Imperial College London

DrSaffronWillis-Owen

Faculty of MedicineNational Heart & Lung Institute

Research Associate
 
 
 
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Contact

 

+44 (0)20 7594 7974s.willis-owen

 
 
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Location

 

305Guy Scadding BuildingRoyal Brompton Campus

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Summary

 

Publications

Publication Type
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71 results found

Cookson W, Turek E, Moffatt M, Cox M, Hunter M, Hui J, James P, Willis-Owen S, Cuthbertson L, James A, Musk Aet al., 2021, Airway microbial communities, smoking and asthma in a general population sample, EBioMedicine, Vol: 71, Pages: 1-9, ISSN: 2352-3964

BackgroundNormal airway microbial communities play a central role in respiratory health but arepoorly characterized. Cigarette smoking is the dominant global environmental influenceon lung function, and asthma has become the most prevalent chronic respiratorydisease worldwide. Both conditions have major microbial components that areincompletely defined.MethodsWe investigated airway bacterial communities in a general population sample of 529Australian adults. Posterior oropharyngeal swabs were analyzed by sequencing of the16S rRNA gene. The microbiota were characterized according to their prevalence,abundance and network memberships.FindingsThe microbiota were similar across the general population, and were stronglyorganized into co-abundance networks. Smoking associated with diversity loss,negative effects on abundant taxa, profound alterations to network structure andexpansion of Streptococcus spp. By contrast, the asthmatic microbiota wereselectively affected by an increase in Neisseria spp. and by reduced numbers of lowabundance but prevalent organisms.InterpretationOur study shows that the healthy airway microbiota in this population were containedwithin a highly structured ecosystem, suggesting balanced relationships between themicrobiome and human host factors. The marked abnormalities in smokers maycontribute to chronic obstructive pulmonary disease (COPD) and lung cancer. Thenarrow spectrum of abnormalities in asthmatics encourages investigation of damagingand protective effects of specific bacteria.

Journal article

Domingo-Sabugo C, Willis-Owen SAG, Mandal A, Nastase A, Dwyer S, Brambilla C, Gálvez JH, Zhuang Q, Popat S, Eveleigh R, Munter M, Lim E, Nicholson AG, Lathrop M, Cookson WOC, Moffatt MFet al., 2021, Distinct pancreatic and neuronal Lung Carcinoid molecular subtypes revealed by integrative omic analysis

<jats:title>Summary</jats:title><jats:p>Lung Carcinoids (L-CDs) are uncommon low-grade neuroendocrine tumours that are only recently becoming characterised at the molecular level. Notably data on the molecular events that precipitate altered gene expression programmes are very limited. Here we have identified two discrete L-CD subtypes from transcriptomic and whole-genome DNA methylation data, and comprehensively defined their molecular profiles using Whole-Exome Sequencing (WES) and Single Nucleotide Polymorphism (SNP) genotyping. Subtype (Group) 1 features upregulation of neuronal markers (L-CD-NeU) and is characterised by focal spindle cell morphology, peripheral location (71%), high mutational load (<jats:italic>P</jats:italic>=3.4×10<jats:sup>−4</jats:sup>), recurrent copy number alterations and is enriched for Atypical Lung Carcinoids. Group 2 (L-CD-PanC) are centrally located and feature upregulation of pancreatic and metabolic pathway genes concordant with promoter hypomethylation of beta cell and genes related to insulin secretion (<jats:italic>P</jats:italic>&lt;1×10<jats:sup>−6</jats:sup>). L-CD-NeU tumours harbour mutations in chromatin remodelling and in SWI/SNF complex members, while L-CD-PanC tumours show aflatoxin mutational signatures and significant DNA methylation loss genome-wide, particularly enriched in repetitive elements (<jats:italic>P</jats:italic>&lt;2.2 × 10<jats:sup>−16</jats:sup>). Our findings provide novel insights into the distinct mechanisms of epigenetic dysregulation in these lung malignancies, potentially opening new avenues for biomarker selection and treatment in L-CD patients.</jats:p>

