226 results on '"Cookson WO"'
Search Results
2. Progression of whole blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in patients with severe influenza
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Dunning, J, Blankley, S, Hoang, LT, Cox, M, Graham, CM, James, PL, Bloom, CI, Chaussabel, D, Banchereau, J, Brett, SJ, Moffatt, MF, Habibi, MS, Johnston, SL, Hansel, TT, Levin, M, Thwaites, RS, Warner, JO, Cookson, WO, Gazzard, BG, Hay, A, McCauley, J, Aylin, P, Ashby, D, Barclay, WS, Elderfield, RA, Nadel, S, Herberg, JA, Drumright, LN, Garcia-Alvarez, L, Holmes, AH, Kon, OM, Aston, SJ, Gordon, SB, Hussell, T, Thompson, C, Zambon, MC, Baillie, KJ, Hume, DA, Simmonds, P, Hayward, A, Smyth, RL, McNamara, PS, Semple, MG, Nguyen-Van-Tam, JS, Ho, LP, McMichael, AJ, Kellam, P, Adamson, WE, Carman, WF, Griffiths, MJ, O'Garra, A, Openshaw, PJM, Wellcome Trust, National Institute for Health Research, Medical Research Council (MRC), and Asthma UK
- Subjects
0301 basic medicine ,Male ,Neutrophils ,Disease ,DISEASE ,Procalcitonin ,Transcriptome ,Pathogenesis ,0302 clinical medicine ,MARKERS ,Interferon ,Immunology and Allergy ,Medicine ,MOSAIC Investigators ,Young adult ,UNITED-KINGDOM ,Middle Aged ,3. Good health ,1107 Immunology ,030220 oncology & carcinogenesis ,Disease Progression ,Female ,Life Sciences & Biomedicine ,medicine.drug ,Adult ,Adolescent ,Immunology ,CIRCULATION ,BIOLOGY ,VIRUS-INFECTION ,Lung injury ,Antiviral Agents ,Article ,03 medical and health sciences ,Young Adult ,Influenza, Human ,Humans ,RNA, Messenger ,PROCALCITONIN ,METAANALYSIS ,Aged ,Science & Technology ,business.industry ,Human genetics ,030104 developmental biology ,Interferons ,business ,LUNG INJURY ,Biomarkers - Abstract
© 2018 The Author(s). Transcriptional profiles and host-response biomarkers are used increasingly to investigate the severity, subtype and pathogenesis of disease. We now describe whole-blood mRNA signatures and concentrations of local and systemic immunological mediators in 131 adults hospitalized with influenza, from whom extensive clinical and investigational data were obtained by MOSAIC investigators. Signatures reflective of interferon-related antiviral pathways were common up to day 4 of symptoms in patients who did not require mechanical ventilator support; in those who needed mechanical ventilation, an inflammatory, activated-neutrophil and cell-stress or death ('bacterial') pattern was seen, even early in disease. Identifiable bacterial co-infection was not necessary for this 'bacterial' signature but was able to enhance its development while attenuating the early 'viral' signature. Our findings emphasize the importance of timing and severity in the interpretation of host responses to acute viral infection and identify specific patterns of immune-system activation that might enable the development of novel diagnostic and therapeutic tools for severe influenza.
- Published
- 2018
3. Role of airway glucose in bacterial infections in chronic obstructive pulmonary disease
- Author
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Tregoning, JS, Mallia, P, Webber, J, Gill, SK, Trujillo-Torralbo, Calderazzo, MA, Finney, L, Bakhsoliani, E, Farne, H, Singanayagam, A, Footitt, J, Hewitt, R, Kebadze, Aniscenko, J, Padmanaban, V, Molyneaux, PL, Adcock, Barnes, PJ, Ito, K, Elkin, SL, Kon, OM, Cookson, WO, MOffatt, MF, Johnston, SL, Imperial Health Charity, Wellcome Trust, Imperial College Healthcare NHS Trust, British Medical Association, Medical Research Council (MRC), National Institute for Health Research, Asthma UK, and Dunhill Medical Trust
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Male ,Allergy ,INCREASES ,METFORMIN ,Immunology ,PATHOGENESIS ,Respiratory System ,RHINOVIRUS INFECTION ,airway inflammation ,Pulmonary Disease, Chronic Obstructive ,HYPERGLYCEMIA ,COPD ,FIBROSIS ,Humans ,Pseudomonas Infections ,glucose ,Respiratory Tract Infections ,Aged ,Science & Technology ,Picornaviridae Infections ,Chronic obstructive pulmonary disease ,Smoking ,bacterial infection ,Sputum ,BLOOD-GLUCOSE ,Middle Aged ,Viral Load ,Nasal Lavage Fluid ,TRANSPORT ,Bacterial Load ,respiratory tract diseases ,EXACERBATIONS ,1107 Immunology ,Female ,viral infection ,Life Sciences & Biomedicine ,Bronchoalveolar Lavage Fluid - Abstract
Background Patients with chronic obstructive pulmonary disease (COPD) have increased susceptibility to respiratory tract infection, which contributes to disease progression and mortality, but mechanisms of increased susceptibility to infection remain unclear. Objectives The aim of this study was to determine whether glucose concentrations were increased in airway samples (nasal lavage fluid, sputum, and bronchoalveolar lavage fluid) from patients with stable COPD and to determine the effects of viral infection on sputum glucose concentrations and how airway glucose concentrations relate to bacterial infection. Methods We measured glucose concentrations in airway samples collected from patients with stable COPD and smokers and nonsmokers with normal lung function. Glucose concentrations were measured in patients with experimentally induced COPD exacerbations, and these results were validated in patients with naturally acquired COPD exacerbations. Relationships between sputum glucose concentrations, inflammatory markers, and bacterial load were examined. Results Sputum glucose concentrations were significantly higher in patients with stable COPD compared with those in control subjects without COPD. In both experimental virus-induced and naturally acquired COPD exacerbations, sputum and nasal lavage fluid glucose concentrations were increased over baseline values. There were significant correlations between sputum glucose concentrations and sputum inflammatory markers, viral load, and bacterial load. Airway samples with higher glucose concentrations supported more Pseudomonas aeruginosa growth in vitro. Conclusions Airway glucose concentrations are increased in patients with stable COPD and further increased during COPD exacerbations. Increased airway glucose concentrations might contribute to bacterial infections in both patients with stable and those with exacerbated COPD. This has important implications for the development of nonantibiotic therapeutic strategies for the prevention or treatment of bacterial infection in patients with COPD.
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- 2017
4. Analysis of global gene expression profile changes during differentiation of the EpiDerM (TM) in vitro human skin equivalent
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Street, TL, Hayden, PJ, Hao, L, Taylor, J, Copley, R, Kubilus, H, Klausner, M, Moffatt, M, and Cookson, WO
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- 2016
5. A 2.8 Mb YAC contig in 11q12-q13 localizes candidate genes for atopy: Fc epsilon RI beta and CD20
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Stafford, AN, Rider, SH, Hopkin, JM, Cookson, WO, and Monaco, AP
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hemic and lymphatic diseases ,food and beverages - Abstract
An important locus for Atopy (familial asthma, hay fever and eczema) has been localized to the 11q12-q13 region with the minimum recombination fraction around the CD20 gene. We have constructed a 2.8 megabase (Mb) Yeast Artificial Chromosome (YAC) contig of the candidate region using 15 STSs. A total of seven genes have been mapped within this interval in the order cen-OSBP-TCN1-GIF-Fc epsilon RI beta-CD20-CD5-PGA-q(ter) and can be covered by a minimum of eight YAC clones. Contig integrity was assayed with fluorescence in-situ hybridization (FISH) and the mapping of YAC ends on somatic cell and radiation hybrid panels. A long range restriction map of the contig has been constructed to establish the order of and distance between loci. Two promising candidates for the atopy locus, the beta subunit of the high affinity immunoglobulin E receptor (Fc epsilon RI beta) and CD20, a molecule involved in B cell differentiation, have been placed within the contig.
- Published
- 2016
6. Effects of different antibiotic classes on airway bacteria in stable COPD using culture and molecular Q1 techniques: a randomised controlled trial
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Brill, S, Law, M, El-Emir, E, Allinson, JP, James, PL, Maddox, V, Donaldson, GC, McHugh, TD, Cookson, WO, Moffatt, MF, Nazareth, I, Hurst, JR, Calverley, PMA, Sweeting, MJ, and Wedzicha, JA
- Published
- 2015
7. Functional analysis of a novel ENU-induced PHD finger 11 (Phf11) mouse mutant
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Zhang, Y, Dean, C, Chessum, L, Dao, N, Stewart, M, Taylor, M, Cookson, WO, and Moffatt, MF
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Genetics - Abstract
Previously, human genetic studies have shown association between polymorphisms within the gene encoding plant homeodomain zinc finger protein 11 (PHF11) and asthma-related phenotypes. Initial functional studies have suggested that PHF11 may be involved in the immune response through regulation of T cell activities. In order to study further the gene's functions, we have investigated the mouse Phf11 locus. We have established and characterised a mouse line harbouring a point mutation in the PHD domain of Phf11. Full-length mouse cDNA for Phf11 was obtained by applying rapid amplification of cDNA ends (RACE). All five exons encoding the PHD domain of Phf11 were directly sequenced in 3840 mouse DNA samples from the UK MRC Harwell ENU (N-ethyl-N-nitrosourea)-mutagenised DNA archive. Mice harbouring a valine to alanine substitution, predicted to have a significant functional impact on the PHD zinc finger domain, were re-derived. These Phf11 mutant mice were outcrossed to C3H mice and then backcrossed for ten generations in order to establish a congenic line harbouring the single point mutation in Phf11. Macroscopic examination, haematology and histological examination of lung structure revealed no significant differences between mutant and wild-type mice. After administration of lipopolysaccharide, the level of expression of Il2, NF-kB and Setdb2 were significantly increased in Phf11 mutant homozygous lungs compared to control littermates. Our results provide evidence that Phf11 can operate as a Th1 cell regulator in immune responses. Moreover, our data indicate that these mice may provide a useful model for future studies on Phf11.
