signature genes of the Th17 pathway, RORγt, and Il17, while reduced expression of the Treg key transcription factor Foxp3 was observed. In vitro, exogenous IL-6-induced IL-17 production in the iTregs and in vivo, conversion of transferred iTregs was dependent on recipient IL-6. Conclusions iTregs similar to nTregs exhibit functional plasticity and can be converted from suppressor cells to pathogenic effector cells enhancing lung allergic responses, but these effects were mediated through different pathways.