Journal article

Willis-Owen S, Domingo Sabugo C, Starren E, Liang L, Freidin M, Arseneault M, Zhang Y, Kiong Lu S, Popat S, Lim E, Nicholson A, Riazalhosseini Y, Lathrop M, Cookson W, Moffatt Met al., 2021, Y disruption, autosomal hypomethylation and poor male lung cancer survival, Scientific Reports, Vol: 11, ISSN: 2045-2322

Lung cancer is the most frequent cause of cancer death worldwide. It affects more men than women, and men generally have worse survival outcomes. We compared gene co-expression networks in affected and unaffected lung tissue from 126 consecutive patients with Stage IA–IV lung cancer undergoing surgery with curative intent. We observed marked degradation of a sex-associated transcription network in tumour tissue. This disturbance, detected in 27.7% of male tumours in the discovery dataset and 27.3% of male tumours in a further 123-sample replication dataset, was coincident with partial losses of the Y chromosome and extensive autosomal DNA hypomethylation. Central to this network was the epigenetic modifier and regulator of sexually dimorphic gene expression, KDM5D. After accounting for prognostic and epidemiological covariates including stage and histology, male patients with tumour KDM5D deficiency showed a significantly increased risk of death (Hazard Ratio [HR] 3.80, 95% CI 1.40–10.3, P = 0.009). KDM5D deficiency was confirmed as a negative prognostic indicator in a further 1100 male lung tumours (HR 1.67, 95% CI 1.4–2.0, P = 1.2 × 10–10). Our findings identify tumour deficiency of KDM5D as a prognostic marker and credible mechanism underlying sex disparity in lung cancer.

Journal article

Laura G, Liu Y, Fernandes K, Willis-Owen SAG, Ito K, Cookson WO, Moffatt MF, Zhang Yet al., 2021, ORMDL3 regulates poly I:C induced inflammatory responses in airway epithelial cells, BMC Pulmonary Medicine, Vol: 21, ISSN: 1471-2466

Background:Oroscomucoid 3 (ORMDL3) has been linked to susceptibility of childhood asthma and respiratory viral infection. Polyinosinic-polycytidylic acid (poly I:C) is a synthetic analog of viral double-stranded RNA, a toll-like receptor 3 (TLR3) ligand and mimic of viral infection.Methods:To investigate the functional role of ORMDL3 in the poly I:C-induced inflammatory response in airway epithelial cells, ORMDL3 knockdown and over-expression models were established in human A549 epithelial cells and primary normal human bronchial epithelial (NHBE) cells. The cells were stimulated with poly I:C or the Th17 cytokine IL-17A. IL-6 and IL-8 levels in supernatants, mRNA levels of genes in the TLR3 pathway and inflammatory response from cell pellets were measured. ORMDL3 knockdown models in A549 and BEAS-2B epithelial cells were then infected with live human rhinovirus (HRV16) followed by IL-6 and IL-8 measurement.Results:ORMDL3 knockdown and over-expression had little influence on the transcript levels of TLR3 in airway epithelial cells. Time course studies showed that ORMDL3-deficient A549 and NHBE cells had an attenuated IL-6 and IL-8 response to poly I:C stimulation. A549 and NHBE cells over-expressing ORMDL3 released relatively more IL-6 and IL-8 following poly I:C stimulation. IL-17A exhibited a similar inflammatory response in ORMDL3 knockdown and over-expressing cells, but co-stimulation of poly I:C and IL-17A did not significantly enhance the IL-6 and IL-8 response. Transcript abundance of IFNB following poly I:C stimulation was not significantly altered by ORMDL3 knockdown or over-expression. Dampening of the IL-6 response by ORMDL3 knockdown was confirmed in HRV16 infected BEAS-2B and A549 cells.Conclusions:ORMDL3 regulates the viral inflammatory response in airway epithelial cells via mechanisms independent of the TLR3 pathway.

