Background Patients with asthma and healthy controls differ in bacterial colonization of the respiratory tract. The upper airways have been shown to reflect colonization of the lower airways, the ...actual site of inflammation in asthma, which is hardly accessible in population studies. Objective We sought to characterize the bacterial communities at 2 sites of the upper respiratory tract obtained from children from a rural area and to relate these to asthma. Methods The microbiota of 327 throat and 68 nasal samples from school-age farm and nonfarm children were analyzed by 454-pyrosequencing of the bacterial 16S ribosomal RNA gene. Results Alterations in nasal microbiota but not of throat microbiota were associated with asthma. Children with asthma had lower α- and β-diversity of the nasal microbiota as compared with healthy control children. Furthermore, asthma presence was positively associated with a specific operational taxonomic unit from the genus Moraxella in children not exposed to farming, whereas in farm children Moraxella colonization was unrelated to asthma. In nonfarm children, Moraxella colonization explained the association between bacterial diversity and asthma to a large extent. Conclusions Asthma was mainly associated with an altered nasal microbiota characterized by lower diversity and Moraxella abundance. Children living on farms might not be susceptible to the disadvantageous effect of Moraxella . Prospective studies may clarify whether Moraxella outgrowth is a cause or a consequence of loss in diversity.
Over the last half century, a dramatic increase in the incidence of chronic inflammatory diseases, such as asthma, allergy, and irritable bowel syndrome, has rightfully led to concern about how the ...modern lifestyle might inappropriately trigger innate physiologic defense mechanisms. Health care research in the Western world is faced with a significant challenge if it is to meet the needs of its populations in the decades ahead. The tools with which we hope to advance our understanding of the intrinsic and extrinsic mechanisms of chronic inflammatory diseases must therefore be adequately exploited and further developed to identify treatment and prevention strategies. There is an urgent need to prioritize resources and identify the most efficient scientific and societal initiatives to be adopted within this area. In this context national collaboration within Europe and beyond to establish state-of-the-art practices with an interdisciplinary perspective and promote an efficient exchange of best practices is essential. Such an approach likely represents the most efficient manner in which strategies for amelioration of the increase of chronic inflammatory diseases in the Western world can be achieved. The present report is based on a Forward Look initiative conducted by the European Medical Research Councils under the European Science Foundation. Experts from industry and academia, as well as relevant interest organizations, have been consulted in the process of conducting this initiative and have, based on this work, developed a set of final recommendations that target academic research, science funders, and policy makers.
Background Asthma is a disease in which both genetic and environmental factors play important roles. The farming environment has consistently been associated with protection from childhood asthma and ...atopy, and interactions have been reported with polymorphisms in innate immunity genes. Objective To detect gene-environment interactions for asthma and atopy in the farming environment. Methods We performed a genome-wide interaction analysis for asthma and atopy by using 500,000 genotyped single nucleotide polymorphisms (SNPs) and farm-related exposures in 1708 children from 4 rural regions of Central Europe. We also tested selectively for interactions between farm exposures and 7 SNPs that emerged as genome-wide significant in a large meta-analysis of childhood asthma and 5 SNPs that had been reported previously as interacting with farm exposures for asthma or atopy. Results Neither the asthma-associated SNPs nor the SNPs previously published for interactions with asthma showed significant interactions. The genome-wide interaction study did not reveal any significant interactions with SNPs within genes in the range of interacting allele frequencies from 30% to 70%, for which our study was well powered. Among rarer SNPs, we identified 15 genes with strong interactions for asthma or atopy in relation to farming, contact with cows and straw, or consumption of raw farm milk. Conclusion Common genetic polymorphisms are unlikely to moderate the protective influence of the farming environment on childhood asthma and atopy, but rarer variants, particularly of the glutamate receptor, metabotropic 1 gene, may do so. Given the limited statistical power of our study, these findings should be interpreted with caution before being replicated in independent farm populations.
