Publications
305 results found
Liu Y, Brossard M, Sarnowski C, et al., 2017, Network-assisted analysis of GWAS data identifies a functionally-relevant gene module for childhood-onset asthma., Scientific Reports, Vol: 7, ISSN: 2045-2322
The number of genetic factors associated with asthma remains limited. To identify new genes with an undetected individual effect but collectively influencing asthma risk, we conducted a network-assisted analysis that integrates outcomes of genome-wide association studies (GWAS) and protein-protein interaction networks. We used two GWAS datasets, each consisting of the results of a meta-analysis of nine childhood-onset asthma GWASs (5,924 and 6,043 subjects, respectively). We developed a novel method to compute gene-level P-values (fastCGP), and proposed a parallel dense-module search and cross-selection strategy to identify an asthma-associated gene module. We identified a module of 91 genes with a significant joint effect on childhood-onset asthma (P < 10(-5)). This module contained a core subnetwork including genes at known asthma loci and five peripheral subnetworks including relevant candidates. Notably, the core genes were connected to APP (encoding amyloid beta precursor protein), a major player in Alzheimer's disease that is known to have immune and inflammatory components. Functional analysis of the module genes revealed four gene clusters involved in innate and adaptive immunity, chemotaxis, cell-adhesion and transcription regulation, which are biologically meaningful processes that may underlie asthma risk. Our findings provide important clues for future research into asthma aetiology.
Ek WE, Ahsan M, Rask-Andersen M, et al., 2017, Epigenome-wide DNA methylation study of IgE concentration in relation to self-reported allergies, EPIGENOMICS, Vol: 9, Pages: 407-418, ISSN: 1750-1911
Vonk JM, Scholtens S, Postma DS, et al., 2017, Adult onset asthma and interaction between genes and active tobacco smoking: The GABRIEL consortium, PLoS ONE, Vol: 12, ISSN: 1932-6203
BackgroundGenome-wide association studies have identified novel genetic associations for asthma, butwithout taking into account the role of active tobacco smoking. This study aimed to identifynovel genes that interact with ever active tobacco smoking in adult onset asthma.MethodsWe performed a genome-wide interaction analysis in six studies participating in theGABRIEL consortium following two meta-analyses approaches based on 1) the overall interaction effect and 2) the genetic effect in subjects with and without smoking exposure.We performed a discovery meta-analysis including 4,057 subjects of European descent andreplicated our findings in an independent cohort (LifeLines Cohort Study), including 12,475subjects.ResultsFirst approach: 50 SNPs were selected based on an overall interaction effect at p<10−4. Themost pronounced interaction effect was observed for rs9969775 on chromosome 9 (discoverymeta-analysis: ORint = 0.50, p = 7.63*10−5, replication: ORint = 0.65, p = 0.02). Secondapproach: 35 SNPs were selected based on the overall genetic effect in exposed subjects(p <10−4). The most pronounced genetic effect was observed for rs5011804 on chromosome12 (discovery meta-analysis ORint = 1.50, p = 1.21*10−4; replication: ORint = 1.40,p = 0.03).ConclusionsUsing two genome-wide interaction approaches, we identified novel polymorphisms in nonannotatedintergenic regions on chromosomes 9 and 12, that showed suggestive evidencefor interaction with active tobacco smoking in the onset of adult asthma.