Journal article

Hoang LT, Domingo-Sabugo C, Starren ES, Willis-Owen SA, Morris-Rosendah DJ, Nicholson AG, Cookson WOCM, Moffatt MFet al., 2019, Metabolomic, transcriptomic and genetic integrative analysis reveals important roles of adenosine diphosphate in haemostasis and platelet activation in non-small-cell lung cancer, Molecular Oncology, Vol: 13, Pages: 2406-2421, ISSN: 1574-7891

Lung cancer is the leading cause of cancer‐related deaths in the world. The most prevalent subtype, accounting for 85% of cases, is non‐small‐cell lung cancer (NSCLC). Lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) are the most common subtypes. Despite recent advances in treatment, the low 5‐year survival rate of NSCLC patients (approximately 13%) reflects the lack of early diagnostic biomarkers and incomplete understanding of the underlying disease mechanisms. We hypothesized that integration of metabolomic, transcriptomic and genetic profiles of tumours and matched normal tissues could help to identify important factors and potential therapeutic targets that contribute to tumorigenesis. We integrated omics profiles in tumours and matched adjacent normal tissues of patients with LUSC (N = 20) and LUAD (N = 17) using multiple system biology approaches. We confirmed the presence of previously described metabolic pathways in NSCLC, particularly those mediating the Warburg effect. In addition, through our combined omics analyses we found that metabolites and genes that contribute to haemostasis, angiogenesis, platelet activation and cell proliferation were predominant in both subtypes of NSCLC. The important roles of adenosine diphosphate in promoting cancer metastasis through platelet activation and angiogenesis suggest this metabolite could be a potential therapeutic target.

Journal article

Hoang L, Domingo-Sabugo C, Starren E, Willis-Owen S, Nicholson A, Morris-Rosendahl D, Moffatt M, Cookson Wet al., 2019, Integrative Omics Analysis Reveals Important Roles of Adenosine Diphosphate in Haemostasis and Platelet Activation in NSCLC, Publisher: ELSEVIER SCIENCE INC, Pages: S419-S419, ISSN: 1556-0864

Conference paper

Ciano M, Mantellato G, Connolly M, Paul-Clark M, Mitchell J, Wilson-Owen S, Cookson W, Moffatt M, Hughes S, Polkey M, Kemp P, Natanek Set al., 2019, EGF receptor (EGFR) inhibition promotes a slow-twitch oxidative, over a fast-twitch, muscle phenotype, Scientific Reports, Vol: 9, ISSN: 2045-2322

A low quadriceps slow-twitch (ST), oxidative (relative to fast-twitch) fiber proportion is prevalent in chronic diseases such Chronic Obstructive Pulmonary Disease (COPD) and is associated with exercise limitation and poor outcomes. Benefits of an increased ST fiber proportion are demonstrated in genetically modified animals. Pathway analysis of published data of differentially expressed genes in mouse ST and FT fibers, mining of our microarray data and a qPCR analysis of quadriceps specimens from COPD patients and controls were performed. ST markers were quantified in C2C12 myotubes with EGF-neutralizing antibody, EGFR inhibitor or an EGFR-silencing RNA added. A zebrafish egfra mutant was generated by genome editing and ST fibers counted. EGF signaling was (negatively) associated with the ST muscle phenotype in mice and humans, and muscle EGF transcript levels were raised in COPD. In C2C12 myotubes, EGFR inhibition/silencing increased ST, including mitochondrial, markers. In zebrafish, egfra depletion increased ST fibers and mitochondrial content. EGF is negatively associated with ST muscle phenotype in mice, healthy humans and COPD patients. EGFR blockade promotes the ST phenotype in myotubes and zebrafish embryos. EGF signaling suppresses the ST phenotype, therefore EGFR inhibitors may be potential treatments for COPD-related muscle ST fiber loss.