Abstract Background Genome-wide association studies have identified the ORMDL3 (ORM (yeast)-like protein isoform 3) gene locus on human chromosome 17q to be a highly significant risk factor for ...childhood-onset asthma. Objective We sought to investigate in vivo the functional role of ORMDL3 in disease inception. Methods An Ormdl3 deficient mouse was generated and the role of ORMDL3 in the generation of allergic airways disease to the fungal aeroallergen Alternaria alternata determined. An adeno-associated viral vector was also utilized to reconstitute ORMDL3 expression in airway epithelial cells of Ormdl3 KO mice. Results Ormdl3 knock-out mice were found to be protected from developing allergic airways disease and showed a marked decrease in pathophysiology, including lung function and airway eosinophilia induced by Alternaria. Alternaria is a potent inducer of cellular stress and the unfolded protein response and ORMDL3 was found to play a critical role in driving the ATF6 mediated arm of this response through Xbp1 and downstream activation of the endoplasmic reticulum-associated degradation pathway. Additionally ORMDL3 mediated uric acid release, another marker of cellular stress. In the knockout mice, reconstitution of Ormdl3 transcript levels specifically in the bronchial epithelium resulted in reinstatement of susceptibility to fungal allergen-induced allergic airways disease. Conclusions This study demonstrates that ORMDL3 , an asthma susceptibility gene identified by genome-wide association studies, contributes to key pathways that promote changes in airway physiology during allergic immune responses.
Background Total IgE is a therapeutic target in patients with allergic diseases. DNA methylation in white blood cells (WBCs) was associated with total IgE levels in an epigenome-wide association ...study of white subjects. Whether DNA methylation of eosinophils explains these findings is insufficiently understood. Methods We tested for association between genome-wide DNA methylation in WBCs and total IgE levels in 2 studies of Hispanic children: the Puerto Rico Genetics of Asthma and Lifestyle Study (PR-GOAL; n = 306) and the Genes-environments and Admixture in Latino Americans (GALA II) study (n = 573). Whole-genome methylation of DNA from WBCs was measured by using the Illumina Infinium HumanMethylation450 BeadChip. Total IgE levels were measured by using the UniCAP 100 system. In PR-GOAL WBC types (ie, neutrophils, eosinophils, basophils, lymphocytes, and monocytes) in peripheral blood were measured by using Coulter Counter techniques. In the GALA II study WBC types were imputed. Multivariable linear regression was used for the analysis of DNA methylation and total IgE levels, which was first conducted separately for each cohort, and then results from the 2 cohorts were combined in a meta-analysis. Results CpG sites in multiple genes, including novel findings and results previously reported in white subjects, were significantly associated with total IgE levels. However, adjustment for WBC types resulted in markedly fewer significant sites. Top findings from this adjusted meta-analysis were in the genes ZFPM1 ( P = 1.5 × 10−12 ), ACOT7 ( P = 2.5 × 10−11 ), and MND1 ( P = 1.4 × 10−9 ). Conclusions In an epigenome-wide association study adjusted for WBC types (including eosinophils), methylation changes in genes enriched in pathways relevant to asthma and immune responses were associated with total IgE levels among Hispanic children.
Background The association between allergic sensitization and eczema has been debated for years. Objective We sought to determine and compare the strength of the association between allergen skin ...sensitization and eczema in both developing and industrialized countries. Methods Twenty-eight thousand five hundred ninety-one randomly selected 8- to 12-year-old schoolchildren in 20 countries were physically examined for flexural eczema and received skin prick testing to Dermatophagoides pteronyssinus , Dermatophagoides farinae , cat hair, Alternaria tenuis , mixed tree and grass pollen, and allergens of local relevance. Results The age- and sex-adjusted odds ratios (ORs) for a positive association between flexural eczema and atopy ranged between 0.74 (95% CI, 0.31-1.81) and 4.53 (95% CI, 1.72-11.93), with a significantly stronger association in affluent compared with nonaffluent countries (combined age- and sex-adjusted ORaffluent = 2.69 95% CI, 2.31-3.13 and ORnonaffluent = 1.17 95% CI, 0.81-1.70). The combined population attributable fraction for atopy in flexural eczema was 27.9% for affluent and 1.2% for nonaffluent-country centers. Correlating gross national per-capita income with either ORs or population attributable fractions for atopy in flexural eczema confirmed a highly significant positive association ( P = .006 and P < .001, respectively). Conclusions The association between atopy and flexural eczema is weak and more variable than previously suggested, and the strength of this association is positively linked to gross national income.
