Publications
396 results found
Sugier P-E, Brossard M, Sarnowski C, et al., 2018, A novel role for ciliary function in atopy: ADGRV1 and DNAH5 interactions, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 141, Pages: 1659-1667.e11, ISSN: 0091-6749
BackgroundAtopy, an endotype underlying allergic diseases, has a substantial genetic component.ObjectiveOur goal was to identify novel genes associated with atopy in asthma-ascertained families.MethodsWe implemented a 3-step analysis strategy in 3 data sets: the Epidemiological Study on the Genetics and Environment of Asthma (EGEA) data set (1660 subjects), the Saguenay-Lac-Saint-Jean study data set (1138 subjects), and the Medical Research Council (MRC) data set (446 subjects). This strategy included a single nucleotide polymorphism (SNP) genome-wide association study (GWAS), the selection of related gene pairs based on statistical filtering of GWAS results, and text-mining filtering using Gene Relationships Across Implicated Loci and SNP-SNP interaction analysis of selected gene pairs.ResultsWe identified the 5q14 locus, harboring the adhesion G protein–coupled receptor V1 (ADGRV1) gene, which showed genome-wide significant association with atopy (rs4916831, meta-analysis P value = 6.8 × 10−9). Statistical filtering of GWAS results followed by text-mining filtering revealed relationships between ADGRV1 and 3 genes showing suggestive association with atopy (P ≤ 10−4). SNP-SNP interaction analysis between ADGRV1 and these 3 genes showed significant interaction between ADGRV1 rs17554723 and 2 correlated SNPs (rs2134256 and rs1354187) within the dynein axonemal heavy chain 5 (DNAH5) gene (Pmeta-int = 3.6 × 10−5 and 6.1 × 10−5, which met the multiple-testing corrected threshold of 7.3 × 10−5). Further conditional analysis indicated that rs2134256 alone accounted for the interaction signal with rs17554723.ConclusionBecause both DNAH5 and ADGRV1 contribute to ciliary function, this study suggests that ciliary dysfunction might represent a novel mechanism underlying atopy. Combining GWAS and epistasis analysis driven by statistical and knowledge-based evidence represents a promising approach for identifying ne
Xu C-J, Soderhall C, Bustamante M, et al., 2018, DNA methylation in childhood asthma: an epigenome-wide meta-analysis, LANCET RESPIRATORY MEDICINE, Vol: 6, Pages: 379-388, ISSN: 2213-2600
BackgroundDNA methylation profiles associated with childhood asthma might provide novel insights into disease pathogenesis. We did an epigenome-wide association study to assess methylation profiles associated with childhood asthma.MethodsWe did a large-scale epigenome-wide association study (EWAS) within the Mechanisms of the Development of ALLergy (MeDALL) project. We examined epigenome-wide methylation using Illumina Infinium Human Methylation450 BeadChips (450K) in whole blood in 207 children with asthma and 610 controls at age 4–5 years, and 185 children with asthma and 546 controls at age 8 years using a cross-sectional case-control design. After identification of differentially methylated CpG sites in the discovery analysis, we did a validation study in children (4–16 years; 247 cases and 2949 controls) from six additional European cohorts and meta-analysed the results. We next investigated whether replicated CpG sites in cord blood predict later asthma in 1316 children. We subsequently investigated cell-type-specific methylation of the identified CpG sites in eosinophils and respiratory epithelial cells and their related gene-expression signatures. We studied cell-type specificity of the asthma association of the replicated CpG sites in 455 respiratory epithelial cell samples, collected by nasal brushing of 16-year-old children as well as in DNA isolated from blood eosinophils (16 with asthma, eight controls [age 2–56 years]) and compared this with whole-blood DNA samples of 74 individuals with asthma and 93 controls (age 1–79 years). Whole-blood transcriptional profiles associated with replicated CpG sites were annotated using RNA-seq data of subsets of peripheral blood mononuclear cells sorted by fluorescence-activated cell sorting.Findings27 methylated CpG sites were identified in the discovery analysis. 14 of these CpG sites were replicated and passed genome-wide significance (p<1·14 × 10−7) after meta-analysi