Journal article

Turek EM, Cox MJ, Hunter M, Hui J, James P, Willis-Owen SAG, Cuthbertson L, James A, Musk AW, Moffatt MF, Cookson WOCMet al., 2019, Smoking, asthma and airway microbial disruption, Publisher: Cold Spring Harbor Laboratory

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Normal airway microbial communities play a central role in respiratory health but are poorly characterized. Cigarette smoking is the dominant global environmental influence on lung function, and asthma has become the most prevalent chronic respiratory disease worldwide. Both conditions have major microbial components that are also poorly defined.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We investigated airway bacterial communities in a general population sample of 529 Australian adults. Posterior oropharyngeal swabs were analysed by sequencing of the 16S rRNA and methionine aminopeptidase genes. The microbiota were characterised according to their prevalence, abundance, and network memberships.</jats:p></jats:sec><jats:sec><jats:title>Findings</jats:title><jats:p>Microbial communities were similar across the population and were strongly organized into co-abundance networks. Smoking associated with diversity loss, negative effects on abundant taxa, profound alterations to network structure and expansion of <jats:italic>Streptococcus</jats:italic> spp. By contrast, the asthmatic microbiota were selectively affected by an increase in <jats:italic>Neisseria</jats:italic> spp. and by reduced numbers of low abundance but prevalent organisms.</jats:p></jats:sec><jats:sec><jats:title>Interpretation</jats:title><jats:p>Our study shows healthy airway microbiota are contained within a highly structured ecosystem, indicating balanced relationships between the microbiome and human host factors. The marked abnormalities in smokers may be pathogenic for chronic obstructive pulmonary disease (COPD) and lung cancer. The narrow spectrum of abnormalities in asthmatics encourages investigation of damaging and

Working paper

Zhang Y, Willis-Owen S, Spiegel S, Lloyd C, Moffatt M, Cookson Wet al., 2019, The ORMDL3 asthma gene regulates ICAM1 and has multiple effects on cellular inflammation, American Journal of Respiratory and Critical Care Medicine, Vol: 199, Pages: 478-488, ISSN: 1073-449X

Rationale: Polymorphisms on chromosome 17q21 confer the major genetic susceptibility to childhood-onset asthma. Risk alleles positively correlate with ORMDL3 expression. The locus influences disease severity and the frequency of human rhinovirus (HRV) initiated exacerbations. ORMDL3 is known to regulate sphingolipid synthesis by binding serine palmitoyltransferase (SPT), but its role in inflammation is incompletely understood. Objectives: To investigate the role of ORMDL3 in cellular inflammation. Methods: We modelled time-series of IL1B-induced inflammation in A549 cells, using cytokine production as outputs and testing effects of ORMDL3 siRNA knockdown, ORMDL3 overexpression, and the SPT inhibitor myriocin. We replicated selected findings in normal human bronchial epithelial (NHBE) cells. Cytokine and metabolite levels were analysed by ANOVA. Transcript abundances were analysed by group means parameterisation, controlling the false discovery rate (FDR) below 0.05. Measurements and Main Results: Silencing ORMDL3 led to steroid-independent reduction of IL6 and IL8 release and reduced ER stress after IL1B. Overexpression and myriocin conversely augmented cytokine release. Knockdown reduced expression of genes regulating host-pathogen interactions, stress responses and ubiquitination: in particular ORMDL3 knockdown strongly reduced expression of the HRV receptor ICAM1. Silencing led to changes in levels of transcripts and metabolites integral to glycolysis. Increased levels of ceramides and the immune mediator sphingosine-1-P (S1P) were also observed. Conclusions: The results show ORMDL3 has pleiotropic effects during cellular inflammation, consistent with its substantial genetic influence on childhood asthma. Actions on ICAM1 provide a mechanism for the locus to confer susceptibility to HRV-induced asthma.