Cox MJ, Turek EM, Hennessy C, et al., 2017, Longitudinal assessment of sputum microbiome by sequencing of the 16S rRNA gene in non-cystic fibrosis bronchiectasis patients, PLOS ONE, Vol: 12, ISSN: 1932-6203
Background:Bronchiectasis is accompanied by chronic bronchial infection that may drive disease progression. However, the evidence base for antibiotic therapy is limited. DNA based methods offer better identification and quantification of microbial constituents of sputum than standard clinical culture and may help inform patient management strategies. Our study objective was to determine the longitudinal variability of the non-cystic fibrosis (CF) bronchiectasis microbiome in sputum with respect to clinical variables. Eighty-five patients with non-CF bronchiectasis and daily sputum production were recruited from outpatient clinics and followed for six months. Monthly sputum samples and clinical measurements were taken, together with additional samples during exacerbations. 16S rRNA gene sequencing of the sputum microbiota was successful for 381 samples from 76 patients and analysed in conjunction with clinical data.Results:Microbial communities were highly individual in composition and stability, usually with limited diversity and often containing multiple pathogens. When compared to DNA sequencing, microbial culture had restricted sensitivity in identifying common pathogens such as Pseudomonas aeruginosa, Haemophilus influenzae, Moraxella catarrhalis. With some exceptions, community characteristics showed poor correlations with clinical features including underlying disease, antibiotic use and exacerbations, with the subject showing the strongest association with community structure. When present, the pathogens mucoid Pseudomonas aeruginosa and Haemophilus influenzae may also shape the structure of the rest of the microbial community.Conclusions:The use of microbial community analysis of sputum added to information from microbial culture. A simple model of exacerbations driven by bacterial overgrowth was not supported, suggesting a need for revision of principles for antibiotic therapy. In individual patients, the management of chronic bronchial infection may be imp
Molyneaux PL, Cox MJ, Wells AU, et al., 2017, Changes in the respiratory microbiome during acute exacerbations of idiopathic pulmonary fibrosis, Respiratory Research, Vol: 18, ISSN: 1465-9921
Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) have been defined as events of clinically significant respiratory deterioration with an unidentifiable cause. They carry a significant mortality and morbidity and while their exact pathogenesis remains unclear, the possibility remains that hidden infection may play a role. The aim of this pilot study was to determine whether changes in the respiratory microbiota occur during an AE-IPF. Bacterial DNA was extracted from bronchoalveolar lavage from patients with stable IPF and those experiencing an AE-IPF. A hyper-variable region of the 16S ribosomal RNA gene (16S rRNA) was amplified, quantified and pyrosequenced. Culture independent techniques demonstrate AE-IPF is associated with an increased BAL bacterial burden compared to stable disease and highlight shifts in the composition of the respiratory microbiota during an AE-IPF.
Gennatas S, Lu SK, Anbunathan H, et al., 2017, Somatic BAP1 and NF2 mutations in pleural malignant mesothelioma and their correlation with clinical phenotype
Dwyer S, Lauener R, Willis-Owen S, et al., 2017, Gene Expression Study Of Childhood Asthma And Atopy In A Rural Environment, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Cuthbertson L, Craven V, Bingle L, et al., 2017, The Pulmonary Microbiome Associated With Persistent Bacterial Bronchitis, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Molyneaux PL, James P, Cuthbertson L, et al., 2017, The Role Of The Fungal Mycobiome In Ipf, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Naeem AS, Tommasi C, Cole C, et al., 2016, A mechanistic target of rapamycin complex 1/2 (mTORC1)/V-Akt murine thymoma viral oncogene homolog 1 (AKT1)/cathepsin H axis controls filaggrin expression and processing in skin, a novel mechanism for skin barrier disruption in patients with atopic dermatitis, Journal of Allergy and Clinical Immunology, Vol: 139, Pages: 1228-1241, ISSN: 0091-6749
BackgroundFilaggrin, 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.ObjectiveWe 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.ResultsWe 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.ConclusionOur findings highlight a novel and potentially treatable signaling axis controlling filaggrin expression and processing that is defective in patients with AD.