Cowman SA, Jacob J, Hansell DM, et al., 2018, Whole blood gene expression in pulmonary non-tuberculous mycobacterial infection, American Journal of Respiratory Cell and Molecular Biology, Vol: 58, Pages: 510-518, ISSN: 1044-1549
RATIONALE: The factors predisposing towards the development of pulmonary non-tuberculous mycobacterial disease (pNTM) and influencing disease progression remain unclear. Impaired immune responses have been reported in individuals with pNTM but data are limited and inconsistent. OBJECTIVES: To use gene expression profiling to examine the host response to pNTM. METHODS: Microarray analysis of whole blood gene expression was performed on 25 subjects with pNTM and 27 uninfected controls with respiratory disease. Gene expression results were compared to phenotypic variables and survival data. MEASUREMENTS AND MAIN RESULTS: Compared with uninfected controls, pNTM was associated with down-regulation of 213 transcripts enriched for terms related to T cell signalling including IFNG. Reduced IFNG expression was associated with more severe CT changes and impaired lung function. Mortality was associated with the expression of transcripts related to the innate immune response and inflammation, whereas transcripts related to T and B cell function were associated with improved survival. CONCLUSIONS: These findings suggest that pNTM is associated with an aberrant immune response which may reflect an underlying propensity to infection, or result from NTM infection itself. There were important differences in the immune response associated with survival and mortality in pNTM.
Margaritte-Jeannin P, Babron M-C, Laprise C, et al., 2018, The <i>COL5A3</i> and <i>MMP9</i> genes interact in eczema susceptibility, Annual Meeting of the International-Genetic-Epidemiology-Society (IGES), Publisher: WILEY, Pages: 297-305, ISSN: 0954-7894
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Zhang Y, Poobalasingam T, Yates LL, et al., 2018, Manipulation of Dipeptidylpeptidase 10 in mouse and human in vivo and in vitro models indicates a protective role in asthma, Disease Models and Mechanisms, Vol: 11, ISSN: 1754-8403
We previously identified dipeptidylpeptidase 10 (DPP10) on chromosome 2 as a human asthma susceptibility gene, through positional cloning. Initial association results were confirmed in many subsequent association studies but the functional role of DPP10 in asthma remains unclear. Using the MRC Harwell N-ethyl-N-nitrosourea (ENU) DNA archive, we identified a point mutation in Dpp10 that caused an amino acid change from valine to aspartic acid in the β-propeller region of the protein. Mice carrying this point mutation were recovered and a congenic line was established (Dpp10145D). Macroscopic examination and lung histology revealed no significant differences between wild-type and Dpp10145D/145D mice. However, after house dust mite (HDM) treatment, Dpp10 mutant mice showed significantly increased airway resistance in response to 100 mg/ml methacholine. Total serum IgE levels and bronchoalveolar lavage (BAL) eosinophil counts were significantly higher in homozygotes than in control mice after HDM treatment. DPP10 protein is present in airway epithelial cells and altered expression is observed in both tissue from asthmatic patients and in mice following HDM challenge. Moreover, knockdown of DPP10 in human airway epithelial cells results in altered cytokine responses. These results show that a Dpp10 point mutation leads to increased airway responsiveness following allergen challenge and provide biological evidence to support previous findings from human genetic studies.