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- 2014
8. Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma
- Author
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Chambers JC, Zhang W, Sehmi J, Li X, Wass MN, Van der Harst P, Holm H, Sanna S, Kavousi M, Baumeister SE, Coin LJ, Deng G, Gieger C, Heard Costa NL, Hottenga JJ, Kühnel B, Kumar V, Lagou V, Liang L, Luan J, Vidal PM, Mateo Leach I, O'Reilly PF, Peden JF, Rahmioglu N, Soininen P, Speliotes EK, Yuan X, Thorleifsson G, Alizadeh BZ, Atwood LD, Borecki IB, Brown MJ, Charoen P, Cucca F, Das D, de Geus EJ, Dixon AL, Döring A, Ehret G, Eyjolfsson GI, Farrall M, Forouhi NG, Friedrich N, Goessling W, Gudbjartsson DF, Harris TB, Hartikainen AL, Heath S, Hirschfield GM, Hofman A, Homuth G, Hyppönen E, Janssen HL, Johnson T, Kangas AJ, Kema IP, Kühn JP, Lai S, Lathrop M, Lerch MM, Li Y, Liang TJ, Lin JP, Loos RJ, Martin NG, Moffatt MF, Montgomery GW, Munroe PB, Musunuru K, Nakamura Y, O'Donnell CJ, Olafsson I, Penninx BW, Pouta A, Prins BP, Prokopenko I, Puls R, Ruokonen A, Savolainen MJ, Schlessinger D, Schouten JN, Seedorf U, Sen Chowdhry S, Siminovitch KA, Smit JH, Spector TD, Tan W, Teslovich TM, Tukiainen T, Uitterlinden AG, Van der Klauw MM, Vasan RS, Wallace C, Wallaschofski H, Wichmann HE, Willemsen G, Würtz P, Xu C, Yerges Armstrong LM, Alcohol Genome wide Association Consortium, Diabetes Genetics Replication, Meta analyses Study, Genetic Investigation of Anthropometric Traits Consortium, Global Lipids Genetics Consortium, Genetics of Liver Disease Consortium, International Consortium for Blood Pressure, Meta analyses of Glucose, Insulin Related Traits Consortium, Abecasis GR, Ahmadi KR, Boomsma DI, Caulfield M, Cookson WO, van Duijn CM, Froguel P, Matsuda K, McCarthy MI, Meisinger C, Mooser V, Pietiläinen KH, Schumann G, Snieder H, Sternberg MJ, Stolk RP, Thomas HC, Thorsteinsdottir U, Uda M, Waeber G, Wareham NJ, Waterworth DM, Watkins H, Whitfield JB, Witteman JC, Wolffenbuttel BH, Fox CS, Ala Korpela M, Stefansson K, Vollenweider P, Völzke H, Schadt EE, Scott J, Järvelin MR, Elliott P, Kooner JS, PAOLISSO, Giuseppe, Chambers, Jc, Zhang, W, Sehmi, J, Li, X, Wass, Mn, Van der Harst, P, Holm, H, Sanna, S, Kavousi, M, Baumeister, Se, Coin, Lj, Deng, G, Gieger, C, Heard Costa, Nl, Hottenga, Jj, Kühnel, B, Kumar, V, Lagou, V, Liang, L, Luan, J, Vidal, Pm, Mateo Leach, I, O'Reilly, Pf, Peden, Jf, Rahmioglu, N, Soininen, P, Speliotes, Ek, Yuan, X, Thorleifsson, G, Alizadeh, Bz, Atwood, Ld, Borecki, Ib, Brown, Mj, Charoen, P, Cucca, F, Das, D, de Geus, Ej, Dixon, Al, Döring, A, Ehret, G, Eyjolfsson, Gi, Farrall, M, Forouhi, Ng, Friedrich, N, Goessling, W, Gudbjartsson, Df, Harris, Tb, Hartikainen, Al, Heath, S, Hirschfield, Gm, Hofman, A, Homuth, G, Hyppönen, E, Janssen, Hl, Johnson, T, Kangas, Aj, Kema, Ip, Kühn, Jp, Lai, S, Lathrop, M, Lerch, Mm, Li, Y, Liang, Tj, Lin, Jp, Loos, Rj, Martin, Ng, Moffatt, Mf, Montgomery, Gw, Munroe, Pb, Musunuru, K, Nakamura, Y, O'Donnell, Cj, Olafsson, I, Penninx, Bw, Pouta, A, Prins, Bp, Prokopenko, I, Puls, R, Ruokonen, A, Savolainen, Mj, Schlessinger, D, Schouten, Jn, Seedorf, U, Sen Chowdhry, S, Siminovitch, Ka, Smit, Jh, Spector, Td, Tan, W, Teslovich, Tm, Tukiainen, T, Uitterlinden, Ag, Van der Klauw, Mm, Vasan, R, Wallace, C, Wallaschofski, H, Wichmann, He, Willemsen, G, Würtz, P, Xu, C, Yerges Armstrong, Lm, Alcohol Genome wide Association, Consortium, Diabetes Genetics, Replication, Meta analyses, Study, Genetic Investigation of Anthropometric Traits, Consortium, Global Lipids Genetics, Consortium, Genetics of Liver Disease, Consortium, International Consortium for Blood, Pressure, Meta analyses of, Glucose, Insulin Related Traits, Consortium, Abecasis, Gr, Ahmadi, Kr, Boomsma, Di, Caulfield, M, Cookson, Wo, van Duijn, Cm, Froguel, P, Matsuda, K, Mccarthy, Mi, Meisinger, C, Mooser, V, Pietiläinen, Kh, Schumann, G, Snieder, H, Sternberg, Mj, Stolk, Rp, Thomas, Hc, Thorsteinsdottir, U, Uda, M, Waeber, G, Wareham, Nj, Waterworth, Dm, Watkins, H, Whitfield, Jb, Witteman, Jc, Wolffenbuttel, Bh, Fox, C, Ala Korpela, M, Stefansson, K, Vollenweider, P, Völzke, H, Schadt, Ee, Scott, J, Järvelin, Mr, Elliott, P, Kooner, J, and Paolisso, Giuseppe
- Published
- 2011
9. IFITM3 restricts the morbidity and mortality associated with influenza
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Everitt, AR, Clare, S, Pertel, T, John, SP, Wash, RS, Smith, SE, Chin, CR, Feeley, EM, Sims, JS, Adams, DJ, Wise, HM, Kane, L, Goulding, D, Digard, P, Anttila, V, Baillie, JK, Walsh, TS, Hume, DA, Palotie, A, Xue, Y, Colonna, V, Tyler-Smith, C, Dunning, J, Gordon, SB, Everingham, K, Dawson, H, Hope, D, Ramsay, P, Walsh Local Lead Investigator, TS, Campbell, A, Kerr, S, Harrison, D, Rowan, K, Addison, J, Donald, N, Galt, S, Noble, D, Taylor, J, Webster Local Lead Investigator, N, Taylor Local Lead Investigator, I, Aldridge Local Lead Investigator, J, Dornan, R, Richard, C, Gilmour, D, Simmons Local Lead Investigator, R, White Local Lead Investigator, R, Jardine, C, Williams Local Lead Investigator, D, Booth Local Lead Investigator, M, Quasim, T, Watson, V, Henry, P, Munro, F, Bell, L, Ruddy Local Lead Investigator, J, Cole Local Lead Investigator, S, Southward, J, Allcoat, P, Gray, S, McDougall Local Lead Investigator, M, Matheson, J, Whiteside Local Lead Investigator, J, Alcorn, D, Rooney Local Lead Investigator, K, Sundaram, R, Imrie Local Lead Investigator, G, Bruce, J, McGuigan, K, Moultrie Local Lead Investigator, S, Cairns Local Lead Investigator, C, Grant, J, Hughes, M, Murdoch Local Lead Investigator, C, Davidson Local Lead Investigator, A, Harris, G, Paterson, R, Wallis Local Lead Investigator, C, Binning Local Lead Investigator, S, Pollock, M, Antonelli, J, Duncan, A, Gibson, J, McCulloch, C, Murphy, L, Haley, C, Faulkner, G, Freeman, T, Baillie Principal Investigator, JK, Chaussabel, D, Adamson, WE, Carman, WF, Thompson, C, Zambon, MC, Aylin, P, Ashby, D, Barclay, WS, Brett, SJ, Cookson, WO, Drumright, LN, Elderfield, RA, Garcia-Alvarez, L, Gazzard, BG, Griffiths, MJ, Habibi, MS, Hansel, TT, Herberg, JA, Holmes, AH, Hussell, T, Johnston, SL, Kon, OM, Levin, M, Moffatt, MF, Nadel, S, Openshaw, PJ, Warner, JO, Aston, SJ, Hay, A, McCauley, J, O'Garra, A, Banchereau, J, Hayward, A, Kellam, P, Simmonds, P, McNamara, PS, Semple, MG, Smyth, RL, Nguyen-Van-Tam, JS, Ho, L-P, Mcmichael, AJ, Dougan, G, and Brass, AL
- Published
- 2012
10. Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma
- Author
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Chambers, JC, Zhang, W, Sehmi, J, Li, X, Wass, MN, Van der Harst, P, Holm, H, Sanna, S, Kavousi, M, Baumeister, SE, Coin, LJ, Deng, G, Gieger, C, Heard-Costa, NL, Hottenga, J-J, Kühnel, B, Kumar, V, Lagou, V, Liang, L, Luan, J, Vidal, PM, Leach, IM, O'Reilly, PF, Peden, JF, Rahmioglu, N, Soininen, P, Speliotes, EK, Yuan, X, Thorleifsson, G, Alizadeh, BZ, Atwood, LD, Borecki, IB, Brown, MJ, Charoen, P, Cucca, F, Das, D, de Geus, EJC, Dixon, AL, Döring, A, Ehret, G, Eyjolfsson, GI, Farrall, M, Forouhi, NG, Friedrich, N, Goessling, W, Gudbjartsson, DF, Harris, TB, Hartikainen, A-L, Heath, S, Hirschfield, GM, Hofman, A, Homuth, G, Hyppönen, E, Janssen, HLA, Johnson, T, Kangas, AJ, Kema, IP, Kühn, JP, Lai, S, Lathrop, M, Lerch, MM, Li, Y, Liang, TJ, Lin, J-P, Loos, RJF, Martin, NG, Moffatt, MF, Montgomery, GW, Munroe, PB, Musunuru, K, Nakamura, Y, O'Donnell, CJ, Olafsson, I, Penninx, BW, Pouta, A, Prins, BP, Prokopenko, I, Puls, R, Ruokonen, A, Savolainen, MJ, Schlessinger, D, Schouten, JNL, Seedorf, U, Sen-Chowdhry, S, Siminovitch, KA, Smit, JH, Spector, TD, Tan, W, Teslovich, TM, Tukiainen, T, Uitterlinden, AG, Van der Klauw, MM, Vasan, RS, Wallace, C, Wallaschofski, H, Wichmann, H-E, Willemsen, G, Würtz, P, Xu, C, Yerges-Armstrong, LM, Abecasis, GR, Ahmadi, KR, Boomsma, DI, Caulfield, M, Cookson, WO, van Duijn, CM, Froguel, P, Matsuda, K, McCarthy, MI, Meisinger, C, Mooser, V, Pietiläinen, KH, Schumann, G, Snieder, H, Sternberg, MJE, Stolk, RP, Thomas, HC, Thorsteinsdottir, U, Uda, M, Waeber, G, Wareham, NJ, Waterworth, DM, Watkins, H, Whitfield, JB, Witteman, JCM, Wolffenbuttel, BHR, Fox, CS, Ala-Korpela, M, Stefansson, K, Vollenweider, P, Völzke, H, Schadt, EE, Scott, J, Järvelin, M-R, Elliott, P, and Kooner, JS
- Published
- 2011
11. A Multi-Centre Study of Candidate Genes for Asthma and Allergy.The International Study of Asthma and Allergies in Childhood Phase 2.