Journal article

Willis-Owen SAG, Thompson AR, Kemp P, Moffatt MF, Polkey M, Cookson W, Natanek Set al., 2018, COPD is accompanied by co-ordinated transcriptional perturbation in the quadriceps affecting the mitochondria and extracellular matrix, Scientific Reports, Vol: 8, ISSN: 2045-2322

Skeletal muscle dysfunction is a frequent extra-pulmonary manifestation of Chronic Obstructive Pulmonary Disease (COPD) with implications for both quality of life and survival. The underlying biology nevertheless remains poorly understood. We measured global gene transcription in the quadriceps using Affymetrix HuGene1.1ST arrays in an unselected cohort of 79 stable COPD patients in secondary care and 16 healthy age- and gender-matched controls. We detected 1,826 transcripts showing COPD-related variation. Eighteen exhibited ≥2fold changes (SLC22A3, FAM184B, CDKN1A, FST, LINC01405, MUSK, PANX1, ANKRD1, C12orf75, MYH1, POSTN, FRZB, TNC, ACTC1, LINC00310, MYH3, MYBPH and AREG). Thirty-one transcripts possessed previous reported evidence of involvement in COPD through genome-wide association, including FAM13A. Network analysis revealed a substructure comprising 6 modules of co-expressed genes. We identified modules with mitochondrial and extracellular matrix features, of which IDH2, a central component of the mitochondrial antioxidant pathway, and ABI3BP, a proposed switch between proliferation and differentiation, represent hubs respectively. COPD is accompanied by coordinated patterns of transcription in the quadriceps involving the mitochondria and extracellular matrix and including genes previously implicated in primary disease processes.

Journal article

Willis-Owen SAG, Cookson WOC, Moffatt MF, 2018, The Genetics and Genomics of Asthma, ANNUAL REVIEW OF GENOMICS AND HUMAN GENETICS, VOL 19, Vol: 19, Pages: 223-246, ISSN: 1527-8204

Journal article

Starren E, Willis-Owen S, Lo SK, Nicholson A, Cookson W, Moffatt Met al., 2017, The Molecular Characterization of Lung Adenocarcinoma Subgroups, Publisher: ELSEVIER SCIENCE INC, Pages: S1943-S1943, ISSN: 1556-0864

Conference paper

Molyneaux PL, Willis Owen SA, Cox MJ, James P, Cowman S, Loebinger M, Blanchard A, Edwards LM, Stock C, Daccord C, Renzoni EA, Wells AU, Moffatt MF, Cookson WO, Maher TMet 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.

Journal article

Mathias RA, Chavan S, Boorgula M, Cookson WOC, Willis-Owen S, Rafaels NM, Hanifin JM, Paller A, Schneider LC, Gallo R, Guttman-Yassky E, Ong PY, Ruczinski I, Beaty T, Gao L, Beck LA, Moffat M, Leung DYM, Barnes KCet 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

Conference paper

Dwyer S, Lauener R, Willis-Owen S, Genuneit J, Horak E, Ege M, Cookson W, von Mutius E, Moffatt Met 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

Conference paper

Zhang Y, Fear D, Willis-Owen S, Cookson W, Moffatt Met 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.

Journal article

Naeem AS, Tommasi C, Cole C, Brown SJ, Zhu Y, Way B, Owen SAGW, Moffatt M, Cookson WO, Harper JI, Di W-L, Brown SJ, Reinheckel T, O'Shaughnessy RFLet 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.

Journal article

Holt RJ, Vandiedonck C, Willis-Owen SA, Knight JC, Cookson WO, Moffatt MF, Zhang Yet 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

Journal article

Holt RJ, Vandiedonck C, Willis-Owen SA, Knight JC, Cookson WO, Moffatt MF, Zhang Yet al., 2015, A functional AT/G polymorphism in the 5'-untranslated region (UTR) of SETDB2 in the IgE locus on human chromosome 13q14, Genes and Immunity, Vol: 16, Pages: 488-494, ISSN: 1476-5470