Zhang Y, Fear D, Willis-Owen S, et al., 2016, Global gene regulation during activation of immunoglobulin class switching in human B cells, Scientific Reports, Vol: 6, ISSN: 2045-2322
Immunoglobulin class switch recombination (CSR) to IgE is a tightly regulated process central to atopic disease. To profile the B-cell transcriptional responses underlying the activation of the germinal centre activities leading to the generation of IgE, naïve human B-cells were stimulated with IL-4 and anti-CD40. Gene expression and alternative splicing were profiled over 12 days using the Affymetrix Human Exon 1.0 ST Array. A total of 1,399 genes, forming 13 temporal profiles were differentially expressed. CCL22 and CCL17 were dramatically induced but followed a temporal trajectory distinct from classical mediators of isotype switching. AICDA, NFIL3, IRF4, XBP1 and BATF3 shared a profile with several genes involved in innate immunity, but with no recognised role in CSR. A transcription factor BHLHE40 was identified at the core of this profile. B-cell activation was also accompanied by variation in exon retention affecting >200 genes including CCL17. The data indicate a circadian component and central roles for the Th2 chemokines CCL22 and CCL17 in the activation of CSR.
Wong EHC, Dhariwal J, Cuthbertson L, et al., 2016, THE AIRWAY MICROBIOTA IN HUMAN RHINOVIRUS INDUCED ASTHMA EXACERBATION, THORAX, Vol: 71, Pages: A218-A218, ISSN: 0040-6376
Sarnowski C, Dizier M-H, Granell R, et al., 2016, Taking into Account Gene-by-Early Environmental Tobacco Smoke Exposure Interactions to Detect Genetic Variants Influencing Time-to-Asthma Onset, Annual Meeting of the International-Genetic-Epidemiology-Society, Publisher: WILEY-BLACKWELL, Pages: 658-659, ISSN: 0741-0395
Miller S, Henry AP, Hodge E, et al., 2016, The Ser82 RAGE Variant Affects Lung Function and Serum RAGE in Smokers and sRAGE Production In Vitro, PLoS ONE, Vol: 11, ISSN: 1932-6203
Ahmed B, Cox MJ, Cuthbertson L, et al., 2016, EARLY DEVELOPMENT OF THE AIRWAY MICROBIOTA IN INFANTS WITH CF, PEDIATRIC PULMONOLOGY, Vol: 51, Pages: 328-328, ISSN: 8755-6863
Löser S, Gregory LG, Zhang Y, et al., 2016, Pulmonary ORMDL3 is critical for induction of Alternaria induced allergic airways disease, Journal of Allergy and Clinical Immunology, Vol: 139, Pages: 1496-1507.e3, ISSN: 1097-6825
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.
Singanayagam A, Glanville N, James P, et al., 2016, Fluticasone propionate alters the respiratory tract microbiota and has dose-related effects on anti-bacterial host defence, ERS Conference London, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Sarnowski C, Laprise C, Malerba G, et al., 2016, DNA methylation within melatonin receptor 1A (MTNR1A) mediates paternally transmitted genetic variant effect on asthma plus rhinitis, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 138, Pages: 748-753, ISSN: 0091-6749
Sarnowski C, Dizier M-H, Granell R, et al., 2016, Influence of gene-by-early environmental tobacco smoke exposure interactions on time-to-asthma onset, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Zhang Y, Dean C, Loeser S, et al., 2016, Systematic dissection of ORMDL3 function in vitro and in vivo, ERS International Congress 2016, Publisher: European Respiratory Society, ISSN: 0903-1936
ORMDL3 on human chromosome 17q21 is a major genetic influence for childhood asthma, severe asthma and asthma exacerbations. To understand further the functional roles of ORMDL3, we established both human airway epithelial models and a recombineering-generated murine Ormdl3 knockout model. The influences of ORMDL3 on inflammatory responses in vitro and in vivo were investigated.We performed gene silencing using siRNA for two days in airway epithelium cells (A549, Beas2B and NHBE cells) after which cells were stimulated with IL1B. ORMDL3 knockdown-epithelial cells released much less IL6 and IL8 at 10 hours after stimulation (P < 0.01 respectively). Over-expression of ORMDL3 in epithelial cells resulted in a significant increase in release of IL6 and IL8 shortly after stimulation. Serine-palmitoyl transferase (SPT) is the key enzyme of sphingolipid metabolism. Treatment of epithelial cells with the SPT inhibitor myriocin resulted in an increase in release of IL6 and IL8 after stimulation, mirroring the results seen with the overexpression model. A systemic metabolic screening of the ORMDL3 knockdown epithelial cells revealed ORMDL3 to be involved not only in regulating sphingolipid metabolism but also lysophospholipids metabolism and the regulation of glycolysis. Parallel global gene expression profiling of the same cells identified key transcripts involved in regulating the inflammatory response. The lung function of Ormdl3 knockout mice also exhibited a reduced response after Alternaria alternata challenge.Our findings indicate ORMDL3 is a key molecule involved in the regulation of the inflammation response through multiple pathways and is a potential therapeutic target for asthma.