- Author
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Genuneit, J, primary, Cantelmo, JL, additional, Weinmayr, G, additional, Weiland, SK, additional, Cookson, WO, additional, Strachan, D, additional, and Moffatt, MF, additional
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- 2009
- Full Text
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12. Nicotinic Acetylcholine Receptor Polymorphism, Smoking History and Lung Function Decline.
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Akhabir, L, primary, Zhang, X, additional, Connett, JE, additional, Anthonisen, NR, additional, Lathrop, M, additional, Cookson, WO, additional, Pare, PD, additional, and Sandford, AJ, additional
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- 2009
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13. Genome-wide association study to identify genetic determinants of severe asthma.
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Wan YI, Shrine NR, Soler Artigas M, Wain LV, Blakey JD, Moffatt MF, Bush A, Chung KF, Cookson WO, Strachan DP, Heaney L, Al-Momani BA, Mansur AH, Manney S, Thomson NC, Chaudhuri R, Brightling CE, Bafadhel M, Singapuri A, and Niven R
- Abstract
Background: The genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear.Objective: To identify common genetic variants affecting susceptibility to severe asthma.Methods: A genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480 889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies.Results: An association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p=1.03×10((-8)) following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p=5.59×10((-8)) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance.Conclusions: The largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study. [ABSTRACT FROM AUTHOR]- Published
- 2012
14. Genetic and genomic approaches to asthma: new insights for the origins.
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Zhang Y, Moffatt MF, Cookson WO, Zhang, Youming, Moffatt, Miriam F, and Cookson, William O C
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- 2012
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15. Radiographic abnormalities and duration of employment in Western Australian iron‐ore miners
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Cookson Wo, Morgan Wk, Arthur W. Musk, and de Klerk Nh
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Adult ,Employment ,Male ,Pediatrics ,medicine.medical_specialty ,Time Factors ,Adolescent ,Iron ,Radiography ,Mining ,Humans ,Medicine ,Lung ,business.industry ,Pneumoconiosis ,Western Australia ,General Medicine ,Middle Aged ,respiratory system ,medicine.disease ,respiratory tract diseases ,Cross-Sectional Studies ,Optometry ,Abnormality ,business - Abstract
Plain chest radiographs of 788 Pilbara iron-ore miners from Western Australia have been examined by two independent observers for evidence of pneumoconiosis. The prevalence of any radiographic abnormality (a profusion grade of 0/1 or greater on the International Labour Office [ILO] scale) was 6.7% for Reader 1 and 9.9% for Reader 2. The prevalence of a definite radiographic abnormality (a profusion grade of 1/0 or greater on the ILO scale) was 1.9% for Reader 1 and 2.8% for Reader 2. The prevalence of any abnormality, as identified by either or by both observers, was significantly related to age. The relationship between a radiographic abnormality and the duration of employment was less clear. The results indicate a need for more detailed and comprehensive studies of the effects of iron-ore dust in this industry.
- Published
- 1988
16. Asbestosis and cryptogenic fibrosing alveolitis: a radiological and functional comparison
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Cookson Wo, Arthur W. Musk, and J. J. Glancy
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Male ,Pathology ,medicine.medical_specialty ,Radiography ,Pulmonary Fibrosis ,Asbestosis ,Vital Capacity ,Pulmonary function testing ,Forced Expiratory Volume ,Pulmonary fibrosis ,Internal Medicine ,medicine ,Humans ,Lung volumes ,Pathological ,Lung ,business.industry ,Pulmonary Gas Exchange ,Total Lung Capacity ,respiratory system ,Middle Aged ,medicine.disease ,respiratory tract diseases ,medicine.anatomical_structure ,Radiology ,Abnormality ,business - Abstract
This study compares the relationship between lung function and radiological abnormality in 46 subjects with asbestosis and 38 subjects with cryptogenic fibrosing alveolitis. Radiographs were graded separately by two observers according to the 1980 International Labour Organisation criteria for classification of the pneumoconioses. The correlation between the transfer factor of the lungs and the radiographic profusion of small parenchymal opacities was found to be greater in subjects with asbestosis than in subjects with cryptogenic fibrosing alveolitis. At any level of radiological profusion transfer factor was higher in cases with asbestosis than in cases with fibrosing alveolitis. As pleural thickening is seen commonly in asbestosis and may influence lung volumes and the ratio of transfer factor to effective alveolar volume, the results of these measurements were compared only in the cases showing absent or minimal pleural thickening. Both of these variables were higher in the subjects with asbestosis. The results indicate that despite pathological, functional and radiographic similarities, lung function for a given degree of radiographic parenchymal abnormality is better in subjects with asbestosis than in subjects with cryptogenic fibrosing alveolitis, and that changes in the plain chest x-ray appearances in asbestosis correlate more closely with the results of lung function tests.
- Published
- 1984
17. Pleural thickening and gas transfer in asbestosis
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Cookson Wo, Arthur W. Musk, and J J Glancy
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Pulmonary and Respiratory Medicine ,Male ,medicine.medical_specialty ,Pathology ,Radiography ,Asbestosis ,Vital Capacity ,Pleural thickening ,Pleural disease ,Gas transfer ,Fibrosis ,Forced Expiratory Volume ,medicine ,Humans ,Alveolar volume ,Aged ,business.industry ,Pulmonary Gas Exchange ,Pneumoconiosis ,respiratory system ,Middle Aged ,medicine.disease ,respiratory tract diseases ,Pulmonary Alveoli ,Pleura ,Radiology ,business ,Research Article - Abstract
Anomalies in the ratio of transfer factor to effective alveolar volume as an indicator of pulmonary gas exchange in cases of asbestosis may be related to diffuse pleural thickening. To examine the effect of pleural disease on gas transfer the plain chest radiographs of patients with asbestosis were assessed by two observers for profusion of parenchymal opacities and extent of pleural disease and the results were related to lung function. In 30 cases of category 1 profusion of parenchymal abnormality (according to the ILO international classification of radiographs for pneumoconiosis) transfer factor was independent of the degree of pleural thickening. The ratio of transfer factor to effective alveolar volume correlated directly with the degree of pleural thickening as alveolar volume fell with increasing severity of pleural disease. The results indicate that correcting transfer factor for alveolar volume does not provide an accurate reflection of severity of diffuse parenchymal fibrosis in patients with asbestosis and even minor pleural disease.
- Published
- 1983
18. Bronchodilator action of the anti-histaminic terfenadine.
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Cookson, WO, primary
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- 1987
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19. Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