Background Asthma and allergic rhinitis (AR) are common allergic comorbidities with a strong genetic component in which epigenetic mechanisms might be involved. Objective We aimed to identify novel ...risk loci for asthma and AR while accounting for parent-of-origin effect. Methods We performed a series of genetic analyses, taking into account the parent-of-origin effect in families ascertained through asthma: (1) genome-wide linkage scan of asthma and AR in 615 European families, (2) association analysis with 1233 single nucleotide polymorphisms (SNPs) covering the significant linkage region in 162 French Epidemiological Study on the Genetics and Environment of Asthma families with replication in 154 Canadian Saguenay-Lac-Saint-Jean asthma study families, and (3) association analysis of disease and significant SNPs with DNA methylation (DNAm) at CpG sites in 40 Saguenay-Lac-Saint-Jean asthma study families. Results We detected a significant paternal linkage of the 4q35 region to asthma and allergic rhinitis comorbidity (AAR; P = 7.2 × 10−5 ). Association analysis in this region showed strong evidence for the effect of the paternally inherited G allele of rs10009104 on AAR ( P = 1.1 × 10−5 , reaching the multiple-testing corrected threshold). This paternally inherited allele was also significantly associated with DNAm levels at the cg02303933 site ( P = 1.7 × 10−4 ). Differential DNAm at this site was found to mediate the identified SNP-AAR association. Conclusion By integrating genetic and epigenetic data, we identified that a differentially methylated CpG site within the melatonin receptor 1A (MTNR1A) gene mediates the effect of a paternally transmitted genetic variant on the comorbidity of asthma and AR. This study provides a novel insight into the role of epigenetic mechanisms in patients with allergic respiratory diseases.
Background Asthma is a heterogeneous disease in which age of onset plays an important role. Objective We sought to identify the genetic variants associated with time to asthma onset (TAO). Methods We ...conducted a large-scale meta-analysis of 9 genome-wide association studies of TAO (total of 5462 asthmatic patients with a broad range of age of asthma onset and 8424 control subjects of European ancestry) performed by using survival analysis techniques. Results We detected 5 regions associated with TAO at the genome-wide significant level ( P < 5 × 10−8 ). We evidenced a new locus in the 16q12 region (near cylindromatosis turban tumor syndrome gene CYLD ) and confirmed 4 asthma risk regions: 2q12 (IL-1 receptor–like 1 IL1RL1 ), 6p21 (HLA-DQA1) , 9p24 (IL33) , and 17q12-q21 (zona pellucida binding protein 2 ZPBP2 –gasdermin A GSDMA ). Conditional analyses identified 2 distinct signals at 9p24 (both upstream of IL33 ) and 17q12-q21 (near ZPBP2 and within GSDMA ). Together, these 7 distinct loci explained 6.0% of the variance in TAO. In addition, we showed that genetic variants at 9p24 and 17q12-q21 were strongly associated with an earlier onset of childhood asthma ( P ≤ .002), whereas the 16q12 single nucleotide polymorphism was associated with later asthma onset ( P = .04). A high burden of disease risk alleles at these loci was associated with earlier age of asthma onset (4 vs 9-12 years, P = 10−4 ). Conclusion The new susceptibility region for TAO at 16q12 harbors variants that correlate with the expression of CYLD and nucleotide-binding oligomerization domain 2 (NOD2) , 2 strong candidates for asthma. This study demonstrates that incorporating the variability of age of asthma onset in asthma modeling is a helpful approach in the search for disease susceptibility genes.