Nastase A, Gennatas S, Mandal A, et al., 2018, Targeted next-generation sequencing of malignant pleural mesothelioma identifies recurrent NRAS oncogene mutations, 16th Annual British Thoracic Oncology Group Conference 2018, Publisher: ELSEVIER IRELAND LTD, Pages: S26-S26, ISSN: 0169-5002
Mandal A, Gennatas S, Liu K, et al., 2018, Copy number variations in malignant pleural mesothelioma reveal novel regions of genomic imbalances, Publisher: ELSEVIER IRELAND LTD, Pages: S27-S27, ISSN: 0169-5002
Cuthbertson L, Craven V, Bingle L, et al., 2017, The impact of persistent bacterial bronchitis on the pulmonary microbiome of children., PLoS ONE, Vol: 12, ISSN: 1932-6203
INTRODUCTION: Persistent bacterial bronchitis (PBB) is a leading cause of chronic wet cough in young children. This study aimed to characterise the respiratory bacterial microbiota of healthy children and to assess the impact of the changes associated with the development of PBB. Blind, protected brushings were obtained from 20 healthy controls and 24 children with PBB, with an additional directed sample obtained from PBB patients. DNA was extracted, quantified using a 16S rRNA gene quantitative PCR assay prior to microbial community analysis by 16S rRNA gene sequencing. RESULTS: No significant difference in bacterial diversity or community composition (R2 = 0.01, P = 0.36) was observed between paired blind and non-blind brushes, showing that blind brushings are a valid means of accessing the airway microbiota. This has important implications for collecting lower respiratory samples from healthy children. A significant decrease in bacterial diversity (P < 0.001) and change in community composition (R2 = 0.08, P = 0.004) was observed among controls, in comparison with patients. Bacterial communities within patients with PBB were dominated by Proteobacteria, and indicator species analysis showed that Haemophilus and Neisseria were significantly associated with the patient group. In 15 (52.9%) cases the dominant organism by sequencing was not identified by standard routine clinical culture. CONCLUSION: The bacteria present in the lungs of patients with PBB were less diverse in terms of richness and evenness. The results validate the clinical diagnosis, and suggest that more attention to bacterial communities in children with chronic cough may lead to more rapid recognition of this condition with earlier treatment and reduction in disease burden.
Demenais F, Margaritte-Jeannin P, Barnes KC, et al., 2017, Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks, Nature Genetics, Vol: 50, Pages: 42-53, ISSN: 1061-4036
We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.
Moffatt MF, Cookson WOCM, 2017, The lung microbiome in health and disease, Clinical Medicine, Vol: 17, Pages: 525-529, ISSN: 1470-2118
The Human Microbiome Project began 10 years ago, leadingto a signifi cant growth in understanding of the role the humanmicrobiome plays in health and disease. In this article, weexplain with an emphasis on the lung, the origins of microbiomeresearch. We discuss how 16S rRNA gene sequencingbecame the fi rst major molecular tool to examine the bacterialcommunities present within the human body. We highlightthe pitfalls of molecular-based studies, such as false fi ndingsresulting from contamination, and the limitations of 16S rRNAgene sequencing. Knowledge about the lung microbiome hasevolved from initial scepticism to the realisation that it mighthave a signifi cant infl uence on many illnesses. We also discussthe lung microbiome in the context of disease by givingexamples of important respiratory conditions. In addition, wedraw attention to the challenges for metagenomic studies ofrespiratory samples and the importance of systematic bacterialisolation to enable host–microbiome interactions to beunderstood. We conclude by discussing how knowledge of thelung microbiome impacts current clinical diagnostics.
Herazo-Maya JD, Sun J, Molyneaux PL, et al., 2017, Validation of a 52-gene risk profile for outcome prediction in patients with idiopathic pulmonary fibrosis: an international, multicentre, cohort study, Lancet Respiratory Medicine, Vol: 5, Pages: 857-868, ISSN: 2213-2600