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Zhaoming Wang, André Scherag, James F. Wilson, Nancy L. Heard-Costa, Ingrid B. Borecki, Sang Hong Lee, Veronique Vitart, Zoltán Kutalik, Jeffrey R. O'Connell, Mieke D. Trip, Lu Qi, Peter Vollenweider, Jennifer L. Bragg-Gresham, Davide Gentilini, Kees Hovingh, Lynda M. Rose, Carolin Pütter, Martin Farrall, Albert V. Smith, Nicholas G. Martin, Tõnu Esko, David J. Hunter, Georg Homuth, Liming Liang, Yudi Pawitan, Winfried März, George Dedoussis, Irene Mateo Leach, Nicholas J. Wareham, Lars Lind, Thomas Illig, Andrew P. Morris, Daniele Cusi, Jouke-Jan Hottenga, Tove Fall, Themistocles L. Assimes, Massimo Mangino, Dmitry Shungin, Kari Stefansson, Anne U. Jackson, Inês Barroso, Sarah E. Medland, Lude Franke, Karen L. Mohlke, Folkert W. Asselbergs, Sarah E. Hunt, Gudmar Thorleifsson, Pablo V. Gejman, Serena Sanna, Mark I. McCarthy, David M. Evans, Joel N. Hirschhorn, Alan F. Wright, Sarah H. Wild, Patricia B. Munroe, Marcel Bruinenberg, Gonneke Willemsen, Ulf de Faire, Markku Laakso, Marja-Liisa Lokki, Andrew C. Heath, Jing Hua Zhao, Lavinia Paternoster, Jana V. van Vliet-Ostaptchouk, Sailaja Vedantam, Danyu Lin, Eric E. Schadt, Stefano Signorini, Harald Grallert, Tsegaselassie Workalemahu, Jonathan Tyrer, Albert Hofman, George Nicholson, Patrik K. E. Magnusson, Arthur W. Musk, Jian Yang, Vilmundur Gudnason, Robert C. Kaplan, Panos Deloukas, Nilesh J. Samani, Inke R. König, Frank B. Hu, Paul M. Ridker, Tamara B. Harris, Bruce H. R. Wolffenbuttel, Ellen A. Nohr, Sarah Edkins, Lambertus A. Kiemeney, Anke Hinney, Eric Boerwinkle, Klaus Stark, Ben A. Oostra, Barbara Thorand, Unnur Thorsteinsdottir, Meena Kumari, Evelin Mihailov, Caroline S. Fox, Michael Boehnke, Aroon D. Hingorani, Jonathan Stephens, Kathleen Stirrups, Inga Prokopenko, Anke Tönjes, Lili Milani, John Beilby, Carlos Iribarren, Kari E. North, Cécile Lecoeur, So-Youn Shin, Marjo-Riitta Järvelin, Matti Uusitupa, Åsa Johansson, Nancy L. Pedersen, Krista Fischer, Fernando Rivadeneira, Wolfgang Koenig, Fredrik Karpe, Antti Jula, Lindsay L. Waite, Gérard Waeber, Mustafa Atalay, Heribert Schunkert, Narisu Narisu, Sita H. Vermeulen, Bernhard R. Winkelmann, Guo Li, Anders Hamsten, Elizabeth K. Speliotes, Ivonne Jarick, Sirkka Keinänen-Kiukaanniemi, L. Adrienne Cupples, Ruth J. F. Loos, Martina Müller-Nurasyid, David-Alexandre Trégouët, Claudia Langenberg, Willem H. Ouwehand, Julius S. Ngwa, Jennifer E. Huffman, H-Erich Wichmann, Amy J. Swift, Marco M Ferrario, Leif Groop, Henrik Grönberg, Peter M. Visscher, Claes Ohlsson, Markku S. Nieminen, Aparna Radhakrishnan, Harold Snieder, Devin Absher, Albertine J. Oldehinkel, Erik Ingelsson, Anna Maria Di Blasio, M. Carola Zillikens, Veikko Salomaa, Colin N. A. Palmer, Lori L. Bonnycastle, Teresa Ferreira, Ronald P. Stolk, Annette Peters, Philippe Froguel, Michael Stumvoll, David Schlessinger, Maria Dimitriou, Timo Saaristo, Cristen J. Willer, Jarmo Virtamo, Jorma Viikari, Alena Stančáková, Mika Kivimäki, Paolo Brambilla, Jaakko Tuomilehto, Dorret I. Boomsma, Harry Campbell, Jianjun Liu, Daniel I. Chasman, Gonçalo R. Abecasis, Ilja M. Nolte, Karl-Heinz Jöckel, Reedik Mägi, Pamela A. F. Madden, Jaana Laitinen, Sonja I. Berndt, Frank Kee, Marcus E. Kleber, Jacqueline C.M. Witteman, Jouko Saramies, Francis S. Collins, Johan G. Eriksson, Melanie M. van der Klauw, Yi-Juan Hu, John F. Peden, Markus Perola, Henri Wallaschofski, Jean Ferrières, Elena Tremoli, Marjolein J. Peters, Olli T. Raitakari, Claudia Lamina, Sekar Kathiresan, Mary F. Feitosa, Diana Kuh, Tim D. Spector, Paul W. Franks, Gerjan Navis, Martin den Heijer, Christian Gieger, Kevin B. Jacobs, Andrea Ganna, Timothy M. Frayling, Iris M. Heid, Bernhard O. Boehm, Eleanor Wheeler, Sonali Pechlivanis, Miriam F. Moffatt, Brenda W.J.H. Penninx, Anna-Liisa Hartikainen, Augusto Rendon, Stefan Schreiber, Stephen J. Chanock, Andrew R. Wood, Jianxin Shi, Najaf Amin, Lenore J. Launer, Michael A. Province, Jeanette Erdmann, Mattias Lorentzon, Hugh Watkins, Johanna Kuusisto, John-Olov Jansson, David P. Strachan, Anne E. Justice, Toby Johnson, Cornelia M. van Duijn, Niina Eklund, Samuli Ripatti, Aarno Palotie, Aldi T. Kraja, Michael Preuss, Rona J. Strawbridge, Ozren Polasek, Elisabeth Widen, Barbara McKnight, Mariano Dei, Vincent Mooser, Josine L. Min, Caroline Hayward, Mika Kähönen, Peter P. Pramstaller, Femmie de Vegt, Rainer Rauramaa, Douglas F. Levinson, Diana Marek, Antonio Liuzzi, Stefan Gustafsson, Andrew A. Hicks, Gemma Cadby, Damien C. Croteau-Chonka, Mark J. Caulfield, Boris Skrobek, Lyle J. Palmer, Alexander Teumer, Ken K. Ong, Ulf Gyllensten, Anneli Pouta, Anuj Goel, Eva Albrecht, Kristian Hveem, Inger Njølstad, David Meyre, Ida Surakka, Francesca Frau, Paolo Manunta, Sabine Schipf, Carolina Medina-Gomez, Kay-Tee Khaw, Alan R. Sanders, Thorkild I. A. Sørensen, André G. Uitterlinden, Alistair S. Hall, Felix R. Day, Karol Estrada, Jennifer G. Sambrook, Eirini V. Theodoraki, Valgerdur Steinthorsdottir, Cecilia M. Lindgren, Talin Haritunian, Benjamin M. Neale, Juha Sinisalo, Kati Kristiansson, Thomas W. Winkler, Pim van der Harst, Peter S. Chines, Joyce B. J. van Meurs, Wendy L. McArdle, Andrew Wong, Grant W. Montgomery, Terho Lehtimäki, Igor Rudan, Keri L. Monda, John M. C. Connell, Jian'an Luan, Per Hall, Joshua C. Randall, Anthony J. Balmforth, Chris Power, Philippe Amouyel, Andres Metspalu, Johannes Hebebrand, Andrew D. Morris, Jaana Lindström, Liesbeth Vandenput, William O.C.M. Cookson, Hanneke Basart, Stavroula Kanoni, Elina Hyppönen, Christian Hengstenberg, Thomas W. Mühleisen, Kari Kuulasmaa, Timo A. Lakka, Nicole Soranzo, Bruce M. Psaty, Antony P. Attwood, Epidemiology, Clinical Genetics, Surgery, Erasmus School of Social and Behavioural Sciences, Public Health, Internal Medicine, Immunology, Child and Adolescent Psychiatry / Psychology, Internal medicine, Psychiatry, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Lifestyle, overweight and diabetes, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Other departments, Vascular Medicine, Biological Psychology, Cognitive Psychology, AIMMS, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Lifestyle, Overweight and Diabetes, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Berndt, S, Gustafsson, S, Mägi, R, Ganna, A, Wheeler, E, Feitosa, M, Justice, A, Monda, K, Croteau Chonka, D, Day, F, Esko, T, Fall, T, Ferreira, T, Gentilini, D, Jackson, A, Luan, J, Randall, J, Vedantam, S, Willer, C, Winkler, T, Wood, A, Workalemahu, T, Hu, Y, Lee, S, Liang, L, Lin, D, Min, J, Neale, B, Thorleifsson, G, Yang, J, Albrecht, E, Amin, N, Bragg Gresham, J, Cadby, G, den Heijer, M, Eklund, N, Fischer, K, Goel, A, Hottenga, J, Huffman, J, Jarick, I, Johansson, Å, Johnson, T, Kanoni, S, Kleber, M, König, I, Kristiansson, K, Kutalik, Z, Lamina, C, Lecoeur, C, Li, G, Mangino, M, Mcardle, W, Medina Gomez, C, Müller Nurasyid, M, Ngwa, J, Nolte, I, Paternoster, L, Pechlivanis, S, Perola, M, Peters, M, Preuss, M, Rose, L, Shi, J, Shungin, D, Smith, A, Strawbridge, R, Surakka, I, Teumer, A, Trip, M, Tyrer, J, Van Vliet Ostaptchouk, J, Vandenput, L, Waite, L, Zhao, J, Absher, D, Asselbergs, F, Atalay, M, Attwood, A, Balmforth, A, Basart, H, Beilby, J, Bonnycastle, L, Brambilla, P, Bruinenberg, M, Campbell, H, Chasman, D, Chines, P, Collins, F, Connell, J, Cookson, W, De, F, U, D, Vegt, F, Dei, M, Dimitriou, M, Edkins, S, Estrada, K, Evans, D, Farrall, M, Ferrario, M, Ferrières, J, Franke, L, Frau, F, Gejman, P, Grallert, H, Grönberg, H, Gudnason, V, Hall, A, Hall, P, Hartikainen, A, Hayward, C, Heard Costa, N, Heath, A, Hebebrand, J, Homuth, G, Hu, F, Hunt, S, Hyppönen, E, Iribarren, C, Jacobs, K, Jansson, J, Jula, A, Kähönen, M, Kathiresan, S, Kee, F, Khaw, K, Kivimäki, M, Koenig, W, Kraja, A, Kumari, M, Kuulasmaa, K, Kuusisto, J, Laitinen, J, Lakka, T, Langenberg, C, Launer, L, Lind, L, Lindström, J, Liu, J, Liuzzi, A, Lokki, M, Lorentzon, M, Madden, P, Magnusson, P, Manunta, P, Marek, D, März, W, Mateo Leach, I, Mcknight, B, Medland, S, Mihailov, E, Milani, L, Montgomery, G, Mooser, V, Mühleisen, T, Munroe, P, Musk, A, Narisu, N, Navis, G, Nicholson, G, Nohr, E, Ong, K, Oostra, B, Palmer, C, Palotie, A, Peden, J, Pedersen, N, Peters, A, Polasek, O, Pouta, A, Pramstaller, P, Prokopenko, I, Pütter, C, Radhakrishnan, A, Raitakari, O, Rendon, A, Rivadeneira, F, Rudan, I, Saaristo, T, Sambrook, J, Sanders, A, Sanna, S, Saramies, J, Schipf, S, Schreiber, S, Schunkert, H, Shin, S, Signorini, S, Sinisalo, J, Skrobek, B, Soranzo, N, Stančáková, A, Stark, K, Stephens, J, Stirrups, K, Stolk, R, Stumvoll, M, Swift, A, Theodoraki, E, Thorand, B, Tregouet, D, Tremoli, E, Van der Klauw, M, van Meurs, J, Vermeulen, S, Viikari, J, Virtamo, J, Vitart, V, Waeber, G, Wang, Z, Widén, E, Wild, S, Willemsen, G, Winkelmann, B, Witteman, J, Wolffenbuttel, B, Wong, A, Wright, A, Zillikens, M, Amouyel, P, Boehm, B, Boerwinkle, E, Boomsma, D, Caulfield, M, Chanock, S, Cupples, L, Cusi, D, Dedoussis, G, Erdmann, J, Eriksson, J, Franks, P, Froguel, P, Gieger, C, Gyllensten, U, Hamsten, A, Harris, T, Hengstenberg, C, Hicks, A, Hingorani, A, Hinney, A, Hofman, A, Hovingh, K, Hveem, K, Illig, T, Jarvelin, M, Jöckel, K, Keinanen Kiukaanniemi, S, Kiemeney, L, Kuh, D, Laakso, M, Lehtimäki, T, Levinson, D, Martin, N, Metspalu, A, Morris, A, Nieminen, M, Njølstad, I, Ohlsson, C, Oldehinkel, A, Ouwehand, W, Palmer, L, Penninx, B, Power, C, Province, M, Psaty, B, Qi, L, Rauramaa, R, Ridker, P, Ripatti, S, Salomaa, V, Samani, N, Snieder, H, Sørensen, T, Spector, T, Stefansson, K, Tönjes, A, Tuomilehto, J, Uitterlinden, A, Uusitupa, M, van der Harst, P, Vollenweider, P, Wallaschofski, H, Wareham, N, Watkins, H, Wichmann, H, Wilson, J, Abecasis, G, Assimes, T, Barroso, I, Boehnke, M, Borecki, I, Deloukas, P, Fox, C, Frayling, T, Groop, L, Haritunian, T, Heid, I, Hunter, D, Kaplan, R, Karpe, F, Moffatt, M, Mohlke, K, O'Connell, J, Pawitan, Y, Schadt, E, Schlessinger, D, Steinthorsdottir, V, Strachan, D, Thorsteinsdottir, U, Van, D, Cm, Visscher, P, Di