Parker J, Piatek S, Cookson W, et al., 2016, LSC Abstract - Global gene expression analysis of the mucociliary differentiation process of human bronchial epithelial cells at the air-liquid interface, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Parker J, Piatek S, Cookson W, et al., 2016, LSC Abstract - Global gene expression analysis of the mucociliary differentiation process of human bronchial epithelial cells at the air-liquid interface, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Brill S, James P, Cuthbertson L, et al., 2016, Profiling the COPD airway microbiome using quantitative culture and 16S rRNA gene sequencing, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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Depner M, Ege MJ, Cox MJ, et al., 2016, Bacterial microbiota of the upper respiratory tract and childhood asthma, Journal of Allergy and Clinical Immunology, ISSN: 1097-6825
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.
López-Álvarez MR, Jiang W, Jones DC, et al., 2016, LILRA6 copy number variation correlates with susceptibility to atopic dermatitis, Immunogenetics, Vol: 68, Pages: 743-747, ISSN: 1432-1211
Leukocyte immunoglobulin-like receptors (LILR) are expressed mostly on myelomonocytic cells where they are mediators of immunological tolerance. Two LILR genes, LILRA3 and LILRA6, exhibit marked copy number variation. We assessed the contribution of these genes to atopic dermatitis (AD) by analysing transmission in 378 AD families. The data indicated that copies of LILRA6 were over-transmitted to affected patients. They are consistent with a contribution of LILR genes to AD. They could affect the equilibrium between activating and inhibitory signals in the immune response.
Fingerlin TE, Zhang W, Yang IV, et al., 2016, Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia, BMC Genetics, Vol: 17, ISSN: 1471-2156
BACKGROUND: Fibrotic idiopathic interstitial pneumonias (fIIP) are a group of fatal lung diseases with largely unknown etiology and without definitive treatment other than lung transplant to prolong life. There is strong evidence for the importance of both rare and common genetic risk alleles in familial and sporadic disease. We have previously used genome-wide single nucleotide polymorphism data to identify 10 risk loci for fIIP. Here we extend that work to imputed genome-wide genotypes and conduct new RNA sequencing studies of lung tissue to identify and characterize new fIIP risk loci. RESULTS: We performed genome-wide genotype imputation association analyses in 1616 non-Hispanic white (NHW) cases and 4683 NHW controls followed by validation and replication (878 cases, 2017 controls) genotyping and targeted gene expression in lung tissue. Following meta-analysis of the discovery and replication populations, we identified a novel fIIP locus in the HLA region of chromosome 6 (rs7887 P meta = 3.7 × 10(-09)). Imputation of classic HLA alleles identified two in high linkage disequilibrium that are associated with fIIP (DRB1*15:01 P = 1.3 × 10(-7) and DQB1*06:02 P = 6.1 × 10(-8)). Targeted RNA-sequencing of the HLA locus identified 21 genes differentially expressed between fibrotic and control lung tissue (Q < 0.001), many of which are involved in immune and inflammatory response regulation. In addition, the putative risk alleles, DRB1*15:01 and DQB1*06:02, are associated with expression of the DQB1 gene among fIIP cases (Q < 1 × 10(-16)). CONCLUSIONS: We have identified a genome-wide significant association between the HLA region and fIIP. Two HLA alleles are associated with fIIP and affect expression of HLA genes in lung tissue, indicating that the potential genetic risk due to HLA alleles may involve gene regula
Holt RJ, Vandiedonck C, Willis-Owen SA, et al., 2016, A functional AT/G polymorphism in the 5'-untranslated region of SETDB2 in the IgE locus on human chromosome 13q14., Genes Immun, Vol: 18, Pages: 57-57
Cox MJ, Turek EM, Hennessy C, et al., 2016, Longitudinal assessment of sputum microbiome by sequencing of the 16S rRNA gene in non-CF bronchiectasis patients