BACKGROUND: The clinical course of idiopathic pulmonary fibrosis (IPF) is unpredictable. Clinical prediction tools are not accurate enough to predict disease outcomes. METHODS: We enrolled patients with IPF diagnosis in a six-cohort study at Yale University (New Haven, CT, USA), Imperial College London (London, UK), University of Chicago (Chicago, IL, USA), University of Pittsburgh (Pittsburgh, PA, USA), University of Freiburg (Freiburg im Breisgau, Germany), and Brigham and Women's Hospital-Harvard Medical School (Boston, MA, USA). Peripheral blood mononuclear cells or whole blood were collected at baseline from 425 participants and from 98 patients (23%) during 4-6 years' follow-up. A 52-gene signature was measured by the nCounter analysis system in four cohorts and extracted from microarray data (GeneChip) in the other two. We used the Scoring Algorithm for Molecular Subphenotypes (SAMS) to classify patients into low-risk or high-risk groups based on the 52-gene signature. We studied mortality with a competing risk model and transplant-free survival with a Cox proportional hazards model. We analysed timecourse data and response to antifibrotic drugs with linear mixed effect models. FINDINGS: The application of SAMS to the 52-gene signature identified two groups of patients with IPF (low-risk and high-risk), with significant differences in mortality or transplant-free survival in each of the six cohorts (hazard ratio [HR] range 2·03-4·37). Pooled data showed similar results for mortality (HR 2·18, 95% CI 1·53-3·09; p<0·0001) or transplant-free survival (2·04, 1·52-2·74; p<0·0001). Adding 52-gene risk profiles to the Gender, Age, and Physiology index significantly improved its mortality predictive accuracy. Temporal changes in SAMS scores were associated with changes in forced vital capacity (FVC) in two cohorts. Untreated patients did not shift their risk profile over time. A simultaneous
Starren E, Mcdonough J, Nicholson A, et al., 2017, Direct Metabolomic Profiling of Lung Cancers, Publisher: ELSEVIER SCIENCE INC, Pages: S1824-S1824, ISSN: 1556-0864
Starren E, Willis-Owen S, Lo SK, et al., 2017, The Molecular Characterization of Lung Adenocarcinoma Subgroups, Publisher: ELSEVIER SCIENCE INC, Pages: S1943-S1943, ISSN: 1556-0864
Cookson WOCM, Cox MJ, Moffatt MF, 2017, New opportunities for managing acute and chronic lung infections., Nature Reviews Microbiology, Vol: 16, Pages: 111-120, ISSN: 1740-1526
Lung diseases caused by microbial infections affect hundreds of millions of children and adults throughout the world. In Western populations, the treatment of lung infections is a primary driver of antibiotic resistance. Traditional therapeutic strategies have been based on the premise that the healthy lung is sterile and that infections grow in a pristine environment. As a consequence, rapid advances in our understanding of the composition of the microbiota of the skin and bowel have not yet been matched by studies of the respiratory tree. The recognition that the lungs are as populated with microorganisms as other mucosal surfaces provides the opportunity to reconsider the mechanisms and management of lung infections. Molecular analyses of the lung microbiota are revealing profound adverse responses to widespread antibiotic use, urbanization and globalization. This Opinion article proposes how technologies and concepts flowing from the Human Microbiome Project can transform the diagnosis and treatment of common lung diseases.
Wong E, Dhariwal J, Cuthbertson L, et al., 2017, An imbalanced airway microbiota correlates with greater peak flow decline in virus-induced asthma exacerbations, European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Cuthbertson L, Craven V, Bingle L, et al., 2017, The impact of persistent bacterial bronchitis on the pulmonary microbiome of children
<jats:title><jats:bold>Abstract</jats:bold></jats:title><jats:p>Persistent bacterial bronchitis is a leading cause of chronic wet cough in young children. This study aimed to characterise the respiratory bacterial microbiota of healthy children and to assess the impact of the changes associated with the development of persistent bacterial bronchitis.</jats:p><jats:p>Blind, protected brushings were obtained from 20 healthy controls and 24 children with persistent bacterial bronchitis, with an additional directed sample obtained from persistent bacterial bronchitis patients. DNA was extracted, quantified using a 16S rRNA gene quantitative PCR assay prior to microbial community analysis by 16S rRNA gene sequencing.</jats:p><jats:p>No significant difference in bacterial diversity or community composition (R<jats:sup>2</jats:sup> = 0.01, <jats:italic>P</jats:italic> = 0.36) was observed between paired blind and non-blind brushes, showing that blind brushings are a valid means of accessing the airway microbiota. This has important implications for collecting lower respiratory samples from healthy children. A significant decrease in bacterial diversity (<jats:italic>P</jats:italic> < 0.001) and change in community composition (R<jats:sup>2</jats:sup> = 0.08, <jats:italic>P</jats:italic> = 0.004) was observed between controls and patients. Bacterial communities within patients with PBB were dominated by <jats:italic>Proteobacteria</jats:italic>, and indicator species analysis showed that <jats:italic>Haemophilus</jats:italic> and <jats:italic>Neisseria</jats:italic> were significantly associated with the patient group. In 15 (52.9%) cases the dominant organism by sequencing was not identified by standard routine clinical culture.</jats:p><jats:p>The bacteria present in the lungs of patients with persistent b