Blasio, A, Hirschhorn, J, Lindgren, C, Meyre, D, Scherag, A, Mccarthy, M, Speliotes, E, North, K, Loos, R, Ingelsson, E, Life Course Epidemiology (LCE), Center for Liver, Digestive and Metabolic Diseases (CLDM), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Cardiovascular Centre (CVC), Medical Research Council (MRC), Berndt, Sonja I, Gustafsson, Stefan, Mägi, Reedik, Ganna, Andrea, Lee, Sang Hong, Hyppönen, Elina Tuulikki, Ingelsson, Erik, Berndt, Si, Feitosa, Mf, Justice, Ae, Monda, Kl, CROTEAU CHONKA, Dc, Day, Fr, Jackson, Au, Randall, Jc, Willer, Cj, Winkler, Tw, Wood, Ar, Hu, Yj, Lee, Sh, Lin, Dy, Min, Jl, Neale, Bm, BRAGG GRESHAM, Jl, DEN HEIJER, M, Hottenga, Jj, Huffman, Je, Johansson, A, Kleber, Me, König, Ir, Mcardle, Wl, MEDINA GOMEZ, C, MÜLLER NURASYID, M, Nolte, Im, Peters, Mj, Rose, Lm, Smith, Av, Strawbridge, Rj, Trip, Md, VAN VLIET OSTAPTCHOUK, Jv, Waite, Ll, Zhao, Jh, Asselbergs, Fw, Attwood, Ap, Balmforth, Aj, Bonnycastle, Ll, Chasman, Di, Connell, Jm, Cookson, Wo, DE FAIRE, U, DE VEGT, F, Evans, Dm, Ferrario, Mm, Gejman, Pv, Hartikainen, Al, HEARD COSTA, Nl, Heath, Ac, Hu, Fb, Hunt, Se, Jacobs, Kb, Jansson, Jo, Khaw, Kt, Kraja, At, Laitinen, Jh, Lakka, Ta, Launer, Lj, Lokki, Ml, Madden, Pa, Magnusson, Pk, Manunta, Paolo, MATEO LEACH, I, Medland, Se, Montgomery, Gw, Mühleisen, Tw, Munroe, Pb, Musk, Aw, Nohr, Ea, Ong, Kk, Oostra, Ba, Palmer, Cn, Peden, Jf, Pramstaller, Pp, Saaristo, Te, Sambrook, Jg, Sanders, Ar, Shin, Sy, Stephens, Jc, Stolk, Rp, Swift, Aj, Theodoraki, Ev, Tregouet, Da, VAN DER KLAUW, Mm, VAN MEURS, Jb, Vermeulen, Sh, Wild, Sh, Winkelmann, Br, Witteman, Jc, Wolffenbuttel, Bh, Wright, Af, Zillikens, Mc, Boehm, Bo, Boomsma, Di, Caulfield, Mj, Chanock, Sj, Cupples, La, Dedoussis, Gv, Eriksson, Jg, Franks, Pw, Harris, Tb, Hicks, Aa, Hovingh, Kg, Jarvelin, Mr, Jöckel, Kh, KEINANEN KIUKAANNIEMI, Sm, Kiemeney, La, Levinson, Df, Martin, Ng, Morris, Ad, Oldehinkel, Aj, Ouwehand, Wh, Palmer, Lj, Province, Ma, Psaty, Bm, Ridker, Pm, Samani, Nj, Sørensen, Ti, Spector, Td, Uitterlinden, Ag, VAN DER HARST, P, Wareham, Nj, Wichmann, He, Wilson, Jf, Abecasis, Gr, Assimes, Tl, Borecki, Ib, Groop, Lc, Heid, Im, Kaplan, Rc, Moffatt, Mf, Mohlke, Kl, O'Connell, Jr, Schadt, Ee, Strachan, Dp, VAN DUIJN, Cm, Visscher, Pm, DI BLASIO, Am, Hirschhorn, Jn, Lindgren, Cm, Morris, Ap, Mccarthy, Mi, Speliotes, Ek, North, Ke, Loos, Rj, and Ingelsson, E.
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Netherlands Twin Register (NTR) ,Linkage disequilibrium ,SORTILIN ,BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA ,Medizin ,Genome-wide association study ,Aetiology, screening and detection [ONCOL 5] ,polymorphism ,Body Mass Index ,0302 clinical medicine ,Missing heritability problem ,MISSING HERITABILITY ,EXTREME OBESITY ,CONFER RISK ,POPULATION ,Genetics & Heredity ,2. Zero hunger ,Genetics ,Medical And Health Sciences ,0303 health sciences ,education.field_of_study ,Anthropometry ,COMMON VARIANTS ,Single Nucleotide ,ASSOCIATION ,Biological Sciences ,Anthropometry, Body Height ,genetics, Body Mass Index, Case-Control Studies, European Continental Ancestry Group ,genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Meta-Analysis as Topic, Obesity ,genetics, Phenotype, Polymorphism ,genetics, Quantitative Trait Loci, Waist-Hip Ratio ,Phenotype ,Life Sciences & Biomedicine ,EXPRESSION ,Genotype ,Missing heritabillity ,Population ,European Continental Ancestry Group ,Quantitative Trait Loci ,EARLY-ONSET ,Genomics ,Biology ,Quantitative trait locus ,Polymorphism, Single Nucleotide ,Article ,White People ,Molecular epidemiology [NCEBP 1] ,03 medical and health sciences ,Meta-Analysis as Topic ,SDG 3 - Good Health and Well-being ,Humans ,Genetic Predisposition to Disease ,Obesity ,body height/genetics ,Polymorphism ,Allele ,Genetik ,education ,Molecular epidemiology Aetiology, screening and detection [NCEBP 1] ,030304 developmental biology ,Science & Technology ,Waist-Hip Ratio ,BMI, height, WHR, obesity, GWS ,ta3121 ,Genetic architecture ,Body Height ,BODY-MASS INDEX ,Case-Control Studies ,gene ,stature ,height ,030217 neurology & neurosurgery ,Developmental Biology ,Genome-Wide Association Study - Abstract
Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups. © 2013 Nature America, Inc. All rights reserved.
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- 2013
20. Seventy-five genetic loci influencing the human red blood cell
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Teresa Nutile, Anna-Liisa Hartikainen, Stavroula Kanoni, Johannes H. Smit, Harm-Jan Westra, Beben Benyamin, Gonneke Willemsen, Clara S. Tang, Maria Dimitriou, Peter Vollenweider, Olle Melander, Inga Prokopenko, W.H. Wilson Tang, John P. Kemp, Tim D. Spector, Evelin Mihailov, Paul F. O'Reilly, Eleonora Porcu, Marcus E. Kleber, Sheila Ulivi, George Dedoussis, Manuela Uda, Matthias Nauck, Brenda W.J.H. Penninx, Daniela Ruggiero, Xinzhong Li, Dirk S. Paul, Niek Verweij, Bernd Genser, Harold Snieder, Willem H. Ouwehand, Ido P. Kema, Miriam F. Moffatt, Carmel Moore, Hilma Holm, Nicola Pirastu, Adamo Pio D'Adamo, Michael Stumvoll, Rossella Sorice, Kay-Tee Khaw, Heather Lloyd-Jones, Federico Murgia, Stephen F. Garner, Jing Hua Zhao, Laura Portas, Abdel Abdellaoui, Ursula Puc, Andres Metspalu, Marleen H. M. de Moor, Isleifur Olafsson, Ruth J. F. Loos, Andres Salumets, François Bastardot, James Scott, Jian Yang, Braxton D. Mitchell, Debora Parracciani, Maria Novatchkova, Panos Deloukas, William O.C.M. Cookson, Lorna M. Lopez, Andrew A. Hicks, Aude Saint-Pierre, Daniel F. Gudbjartsson, Vinicius Tragante, Mario Pirastu, Jacques S. Beckmann, L. Joost van Pelt, Winfried Maerz, Hooman Allayee, Jouke-Jan Hottenga, Kari Stefansson, Debashish Das, Weihua Zhang, Anke Tönjes, Michela Traglia, Stuart Meacham, Antonio Piga, Cornelis A. Albers, Nicholas G. Martin, John C. Chambers, Christa Meisinger, Leo-Pekka Lyytikäinen, Nicole Soranzo, Mika Kähönen, Katrin Voss, Micha Hersch, Claudia Langenberg, Sian Tsung Tan, Sandosh Padmanabhan, Christian X. Weichenberger, J. Gustav Smith, Antony P. Attwood, Claire E. Hastie, Gunnar Engström, Janina S. Ried, Carsten Oliver Schmidt, Pall T. Onundarson, Kathy Miller, Francisco S. Domingues, Stefania Bandinelli, Ulrich Elling, Augusto Rendon, Paul Elliott, Quince Gibson, Tõnu Esko, Robert Sladek, Marina Ciullo, Gerald Wirnsberger, Franco Anni, Antonietta Robino, Serena Sanna, Hein Schepers, Jonathan Stephens, Joban Sehmi, Beverley Balkau, Jennifer G. Sambrook, Lucia Perseu, Ilja M. Nolte, Herman H W Silljé, John M. Starr, Cinzia Sala, Peter P. Pramstaller, David M. Evans, Renzo Galanello, Uwe Völker, Philippe Froguel, Dorret I. Boomsma, Vasiliki Lagou, Gerjan Navis, Christian Gieger, Susan M. Ring, Alexander Teumer, Angela Döring, Ale Algra, Toshiko Tanaka, Bo Hedblad, Anneli Pouta, Unnur Thorsteinsdottir, Bernhard R. Winkelmann, Liming Liang, John Danesh, Paolo Gasparini, Sarah E. Medland, Ian J. Deary, Martin Gögele, Pim van der Harst, Giorgia Girotto, Josef M. Penninger, Jaspal S. Kooner, Patrick Sulem, Thomas Illig, Yasin Memari, Sarah E. Harris, Wiek H. van Gilst, Francesco Cucca, Dirk J. van Veldhuisen, So-Youn Shin, Giorgio Pistis, Olli T. Raitakari, Lude Franke, Folkert W. Asselbergs, Abtehale Al-Hussani, Stanley L. Hazen, Manuel A. R. Ferreira, Aimo Ruokonen, Christian Dina, Aparna Radhakrishnan, Irene Mateo Leach, Nicholas J. Wareham, George Davey Smith, Eric E. Schadt, Alan R. Shuldiner, John Whitfield, Gudmundur I. Eyjolfsson, Eco J. C. de Geus, Grant W. Montgomery, Afshin Parsa, Terho Lehtimäki, Paolo Fortina, Luigi Ferrucci, Andreas Greinacher, Marjo-Riitta Järvelin, Krista Fischer, Fabrice Danjou, Rudolf A. de Boer, Paul I.W. de Bakker, Peter M. Visscher, Anna F. Dominiczak, Ramiro Ramirez-Solis, Jennifer Jolley, Bruce H. R. Wolffenbuttel, Jaana Hartiala, Daniela Toniolo, Bernhard O. Boehm, van der Harst, P, Zhang, W, Mateo Leach, I, Rendon, A, Verweij, N, Sehmi, J, Paul, D, Elling, U, Allayee, H, Li, X, Radhakrishnan, A, Tan, St, Voss, K, Weichenberger, Cx, Albers, Ca, Al Hussani, A, Asselbergs, Fw, Ciullo, M, Danjou, F, Dina, C, Esko, T, Evans, Dm, Franke, L, Gögele, M, Hartiala, J, Hersch, M, Holm, H, Hottenga, Jj, Kanoni, S, Kleber, Me, Lagou, V, Langenberg, C, Lopez, Lm, Lyytikäinen, Lp, Melander, O, Murgia, F, Nolte, Im, O'Reilly, Pf, Padmanabhan, S, Parsa, A, Pirastu, Nicola, Porcu, E, Portas, L, Prokopenko, I, Ried, J, Shin, Sy, Tang, C, Teumer, A, Traglia, Michela, Ulivi, S, Westra, Hj, Yang, J, Zhao, Jh, Anni, F, Abdellaoui, A, Attwood, A, Balkau, B, Bandinelli, S, Bastardot, F, Benyamin, B, Boehm, Bo, Cookson, Wo, Das, D, de Bakker, Pi, de Boer, Ra, de Geus, Ej, de Moor, Mh, Dimitriou, M, Domingues, F, Döring, A, Engström, G, Eyjolfsson, Gi, Ferrucci, L, Fischer, K, Galanello, R, Garner, Sf, Genser, B, Gibson, Qd, Girotto, Giorgia, Gudbjartsson, Df, Harris, Se, Hartikainen, Al, Hastie, Ce, Hedblad, B, Illig, T, Jolley, J, Kähönen, M, Kema, Ip, Kemp, Jp, Liang, L, Lloyd