Background Filaggrin, which is encoded by the filaggrin gene (FLG) , is an important component of the skin's barrier to the external environment, and genetic defects in FLG strongly associate with ...atopic dermatitis (AD). However, not all patients with AD have FLG mutations. Objective We hypothesized that these patients might possess other defects in filaggrin expression and processing contributing to barrier disruption and AD, and therefore we present novel therapeutic targets for this disease. Results We describe the relationship between the mechanistic target of rapamycin complex 1/2 protein subunit regulatory associated protein of the MTOR complex 1 (RAPTOR), the serine/threonine kinase V-Akt murine thymoma viral oncogene homolog 1 (AKT1), and the protease cathepsin H (CTSH), for which we establish a role in filaggrin expression and processing. Increased RAPTOR levels correlated with decreased filaggrin expression in patients with AD. In keratinocyte cell cultures RAPTOR upregulation or AKT1 short hairpin RNA knockdown reduced expression of the protease CTSH. Skin of CTSH-deficient mice and CTSH short hairpin RNA knockdown keratinocytes showed reduced filaggrin processing, and the mouse had both impaired skin barrier function and a mild proinflammatory phenotype. Conclusion Our findings highlight a novel and potentially treatable signaling axis controlling filaggrin expression and processing that is defective in patients with AD.
Furthermore, we examined the evidence for association to SNPs within PDE11A in 5 independent case/control populations, of which 3 had at least 1 SNP with a nominally significant P value.\n1 295 59.6 ...Yes 32 48.5 21 51.2 56 54.9 200 40.4 Sibling asthma         None 27 40.9 23 54.8 44 44.9 386 77.5 1 or more 39 59.1 19 45.2 54 55.1 112 22.5 Sex         Male 37 66.1 17 47.2 57 65.5 210 45.8 Female 19 33.9 19 52.8 30 34.5 248 54.2 low * Demographic and phenotype data      GWAS All PRAM rs # Chromosome Position Gene Risk allele Alleliclow * Genotypiclow * ORhom (95% CI) ORhet (95%CI) Alleliclow * Genotypiclow * ORhom (95% CI) ORhet (95%CI) Selection rs710235 1 41975301 HIVEP3 G 1.78E-05 2.15E-03 12.7 (1.6-101.7) 3.7 (1.1-12.0) -- -- -- -- GWAS rs4284254dagger 1 41985663 HIVEP3 G 1.98E-06 4.16E-04 12.7 (1.6-101.7) 7.3 (1.6-34.2) -- -- -- -- GWAS rs7517484 1 42023043 HIVEP3 C 3.16E-06 1.98E-04 11.3 (1.4-91.8) 8.7 (1.9-40.4) -- -- -- -- GWAS rs1154799double dagger 3 125584866 KALRN C 1.04E-04 3.55E-05 6.6§ (2.7-16.4) -- 1.25E-02 3.99E-02 3.5 (0.5-27.1) 1.9 (0.2-15.4) GWAS rs9832203 3 125585007 KALRN A 1.26E-04 9.88E-05 5.6§ (2.3-13.6) -- -- -- -- -- GWAS rs7216389double dagger 17 35323475 ORMDL3 T 7.67E-01 7.40E-01 1.0 (0.3-3.9) 0.7 (0.2-2.6) 2.40E-01 2.97E-01 1.4 (0.7-2.5) 0.9 (0.5-1.7) Candidate low * Information on additional top and candidate SNPs genotyped in PRAM children ORhet, Odds ratio comparing the heterozygous risk genotype to the homozygous wild-type genotype; ORhom, odds ratio comparing the homozygous risk genotype to the homozygous wild-type genotype.- Indicates that these SNPs were not genotyped in the All PRAM samples.
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