Moffatt MF, Cullinan P, James PL, et al., 2017, Metal worker’s lung; spatial association with Mycobacterium avium, Thorax, Vol: 73, Pages: 151-156, ISSN: 1468-3296
Background Outbreaks of hypersensitivity pneumonitis(HP) are not uncommon in workplaces where metalworking fluid (MWF) is used to facilitate metal turning.Inhalation of microbe-contaminated MWF has beenassumed to be the cause, but previous investigationshave failed to establish a spatial relationship between acontaminated source and an outbreak.Objectives After an outbreak of five cases of HP ina UK factory, we carried out blinded, molecular-basedmicrobiological investigation of MWF samples in orderto identify potential links between specific microbial taxaand machines in the outbreak zone.Methods Custom-quantitative PCR assays, microscopyand phylogenetic analyses were performed on blindedMWF samples to quantify microbial burden and identifypotential aetiological agents of HP in metal workers.Measurements and main results MWF frommachines fed by a central sump, but not those with anisolated supply, was contaminated by mycobacteria. Thefactory sump and a single linked machine at the centre ofthe outbreak zone, known to be the workstation of theindex cases, had very high levels of detectable organisms.Phylogenetic placement of mycobacterial taxonomicmarker genes generated from these samples indicatedthat the contaminating organisms were closely related toMycobacterium avium.Conclusions We describe, for the first time, a closespatial relationship between the abundance of amycobacterium-like organism, most probably M. avium,and a localised outbreak of MWF-associated HP.The further development of sequence-based analytictechniques should assist in the prevention of thisimportant occupational disease.
SANDFORD AJ, MOFFATT MF, DANIELS SE, et al., 2017, A GENETIC-MAP OF CHROMOSOME 11Q, INCLUDING THE ATOPY LOCUS, EUROPEAN JOURNAL OF HUMAN GENETICS, Vol: 3, Pages: 188-194, ISSN: 1018-4813
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Chen W, Wang T, Pino-Yanes M, et al., 2017, An epigenome-wide association study of total serum IgE in Hispanic children, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 140, Pages: 571-577, ISSN: 0091-6749
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- Citations: 40
Molyneaux PL, Willis Owen SA, Cox MJ, et al., 2017, Host-microbial interactions in idiopathic pulmonary fibrosis, American Journal of Respiratory and Critical Care Medicine, Vol: 195, Pages: 1640-1650, ISSN: 1535-4970
RATIONALE: Changes in the respiratory microbiome are associated with disease progression in Idiopathic pulmonary fibrosis (IPF). The role of the host response to the respiratory microbiome however remains unknown. OBJECTIVES: To explore the host-microbial interaction in IPF. METHODS: Sixty patients diagnosed with IPF were prospectively enrolled, together with 20 matched controls. Subjects underwent bronchoalveolar lavage (BAL) and peripheral whole blood was collected into PAXgene tubes for all subjects at baseline. For IPF subjects additional samples were taken at 1, 3, and 6 months and (if alive) a year. Gene expression profiles were generated using Affymetrix Human Gene1.1ST Arrays. MEASUREMENTS AND MAIN RESULTS: Network analysis of gene expression data identified two gene modules that strongly associate with a diagnosis of IPF, BAL bacterial burden (determined by 16S quantitative PCR) and specific microbial OTUs, as well as lavage and peripheral blood neutrophilia. Genes within these modules that are involved in the host defence response include NLRC4, PGLYRP1, MMP9, DEFA4. The modules also contain two genes encoding specific antimicrobial peptides (SLPI and CAMP). Many of these particular transcripts were associated with survival and showed longitudinal over expression in subjects experiencing disease progression, further strengthening their relationship with disease. CONCLUSIONS: Integrated analysis of the host transcriptome and microbial signatures demonstrates an apparent host response to the presence of an altered or more abundant microbiome. These responses remain elevated on longitudinal follow up, suggesting that the bacterial communities of the lower airways may be acting as persistent stimuli for repetitive alveolar injury in IPF.