Jones, H, Loos, Rj, Meacham, S, Medland, Se, Meisinger, C, Memari, Y, Mihailov, E, Miller, K, Moffatt, Mf, Nauck, M, Novatchkova, M, Nutile, T, Olafsson, I, Onundarson, Pt, Parracciani, D, Penninx, Bw, Perseu, L, Piga, A, Pistis, G, Pouta, A, Puc, U, Raitakari, O, Ring, Sm, Robino, Antonietta, Ruggiero, D, Ruokonen, A, Saint Pierre, A, Sala, C, Salumets, A, Sambrook, J, Schepers, H, Schmidt, Co, Silljé, Hh, Sladek, R, Smit, Jh, Starr, Jm, Stephens, J, Sulem, P, Tanaka, T, Thorsteinsdottir, U, Tragante, V, van Gilst, Wh, van Pelt, Lj, van Veldhuisen, Dj, Völker, U, Whitfield, Jb, Willemsen, G, Winkelmann, Br, Wirnsberger, G, Algra, A, Cucca, F, D'Adamo, ADAMO PIO, Danesh, J, Deary, Ij, Dominiczak, Af, Elliott, P, Fortina, P, Froguel, P, Gasparini, Paolo, Greinacher, A, Hazen, Sl, Jarvelin, Mr, Khaw, Kt, Lehtimäki, T, Maerz, W, Martin, Ng, Metspalu, A, Mitchell, Bd, Montgomery, Gw, Moore, C, Navis, G, Pirastu, M, Pramstaller, Pp, Ramirez Solis, R, Schadt, E, Scott, J, Shuldiner, Ar, Smith, Gd, Smith, Jg, Snieder, H, Sorice, R, Spector, Td, Stefansson, K, Stumvoll, M, Tang, Wh, Toniolo, D, Tönjes, A, Visscher, Pm, Vollenweider, P, Wareham, Nj, Wolffenbuttel, Bh, Boomsma, Di, Beckmann, J, Dedoussis, Gv, Deloukas, P, Ferreira, Ma, Sanna, S, Uda, M, Hicks, Aa, Penninger, Jm, Gieger, C, Kooner, J, Ouwehand, Wh, Soranzo, N, Chambers, J. C., Psychiatry, EMGO - Mental health, NCA - Anxiety & Depression, Biological Psychology, Neuroscience Campus Amsterdam - Anxiety & Depression, EMGO+ - Mental Health, Van Der Harst, Pim, Zhang, Weihua, Mateo Leach, Irene, Rendon, Augusto, Benyamin, Beben, Chambers, John C, Cardiovascular Centre (CVC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Lifestyle Medicine (LM), Stem Cell Aging Leukemia and Lymphoma (SALL), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), and Center for Liver, Digestive and Metabolic Diseases (CLDM)
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Male ,Netherlands Twin Register (NTR) ,Candidate gene ,Erythrocytes ,PROTEIN ,Genome-wide association study ,DISEASE ,Hemoglobins ,Mice ,0302 clinical medicine ,Genetics ,Genomics, blood ,0303 health sciences ,Multidisciplinary ,biology ,Cell Cycle ,COMMON VARIANTS ,Genomics ,Phenotype ,anemia ,3. Good health ,Haematopoiesis ,DROSOPHILA ,Drosophila melanogaster ,medicine.anatomical_structure ,HEMOGLOBIN LEVELS ,Organ Specificity ,030220 oncology & carcinogenesis ,Cytokines ,Female ,RNA Interference ,TRAITS ,Signal Transduction ,EXPRESSION ,Polymorphism, Single Nucleotide ,Article ,Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3] ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Genetic ,blood ,medicine ,Animals ,Humans ,GENOME-WIDE ASSOCIATION ,030304 developmental biology ,RECEPTOR ,CONSORTIUM ,ta3121 ,hemoglobin ,biology.organism_classification ,Hematopoiesis ,meta-analysis ,Red blood cell ,Gene Expression Regulation ,Genetic Loci ,Expression quantitative trait loci ,genome-wide association studies ,Genome-Wide Association Study - Abstract
Item does not contain fulltext Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.
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- 2012
21. International variation in prevalence of rhinitis and its relationship with sensitisation to perennial and seasonal allergens
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Riccardo Di Domenicantonio, Elpis Hatziagorou, Luis Garcia-Marcos, Lennart Nilsson, RENATO STEIN, Francesco Forastiere, Neil Pearce, Tamar Abramidze, Antonio Martínez-Gimeno, Philippa Ellwood, Lennart Bråbäck, Bert Brunekreef, Raju Khubchandani, Manuela De Sario, Epidémiologie des maladies infectieuses et modélisation (ESIM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Weinmayr G, Forastiere F, von Mutius E, Pistelli R, Strachan DP, ISAAC Phase Two Study Group., Weiland SK, Rzehak P, Abramidze T, Annesi-Maesano I, Björkstén B, Brunekreef B, Büchele G, and Cookson WO
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Male ,Allergy ,medicine.disease_cause ,Atopy ,MESH: Conjunctivitis ,0302 clinical medicine ,Allergen ,MESH: Child ,Epidemiology ,Prevalence ,030212 general & internal medicine ,Child ,Rhinitis ,education.field_of_study ,MESH: Rhinitis ,3. Good health ,Female ,Seasons ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Rhinitis, Allergic, Perennial ,MESH: Allergens ,MESH: Hypersensitivity ,Population ,International Study of Asthma and Allergies in Childhood Phase Two study ,perennial ,population attributable risk ,rhinitis ,seasonal ,skin-prick test ,03 medical and health sciences ,MESH: Cross-Sectional Studies ,MESH: Skin Tests ,Hypersensitivity ,medicine ,Humans ,education ,MESH: Prevalence ,Skin Tests ,Asthma ,Models, Statistical ,MESH: Humans ,MESH: Rhinitis, Allergic, Perennial ,business.industry ,Rhinitis, Allergic, Seasonal ,MESH: Rhinitis, Allergic, Seasonal ,Allergens ,Conjunctivitis ,medicine.disease ,MESH: Male ,Cross-Sectional Studies ,030228 respiratory system ,Immunology ,Attributable risk ,Etiology ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,business ,MESH: Seasons ,MESH: Female ,MESH: Models, Statistical ,Demography - Abstract
International audience; The relative importance of atopy in the aetiology of rhinitis is largely unknown. The present study investigated the geographical variations in rhinitis in relation to atopy. The cross-sectional study involved 54,178 children (aged 8-12 yrs) from 30 study centres in 22 countries worldwide. Symptoms of rhinoconjunctivitis and rhinitis without conjunctivitis in the last 12 months were reported in parental questionnaires and children were skin-prick tested. The prevalence of rhinoconjunctivitis and rhinitis without conjunctivitis varied widely (1.5-24.5% and 1.4-45.2%, respectively). For rhinoconjunctivitis, the population attributable fraction (PAF) varied 0-71% for a positive skin-prick test to one or more seasonal allergens and 0-41% for perennial allergens. The PAF for sensitisation to seasonal and perennial allergens was higher in affluent countries (36 and 25%, respectively) than nonaffluent countries (1.3 and 12.6%, respectively). For rhinitis without conjunctivitis, the PAF for perennial allergens was 8 and 4% for affluent and nonaffluent countries, respectively. No significant PAF was found for seasonal allergens. Overall, atopy explained only a limited proportion of rhinitis symptoms, suggesting that the importance of other environmental factors has been under emphasised, particularly in less affluent countries. Atopy seems to be only marginally relevant for rhinitis without conjunctivitis, which seems mainly to reflect nonatopic rhinitis.
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- 2008
22. Delayed acquisition of airway commensals in antibiotic naïve children and its relationship with wheezing in rural Ecuador.
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Cardenas PA, Cox MJ, Willis-Owen SA, Moffatt MF, Cookson WO, and Cooper PJ
- Abstract
Introduction: The hygiene hypothesis identified a relationship between living in rural areas and acquiring protective environmental factors against the development of asthma and atopy. In our previous study, we found a correlation between particular bacterial species and early-onset wheezing in infants from the rural tropics of Ecuador who were corticosteroid-naïve and had limited antibiotic exposure. We now describe a longitudinal study of infants conducted to determine the age-related changes of the microbiome and its relationship with wheezing., Methods: We performed an amplicon sequencing of the 16S rRNA bacterial gene from the oropharyngeal samples obtained from 110 infants who had a history of recurrent episodic wheezing sampled at different ages (7, 12, and 24 months) and compared it to the sequencing of the oropharyngeal samples from 150 healthy infants sampled at the same time points. Bioinformatic analyses were conducted using QIIME and R., Results: As expected, the microbiota diversity consistently increased as the infants grew older. Considering age-based microbiota changes, we found that infants with wheeze had significantly lower species richness than the healthy infants at 7 months, but not at 12 or 24 months. Most of the core and accessory organisms increased in abundance and prevalence with age, except for a few which decreased. At 7 months of age, infants with wheeze had notably higher levels of a single Streptococcus operational taxonomic unit and core microbiota member than controls., Conclusions: In a cohort with limited antibiotic and corticosteroid use, a progressively more complex and diverse respiratory microbial community develops with age. The respiratory microbiota in early life is altered in infants with wheeze, but this does not hold true in older infants., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Cardenas, Cox, Willis-Owen, Moffatt, Cookson and Cooper.)