The IgE associated locus on human chromosome 13q14 influencing asthma related traits contains the genes PHF11 and SETDB2. SETDB2 is located in the same linkage disequilibrium region as PHF11 and polymorphisms within SETDB2 have been shown to associate with total serum IgE levels. In this report, we sequenced the 15 exons of SETDB2 and identified a single previously un-genotyped mutation (AT/G, rs386770867) in the 5’ untranslated region (UTR) of the gene. The polymorphism was found to be significantly associated with serum IgE levels in our asthma cohort (P = 0.0012). Electrophoretic mobility shift assays (EMSA) revealed that the transcription factor YY1 binds to the AT allele whilst SRY binds to the G allele. Allele-specific transcription analysis (allelotyping) was performed in 35 individuals heterozygous for rs386770867 from a panel of 200 British families ascertained through probands with severe Stage 3 asthma. The AT allele was found to be significantly over expressed in these individuals (P = 1.26 x 10-21). A dual luciferase assay with the pGL3 Luciferase report gene showed that the AT allele significantly affects transcriptional activities. Our results indicate the IgE-associated AT/G polymorphism (rs386770867) regulates transcription of SETDB2.

Journal article

Liang L, Willis-Owen SA, Laprise C, Wong KC, Davies GA, Hudson TJ, Binia A, Hopkin JM, Yang IV, Grundberg E, Busche S, Hudson M, Rönnblom L, Pastinen TM, Schwartz DA, Lathrop GM, Moffatt MF, Cookson WOet al., 2015, An epigenome-wide association study of total serum immunoglobulin E concentration, Nature, Vol: 520, Pages: 670-674, ISSN: 0028-0836

Immunoglobulin E (IgE) is a central mediator of allergic (atopic) inflammation. Therapies directed against IgE can alleviate hay fever and allergic asthma. Genetic association studies have not yet identified novel therapeutic targets or pathways underlying IgE regulation. We therefore surveyed epigenetic associations between serum IgE concentrations and methylation at loci concentrated in CpG islands genome wide in 95 nuclear pedigrees, using DNA from peripheral blood leukocytes. We validated positive results in additional families and in subjects from the general population. Here we show replicated associations-with a meta-analysis false discovery rate less than 10(-4)-between IgE and low methylation at 36 loci. Genes annotated to these loci encode known eosinophil products, and also implicate phospholipid inflammatory mediators, specific transcription factors and mitochondrial proteins. We confirmed that methylation at these loci differed significantly in isolated eosinophils from subjects with and without asthma and high IgE levels. The top three loci accounted for 13% of IgE variation in the primary subject panel, explaining the tenfold higher variance found compared with that derived from large single-nucleotide polymorphism genome-wide association studies. This study identifies novel therapeutic targets and biomarkers for patient stratification for allergic diseases.

Journal article

Hu H, Haas SA, Chelly J, Van Esch H, Raynaud M, de Brouwer APM, Weinert S, Froyen G, Frints SGM, Laumonnier F, Zemojtel T, Love MI, Richard H, Emde A-K, Bienek M, Jensen C, Hambrock M, Fischer U, Langnick C, Feldkamp M, Wissink-Lindhout W, Lebrun N, Castelnau L, Rucci J, Montjean R, Dorseuil O, Billuart P, Stuhlmann T, Shaw M, Corbett MA, Gardner A, Willis-Owen S, Tan C, Friend KL, Belet S, van Roozendaal KEP, Jimenez-Pocquet M, Moizard M-P, Ronce N, Sun R, O'Keeffe S, Chenna R, Van Boemmel A, Goeke J, Hackett A, Field M, Christie L, Boyle J, Haan E, Nelson J, Turner G, Baynam G, Gillessen-Kaesbach G, Mueller U, Steinberger D, Budny B, Badura-Stronka M, Latos-Bielenska A, Ousager LB, Wieacker P, Criado GR, Bondeson M-L, Anneren G, Dufke A, Cohen M, Van Maldergem L, Vincent-Delorme C, Echenne B, Simon-Bouy B, Kleefstra T, Willemsen M, Fryns J-P, Devriendt K, Ullmann R, Vingron M, Wrogemann K, Wienker TF, Tzschach A, van Bokhoven H, Gecz J, Jentsch TJ, Chen W, Ropers H-H, Kalscheuer VMet al., 2015, X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes, Molecular Psychiatry, Vol: 21, Pages: 133-148, ISSN: 1476-5578

X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remainedunresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved familieswith XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these maleswere previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sangersequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonicvariants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%)carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missensevariants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleteriousvariants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functionsas indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4− / − mice or aftermRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles incognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in acohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.