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Bronchiectasis is accompanied by chronic bronchial infection that may drive disease progression. However, the evidence base for antibiotic therapy is limited. DNA based methods offer better identification and quantification of microbial constituents of sputum than standard clinical culture and may help inform patient management strategies. Our study objective was to determine the longitudinal variability of the non-CF bronchiectasis microbiome in sputum with respect to clinical variables.</jats:p><jats:p>Eighty-five patients with non-cystic fibrosis (CF) bronchiectasis and daily sputum production were recruited from outpatient clinics and followed for six months. Monthly sputum samples and clinical measurements were taken, together with additional samples during exacerbations. 16S rRNA gene sequencing of the sputum microbiota was successful for 381 samples from 76 patients and analysed in conjunction with clinical data.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Microbial communities were highly individual in composition and stability, usually with limited diversity and often containing multiple pathogens. When compared to DNA sequencing, microbial culture had restricted sensitivity in identifying common pathogens. With some exceptions, community characteristics showed poor correlations with clinical features including underlying disease, antibiotic use and exacerbations, with the subject showing the strongest association with community structure. When present, certain pathogens may also shape the structure of the rest of the microbial community.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>The use of microbial community analysis of sputum added to information from microbial culture. A simple model of exacerbat
Zhang Q, Cox M, Liang Z, et al., 2016, Airway microbiota in severe asthma and relationship to asthma severity and phenotypes, PLOS One, Vol: 11, ISSN: 1932-6203
Background: The lower airways harbor a community of bacterial species which is altered in asthma. Objectives: We examined whether the lower airway microbiota were related to measures of asthma severityMethods: We prospectively recruited 26 severe asthma, 18 non-severe asthma and 12 healthy subjects. DNA was extracted from induced sputum and PCR amplification of the V3-V5 region of bacterial 16S rRNA gene was performed. Results: We obtained 138,218 high quality sequences which were rarefied at 133 sequences/sample. Twenty OTUs had sequences ≥1% of total. There were marked differences in the distribution of Phyla between groups (P=2.8x10-118). Bacteroidetes and Fusobacteria were reduced in non-severe and severe asthmatic groups. Proteobacteria were more common in non-severe asthmatics compared to controls (OR=2.26; 95% CI=1.94-2.64) and Firmicutes were increased in severe asthmatics compared to controls (OR=2.15; 95%CI=1.89-2.45). Streptococcal OTUs amongst the Firmicutes were associated with recent onset asthma, rhinosinusitis and sputum eosinophilia.Conclusions: Sputum microbiota in severe asthma differs from healthy controls and non-severe asthmatics, and is characterized by the presence of Streptococcus spp with eosinophilia. Whether these organisms are causative for the pathophysiology of asthma remains to be determined.
Sarnowski C, Sugier PE, Granell R, et al., 2016, Identification of a new locus at 16q12 associated with time to asthma onset, Journal of Allergy and Clinical Immunology, Vol: 138, Pages: 1071-1080, ISSN: 1097-6825
BackgroundAsthma is a heterogeneous disease in which age of onset plays an important role.ObjectiveWe sought to identify the genetic variants associated with time to asthma onset (TAO).MethodsWe 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.ResultsWe 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).ConclusionThe 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.
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