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- 2023
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23. An invisible threat? Aspergillus positive cultures and co-infecting bacteria in airway samples.
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Hughes DA, Rosenthal M, Cuthbertson L, Ramadan N, Felton I, Simmonds NJ, Loebinger MR, Price H, Armstrong-James D, Elborn JS, Cookson WO, Moffatt MF, and Davies JC
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- Humans, Aspergillus, Lung, Bacteria, Pseudomonas aeruginosa, Cystic Fibrosis complications, Cystic Fibrosis diagnosis, Cystic Fibrosis epidemiology, Aspergillosis microbiology, Staphylococcal Infections complications
- Abstract
Background: Aspergillus fumigatus (Af) infection is associated with poor lung health in chronic suppurative lung diseases but often goes undetected. We hypothesised that inhibition of Af growth by Pseudomonas aeruginosa (Pa) increases the frequency of false-negative Af culture in co-infected people. Using a substantial group of cystic fibrosis (CF) airway samples, we assessed the relationship between Af and bacterial pathogens, additionally comparing fungal culture with next-generation sequencing., Methods: Frequency of co-culture was assessed for 44,554 sputum/BAL cultures, from 1,367 CF patients between the years 2010-2020. In a subgroup, Internal Transcribed Spacer-2 (ITS2) fungal sequencing was used to determine sequencing-positive, culture-negative (S+/C-) rates., Results: Pa+ samples were nearly 40% less likely (P<0.0001) than Pa- samples to culture Af, an effect that was also seen with some other Gram-negative isolates. This impact varied with Pa density and appeared to be moderated by Staphylococcus aureus co-infection. Sequencing identified Af-S+/C- for 40.1% of tested sputa. Samples with Pa had higher rates of Af-S+/C- (49.3%) than those without (35.7%; RR 1.38 [1.02-1.93], P<0.05). Af-S+/C- rate was not changed by other common bacterial infections. Pa did not affect the S+/C- rates of Candida, Exophiala or Scedosporium., Conclusions: Pa/ Af co-positive cultures are less common than expected in CF. Our findings suggest an Af-positive culture is less likely in the presence of Pa. Interpretation of negative cultures should be cautious, particularly in Pa-positive samples, and a companion molecular diagnostic could be useful. Further work investigating mechanisms, alternative detection techniques and other chronic suppurative lung diseases is needed., Competing Interests: Declaration of Competing Interest No authors declare competing interests directly relating to this manuscript. NS reports personal fees from Vertex, Chiesi, Gilead, Menarini, Pulmocide, Zambon and Roche. ML reports personal fees from Insmed, Astra Zeneca, and Grifols. JCD reports advisory roles with Algipharma AS, Bayer AG, Boehringer Ingelheim Pharma GmbH & Co. KG, Galapagos NV, ImevaX GmbH, Nivalis Therapeutics Inc., ProQR Therapeutics III B.V., Proteostasis Therapeutics Inc., Raptor Pharmaceuticals Inc., Vertex Pharmaceuticals (Europe) Limited, Enterprise, Novartis, Pulmocide, Flatley, and Teva., (Copyright © 2022. Published by Elsevier B.V.)
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- 2023
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24. Airway mucins promote immunopathology in virus-exacerbated chronic obstructive pulmonary disease.
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Singanayagam A, Footitt J, Marczynski M, Radicioni G, Cross MT, Finney LJ, Trujillo-Torralbo MB, Calderazzo M, Zhu J, Aniscenko J, Clarke TB, Molyneaux PL, Bartlett NW, Moffatt MF, Cookson WO, Wedzicha J, Evans CM, Boucher RC, Kesimer M, Lieleg O, Mallia P, and Johnston SL
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- Adenosine Triphosphate metabolism, Animals, Disease Models, Animal, Humans, Inflammation metabolism, Mice, Mucin-5B genetics, Mucin-5B metabolism, Mucus metabolism, Respiratory Mucosa metabolism, Respiratory Mucosa pathology, Mucin 5AC genetics, Mucin 5AC metabolism, Pulmonary Disease, Chronic Obstructive metabolism, Pulmonary Disease, Chronic Obstructive virology
- Abstract
The respiratory tract surface is protected from inhaled pathogens by a secreted layer of mucus rich in mucin glycoproteins. Abnormal mucus accumulation is a cardinal feature of chronic respiratory diseases, but the relationship between mucus and pathogens during exacerbations is poorly understood. We identified elevations in airway mucin 5AC (MUC5AC) and MUC5B concentrations during spontaneous and experimentally induced chronic obstructive pulmonary disease (COPD) exacerbations. MUC5AC was more sensitive to changes in expression during exacerbation and was therefore more predictably associated with viral load, inflammation, symptom severity, decrements in lung function, and secondary bacterial infections. MUC5AC was functionally related to inflammation, as Muc5ac-deficient (Muc5ac-/-) mice had attenuated RV-induced (RV-induced) airway inflammation, and exogenous MUC5AC glycoprotein administration augmented inflammatory responses and increased the release of extracellular adenosine triphosphate (ATP) in mice and human airway epithelial cell cultures. Hydrolysis of ATP suppressed MUC5AC augmentation of RV-induced inflammation in mice. Therapeutic suppression of mucin production using an EGFR antagonist ameliorated immunopathology in a mouse COPD exacerbation model. The coordinated virus induction of MUC5AC and MUC5B expression suggests that non-Th2 mechanisms trigger mucin hypersecretion during exacerbations. Our data identified a proinflammatory role for MUC5AC during viral infection and suggest that MUC5AC inhibition may ameliorate COPD exacerbations.
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- 2022
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25. ORMDL3 regulates poly I:C induced inflammatory responses in airway epithelial cells.
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Laura G, Liu Y, Fernandes K, Willis-Owen SAG, Ito K, Cookson WO, Moffatt MF, and Zhang Y
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- A549 Cells, Asthma genetics, Asthma pathology, Bronchi pathology, Epithelial Cells pathology, Humans, Interleukin-17 metabolism, Interleukin-6 metabolism, Interleukin-8 metabolism, Membrane Proteins genetics, Poly I-C metabolism, RNA Interference, Respiratory Mucosa metabolism, Virus Diseases pathology, Bronchi metabolism, Epithelial Cells metabolism, Membrane Proteins metabolism, Poly I-C genetics, Toll-Like Receptor 3 metabolism, Virus Diseases metabolism
- Abstract
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.
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- 2021
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26. Estimating cell-type-specific DNA methylation effects in heterogeneous cellular populations.
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Feng YA, Guo Y, Pain L, Lathrop GM, Laprise C, Moffatt MF, Cookson WO, and Liang L
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- Algorithms, CpG Islands genetics, Epigenomics methods, Genome-Wide Association Study methods, Humans, DNA Methylation genetics, Epigenesis, Genetic genetics
- Abstract
Aim: To develop a method for estimating cell-specific effects in epigenomic association studies in the presence of cell type heterogeneity. Materials & methods: We utilized Monte Carlo Expectation-Maximization algorithm with Metropolis-Hastings sampler to reconstruct the 'missing' cell-specific methylations and to estimate their associations with phenotypes free of confounding by cell type proportions. Results: Simulations showed reliable performance of the method under various settings including when the cell type is rare. Application to a real dataset recapitulated the directly measured cell-specific methylation pattern in whole blood. Conclusion: This work provides a framework to identify important cell groups and account for cell type composition useful for studying the role of epigenetic changes in human traits and diseases.
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- 2021
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27. Inhaled corticosteroid suppression of cathelicidin drives dysbiosis and bacterial infection in chronic obstructive pulmonary disease.
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Singanayagam A, Glanville N, Cuthbertson L, Bartlett NW, Finney LJ, Turek E, Bakhsoliani E, Calderazzo MA, Trujillo-Torralbo MB, Footitt J, James PL, Fenwick P, Kemp SV, Clarke TB, Wedzicha JA, Edwards MR, Moffatt M, Cookson WO, Mallia P, and Johnston SL
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- Adrenal Cortex Hormones administration & dosage, Aged, Animals, Antimicrobial Cationic Peptides pharmacology, Bacterial Infections metabolism, Bacterial Infections microbiology, Female, Fluticasone pharmacology, Humans, Lung drug effects, Lung metabolism, Lung microbiology, Male, Mice, Streptococcus pneumoniae drug effects, Streptococcus pneumoniae pathogenicity, Cathelicidins, Adrenal Cortex Hormones pharmacology, Antimicrobial Cationic Peptides metabolism, Dysbiosis metabolism, Dysbiosis microbiology, Pulmonary Disease, Chronic Obstructive metabolism, Pulmonary Disease, Chronic Obstructive microbiology
- Abstract
Bacterial infection commonly complicates inflammatory airway diseases such as chronic obstructive pulmonary disease (COPD). The mechanisms of increased infection susceptibility and how use of the commonly prescribed therapy inhaled corticosteroids (ICS) accentuates pneumonia risk in COPD are poorly understood. Here, using analysis of samples from patients with COPD, we show that ICS use is associated with lung microbiota disruption leading to proliferation of streptococcal genera, an effect that could be recapitulated in ICS-treated mice. To study mechanisms underlying this effect, we used cellular and mouse models of streptococcal expansion with Streptococcus pneumoniae , an important pathogen in COPD, to demonstrate that ICS impairs pulmonary clearance of bacteria through suppression of the antimicrobial peptide cathelicidin. ICS impairment of pulmonary immunity was dependent on suppression of cathelicidin because ICS had no effect on bacterial loads in mice lacking cathelicidin ( Camp
-/- ) and exogenous cathelicidin prevented ICS-mediated expansion of streptococci within the microbiota and improved bacterial clearance. Suppression of pulmonary immunity by ICS was mediated by augmentation of the protease cathepsin D. Collectively, these data suggest a central role for cathepsin D/cathelicidin in the suppression of antibacterial host defense by ICS in COPD. Therapeutic restoration of cathelicidin to boost antibacterial immunity and beneficially modulate the lung microbiota might be an effective strategy in COPD., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)- Published
- 2019
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28. Role of airway glucose in bacterial infections in patients with chronic obstructive pulmonary disease.