Manousaki D, Paternoster L, Standl M, et al., 2017, Vitamin D levels and susceptibility to asthma, elevated immunoglobulin E levels, and atopic dermatitis: a Mendelian randomization study, PLoS Medicine, Vol: 14, Pages: 1-16, ISSN: 1549-1277
Background:Low circulating vitamin D levels have been associated with risk of asthma, atopic dermatitis, and elevated total immunoglobulin E (IgE). These epidemiological associations, if true, would have public health importance, since vitamin D insufficiency is common and correctable.Methods and findings:We aimed to test whether genetically lowered vitamin D levels were associated with risk of asthma, atopic dermatitis, or elevated serum IgE levels, using Mendelian randomization (MR) methodology to control bias owing to confounding and reverse causation. The study employed data from the UK Biobank resource and from the SUNLIGHT, GABRIEL and EAGLE eczema consortia. Using four single-nucleotide polymorphisms (SNPs) strongly associated with 25-hydroxyvitamin D (25OHD) levels in 33,996 individuals, we conducted MR studies to estimate the effect of lowered 25OHD on the risk of asthma (n = 146,761), childhood onset asthma (n = 15,008), atopic dermatitis (n = 40,835), and elevated IgE level (n = 12,853) and tested MR assumptions in sensitivity analyses. None of the four 25OHD-lowering alleles were associated with asthma, atopic dermatitis, or elevated IgE levels (p ≥ 0.2). The MR odds ratio per standard deviation decrease in log-transformed 25OHD was 1.03 (95% confidence interval [CI] 0.90–1.19, p = 0.63) for asthma, 0.95 (95% CI 0.69–1.31, p = 0.76) for childhood-onset asthma, and 1.12 (95% CI 0.92–1.37, p = 0.27) for atopic dermatitis, and the effect size on log-transformed IgE levels was −0.40 (95% CI −1.65 to 0.85, p = 0.54). These results persisted in sensitivity analyses assessing population stratification and pleiotropy and vitamin D synthesis and metabolism pathways. The main limitations of this study are that the findings do not exclude an association between the studied outcomes and 1,25-dihydoxyvitamin D, the active form of vitamin D, the study was underpowered to detect effects smaller than an OR of 1.33 for childhood asthma, a
Edwards MR, Saglani S, Schwarze J, et al., 2017, Addressing unmet needs in understanding asthma mechanisms: From the European Asthma Research and Innovation Partnership (EARIP) Work Package (WP)2 collaborators, European Respiratory Journal, Vol: 49, ISSN: 1399-3003
Asthma is a heterogeneous, complex disease with clinical phenotypes that incorporate persistent symptoms and acute exacerbations. It affects many millions of Europeans throughout their education and working lives and puts a heavy cost on European productivity. There is a wide spectrum of disease severity and control. Therapeutic advances have been slow despite greater understanding of basic mechanisms and the lack of satisfactory preventative and disease modifying management for asthma constitutes a significant unmet clinical need. Preventing, treating and ultimately curing asthma requires co-ordinated research and innovation across Europe. The European Asthma Research and Innovation Partnership (EARIP) is an FP7-funded programme which has taken a co-ordinated and integrated approach to analysing the future of asthma research and development. This report aims to identify the mechanistic areas in which investment is required to bring about significant improvements in asthma outcomes.
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.
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.
Mathias RA, Chavan S, Boorgula M, et al., 2017, Whole Genome Sequencing Identifies Four Novel Variants in the Epidermal Differentiation Complex That Increase Risk and Severity for Atopic Dermatitis, Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI), Publisher: MOSBY-ELSEVIER, Pages: AB85-AB85, ISSN: 0091-6749
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
Nicolaou G, Parkerl J, Cookson W, et al., 2017, Functional Investigations Of The Role Of Thymic Stromal Lymphopoietin In Asthma, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
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