Journal article

Molyneaux PL, Willis-Owen SA, Blanchard A, Lukey P, Simpson J, Marshall R, Cookson WO, Moffatt MF, Maher TMet al., 2015, The Longitudinal Peripheral Whole Blood Transcriptome In Idiopathic Pulmonary Fibrosis, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X

Conference paper

Molyneaux PL, Cox MJ, Willis-Owen SAG, Mallia P, Russell KE, Russel A-M, Murphy E, Johnston SL, Schwarte DA, Wells AU, Cookson WOC, Maher TM, Moffatt MFet al., 2014, The role of bacteria in the pathogenesis and progression of idiopathic pulmonary fibrosis, American Journal of Respiratory and Critical Care Medicine, Vol: 190, Pages: 906-913, ISSN: 1535-4970

Rationale:Idiopathic pulmonaryfibrosis (IPF)isa progressivelung diseaseof unknown cause that leads to respiratory failure and death within 5 yearsof diagnosis. Overt respiratory infection and immunosuppression carrya high morbidity and mortality, and polymorphisms in genes related toepithelial integrity and host defense predispose to IPF.Objectives: To investigate the role of bacteria in the pathogenesisand progression of IPF.Methods: We prospectively enrolled patients diagnosed with IPFaccording to international criteria together with healthy smokers,nonsmokers, and subjectswithmoderate chronic obstructive pulmonarydisease as control subjects. Subjects underwent bronchoalveolarlavage (BAL), from which genomic DNA was isolated. The V3–V5region of the bacterial 16S rRNA gene was amplified, allowingquantification of bacterial load and identification of communities by 16SrRNA quantitative polymerase chain reaction and pyrosequencing. Measurements and Main Results: Sixty-five patients with IPFhad double the burden of bacteria in BAL fluid compared with 44 controlsubjects. Baseline bacterial burden predicted the rate of decline in lungvolume and risk of death and associated independently with thers35705950 polymorphism of the MUC5B mucin gene, a proven hostsusceptibilityfactorfor IPF. Sequencing yielded912,883 high-quality readsfrom all subjects.WeidentifiedHaemophilus, Streptococcus,Neisseria, andVeillonella spp. to be more abundant in cases than control subjects.Regression analyses indicated that these specific operational taxonomicunits as well as bacterial burden associated independently with IPF.Conclusions: IPF is characterized by an increased bacterial burdenin BAL that predicts decline in lung function and death. Trials ofantimicrobial therapy are needed to determine if microbial burdenis pathogenic in the disease.

Journal article

Ma B, Wilker EH, Willis-Owen SAG, Byun H-M, Wong KCC, Motta V, Baccarelli AA, Schwartz J, Cookson WOCM, Khabbaz K, Mittleman MA, Moffatt MF, Liang Let al., 2014, Predicting DNA methylation level across human tissues, NUCLEIC ACIDS RESEARCH, Vol: 42, Pages: 3515-3528, ISSN: 0305-1048

Journal article

Weidinger S, Willis-Owen SA, Kamatani Y, Baurecht H, Liang L, Rodriguez E, Novak N, Kabesch M, Bradley M, McLean I, Cookson WO, Irvine AD, Moffatt MFet al., 2014, A genome-wide association study of atopic dermatitis identifies loci with overlapping effects on asthma and psoriasis, 41st Annual Meeting of the Arbeitsgemeinschaft-Dermatologische-Forschung (ADF), Publisher: WILEY-BLACKWELL, Pages: E21-E21, ISSN: 0906-6705

Conference paper

Weidinger S, Willis-Owen SAG, Kamatani Y, Baurecht H, Morar N, Liang L, Edser P, Street T, Rodriguez E, O'Regan GM, Beattie P, Foelster-Holst R, Franke A, Novak N, Fahy CM, Winge MCG, Kabesch M, Illig T, Heath S, Soderhall C, Melen E, Pershagen G, Kere J, Bradley M, Lieden A, Nordenskjold M, Harper JI, Mclean WHI, Brown SJ, Cookson WOC, Lathrop GM, Irvine AD, Moffatt MFet al., 2013, A genome-wide association study of atopic dermatitis identifies loci with overlapping effects on asthma and psoriasis, Human Molecular Genetics, Vol: 22, Pages: 4841-4856, ISSN: 0964-6906

Atopic dermatitis (AD) is the most common dermatological disease of childhood. Many children with AD have asthma and AD shares regions of genetic linkage with psoriasis, another chronic inflammatory skin disease. We present here a genome-wide association study (GWAS) of childhood-onset AD in 1563 European cases with known asthma status and 4054 European controls. Using Illumina genotyping followed by imputation, we generated 268 034 consensus genotypes and in excess of 2 million single nucleotide polymorphisms (SNPs) for analysis. Association signals were assessed for replication in a second panel of 2286 European cases and 3160 European controls. Four loci achieved genome-wide significance for AD and replicated consistently across all cohorts. These included the epidermal differentiation complex (EDC) on chromosome 1, the genomic region proximal to LRRC32 on chromosome 11, the RAD50/IL13 locus on chromosome 5 and the major histocompatibility complex (MHC) on chromosome 6; reflecting action of classical HLA alleles. We observed variation in the contribution towards co-morbid asthma for these regions of association. We further explored the genetic relationship between AD, asthma and psoriasis by examining previously identified susceptibility SNPs for these diseases. We found considerable overlap between AD and psoriasis together with variable coincidence between allergic rhinitis (AR) and asthma. Our results indicate that the pathogenesis of AD incorporates immune and epidermal barrier defects with combinations of specific and overlapping effects at individual loci.

Journal article

Molyneaux PL, Mallia P, Cox MJ, Footitt J, Willis-Owen SAG, Homola D, Trujillo-Torralbo M-B, Elkin S, Kon OM, Cookson WOC, Moffatt MF, Johnston SLet al., 2013, Outgrowth of the Bacterial Airway Microbiome after Rhinovirus Exacerbation of Chronic Obstructive Pulmonary Disease, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 188, Pages: 1224-1231, ISSN: 1073-449X

Journal article

Huang L, Jolly LA, Willis-Owen S, Gardner A, Kumar R, Douglas E, Shoubridge C, Wieczorek D, Tzschach A, Cohen M, Hackett A, Field M, Froyen G, Hu H, Haas SA, Ropers H-H, Kalscheuer VM, Corbett MA, Gecz Jet al., 2012, A Noncoding, Regulatory Mutation Implicates HCFC1 in Nonsyndromic Intellectual Disability, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 91, Pages: 694-702, ISSN: 0002-9297

Journal article

Field M, Scheffer IE, Gill D, Wilson M, Christie L, Shaw M, Gardner A, Glubb G, Hobson L, Corbett M, Friend K, Willis-Owen S, Gecz Jet al., 2012, Expanding the molecular basis and phenotypic spectrum of X-linked Joubert syndrome associated with OFD1 mutations, EUROPEAN JOURNAL OF HUMAN GENETICS, Vol: 20, Pages: 806-809, ISSN: 1018-4813

Journal article

Subramanian P, Kantharuban S, Subramanian V, Willis-Owen SAG, Willis-Owen CAet al., 2011, CHRISTMAS 2011: SURGERY Orthopaedic surgeons: as strong as an ox and almost twice as clever? Multicentre prospective comparative study, BRITISH MEDICAL JOURNAL, Vol: 343, ISSN: 0959-535X

Journal article

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