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Mallia P, Webber J, Gill SK, Trujillo-Torralbo MB, Calderazzo MA, Finney L, Bakhsoliani E, Farne H, Singanayagam A, Footitt J, Hewitt R, Kebadze T, Aniscenko J, Padmanaban V, Molyneaux PL, Adcock IM, Barnes PJ, Ito K, Elkin SL, Kon OM, Cookson WO, Moffat MF, Johnston SL, and Tregoning JS
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- Aged, Bacterial Load, Bronchoalveolar Lavage Fluid chemistry, Female, Humans, Male, Middle Aged, Nasal Lavage Fluid chemistry, Picornaviridae Infections metabolism, Picornaviridae Infections microbiology, Pseudomonas Infections microbiology, Pulmonary Disease, Chronic Obstructive microbiology, Respiratory System metabolism, Respiratory System microbiology, Respiratory Tract Infections microbiology, Smoking metabolism, Sputum metabolism, Viral Load, Glucose metabolism, Pseudomonas Infections metabolism, Pulmonary Disease, Chronic Obstructive metabolism, Respiratory Tract Infections metabolism
- Abstract
Background: Patients with chronic obstructive pulmonary disease (COPD) have increased susceptibility to respiratory tract infection, which contributes to disease progression and mortality, but mechanisms of increased susceptibility to infection remain unclear., Objectives: The aim of this study was to determine whether glucose concentrations were increased in airway samples (nasal lavage fluid, sputum, and bronchoalveolar lavage fluid) from patients with stable COPD and to determine the effects of viral infection on sputum glucose concentrations and how airway glucose concentrations relate to bacterial infection., Methods: We measured glucose concentrations in airway samples collected from patients with stable COPD and smokers and nonsmokers with normal lung function. Glucose concentrations were measured in patients with experimentally induced COPD exacerbations, and these results were validated in patients with naturally acquired COPD exacerbations. Relationships between sputum glucose concentrations, inflammatory markers, and bacterial load were examined., Results: Sputum glucose concentrations were significantly higher in patients with stable COPD compared with those in control subjects without COPD. In both experimental virus-induced and naturally acquired COPD exacerbations, sputum and nasal lavage fluid glucose concentrations were increased over baseline values. There were significant correlations between sputum glucose concentrations and sputum inflammatory markers, viral load, and bacterial load. Airway samples with higher glucose concentrations supported more Pseudomonas aeruginosa growth in vitro., Conclusions: Airway glucose concentrations are increased in patients with stable COPD and further increased during COPD exacerbations. Increased airway glucose concentrations might contribute to bacterial infections in both patients with stable and those with exacerbated COPD. This has important implications for the development of nonantibiotic therapeutic strategies for the prevention or treatment of bacterial infection in patients with COPD., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2018
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29. Corticosteroid suppression of antiviral immunity increases bacterial loads and mucus production in COPD exacerbations.
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Singanayagam A, Glanville N, Girkin JL, Ching YM, Marcellini A, Porter JD, Toussaint M, Walton RP, Finney LJ, Aniscenko J, Zhu J, Trujillo-Torralbo MB, Calderazzo MA, Grainge C, Loo SL, Veerati PC, Pathinayake PS, Nichol KS, Reid AT, James PL, Solari R, Wark PAB, Knight DA, Moffatt MF, Cookson WO, Edwards MR, Mallia P, Bartlett NW, and Johnston SL
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- Administration, Inhalation, Adrenal Cortex Hormones administration & dosage, Adrenal Cortex Hormones immunology, Animals, Bacterial Infections microbiology, Bacterial Infections prevention & control, Cell Line, Fluticasone administration & dosage, Fluticasone immunology, Fluticasone pharmacology, Humans, Lung drug effects, Lung microbiology, Lung virology, Mice, Knockout, Mucus microbiology, Mucus virology, Picornaviridae Infections prevention & control, Picornaviridae Infections virology, Pulmonary Disease, Chronic Obstructive microbiology, Pulmonary Disease, Chronic Obstructive virology, Receptor, Interferon alpha-beta genetics, Receptor, Interferon alpha-beta metabolism, Rhinovirus immunology, Rhinovirus physiology, Adrenal Cortex Hormones pharmacology, Bacterial Load drug effects, Immunity, Innate drug effects, Mucus drug effects, Pulmonary Disease, Chronic Obstructive prevention & control, Rhinovirus drug effects
- Abstract
Inhaled corticosteroids (ICS) have limited efficacy in reducing chronic obstructive pulmonary disease (COPD) exacerbations and increase pneumonia risk, through unknown mechanisms. Rhinoviruses precipitate most exacerbations and increase susceptibility to secondary bacterial infections. Here, we show that the ICS fluticasone propionate (FP) impairs innate and acquired antiviral immune responses leading to delayed virus clearance and previously unrecognised adverse effects of enhanced mucus, impaired antimicrobial peptide secretion and increased pulmonary bacterial load during virus-induced exacerbations. Exogenous interferon-β reverses these effects. FP suppression of interferon may occur through inhibition of TLR3- and RIG-I virus-sensing pathways. Mice deficient in the type I interferon-α/β receptor (IFNAR1
-/- ) have suppressed antimicrobial peptide and enhanced mucin responses to rhinovirus infection. This study identifies type I interferon as a central regulator of antibacterial immunity and mucus production. Suppression of interferon by ICS during virus-induced COPD exacerbations likely mediates pneumonia risk and raises suggestion that inhaled interferon-β therapy may protect.- Published
- 2018
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30. The COL5A3 and MMP9 genes interact in eczema susceptibility.
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Margaritte-Jeannin P, Babron MC, Laprise C, Lavielle N, Sarnowski C, Brossard M, Moffatt M, Gagné-Ouellet V, Etcheto A, Lathrop M, Just J, Cookson WO, Bouzigon E, Demenais F, and Dizier MH
- Subjects
- Adult, Aged, Female, Genotype, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Collagen Type V genetics, Eczema genetics, Epistasis, Genetic genetics, Genetic Predisposition to Disease genetics, Matrix Metalloproteinase 9 genetics
- Abstract
Background: Genetic studies of eczema have identified many genes, which explain only 14% of the heritability. Missing heritability may be partly due to ignored gene-gene (G-G) interactions., Objective: Our aim was to detect new interacting genes involved in eczema., Methods: The search for G-G interaction in eczema was conducted using a two-step approach, which included as a first step, a biological selection of genes, which are involved either in the skin or epidermis development or in the collagen metabolism, and as a second step, an interaction analysis of the selected genes. Analyses were carried out at both SNP and gene levels in three asthma-ascertained family samples: the discovery dataset of 388 EGEA (Epidemiological study on the Genetics and Environment of Asthma) families and the two replication datasets of 253 SLSJ (Saguenay-Lac-Saint-Jean) families and 207 MRCA (Medical Research Council) families., Results: One pair of SNPs, rs2287807 in COL5A3 and rs17576 in MMP9, that were detected in EGEA at P ≤ 10
-5 showed significant interaction by meta-analysis of EGEA, SLSJ and MRCA samples (P = 1.1 × 10-8 under the significant threshold of 10-7 ). Gene-based analysis confirmed strong interaction between COL5A3 and MMP9 (P = 4 × 10-8 under the significant threshold of 4 × 10-6 ) by meta-analysis of the three datasets. When stratifying the data on asthma, this interaction remained in both groups of asthmatic and non-asthmatic subjects., Conclusion: This study identified significant interaction between two new genes, COL5A3 and MMP9, which may be accounted for by a degradation of COL5A3 by MMP9 influencing eczema susceptibility. Further confirmation of this interaction as well as functional studies is needed to better understand the role of these genes in eczema., (© 2017 John Wiley & Sons Ltd.)- Published
- 2018
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31. Manipulation of dipeptidylpeptidase 10 in mouse and human in vivo and in vitro models indicates a protective role in asthma.
- Author
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Zhang Y, Poobalasingam T, Yates LL, Walker SA, Taylor MS, Chessum L, Harrison J, Tsaprouni L, Adcock IM, Lloyd CM, Cookson WO, Moffatt MF, and Dean CH
- Subjects
- Amino Acid Sequence, Animals, Asthma complications, Asthma pathology, Base Sequence, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases chemistry, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases genetics, Disease Models, Animal, Epithelial Cells metabolism, Ethylnitrosourea, Genotype, Homozygote, Humans, Hypersensitivity complications, Hypersensitivity pathology, Inflammation complications, Inflammation pathology, Inflammation Mediators metabolism, Lung parasitology, Lung pathology, Mice, Mice, Mutant Strains, Mutation genetics, Pyroglyphidae, Reproducibility of Results, Asthma enzymology, Asthma prevention & control, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases metabolism
- Abstract
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 ( Dpp10
145D ). 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. This article has an associated First Person interview with the first author of the paper., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)- Published
- 2018
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32. The lung microbiome in health and disease.
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Moffatt MF and Cookson WO
- Subjects
- Asthma microbiology, Bronchiectasis microbiology, Cystic Fibrosis microbiology, Humans, Metagenomics, Pulmonary Disease, Chronic Obstructive microbiology, RNA, Ribosomal, 16S genetics, Lung microbiology, Lung Diseases microbiology, Microbiota genetics
- Abstract
The Human Microbiome Project began 10 years ago, leading to a significant growth in understanding of the role the human microbiome plays in health and disease. In this article, we explain with an emphasis on the lung, the origins of microbiome research. We discuss how 16S rRNA gene sequencing became the first major molecular tool to examine the bacterial communities present within the human body. We highlight the pitfalls of molecular-based studies, such as false findings resulting from contamination, and the limitations of 16S rRNA gene sequencing. Knowledge about the lung microbiome has evolved from initial scepticism to the realisation that it might have a significant influence on many illnesses. We also discuss the lung microbiome in the context of disease by giving examples of important respiratory conditions. In addition, we draw attention to the challenges for metagenomic studies of respiratory samples and the importance of systematic bacterial isolation to enable host-microbiome interactions to be understood. We conclude by discussing how knowledge of the lung microbiome impacts current clinical diagnostics., (© Royal College of Physicians 2017. All rights reserved.)
- Published
- 2017
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33. Validation of a 52-gene risk profile for outcome prediction in patients with idiopathic pulmonary fibrosis: an international, multicentre, cohort study.
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Herazo-Maya JD, Sun J, Molyneaux PL, Li Q, Villalba JA, Tzouvelekis A, Lynn H, Juan-Guardela BM, Risquez C, Osorio JC, Yan X, Michel G, Aurelien N, Lindell KO, Klesen MJ, Moffatt MF, Cookson WO, Zhang Y, Garcia JGN, Noth I, Prasse A, Bar-Joseph Z, Gibson KF, Zhao H, Herzog EL, Rosas IO, Maher TM, and Kaminski N
- Subjects
- Aged, Cohort Studies, Female, Genetic Markers genetics, Humans, Idiopathic Pulmonary Fibrosis mortality, Leukocytes, Mononuclear, Linear Models, Male, Middle Aged, Prognosis, Proportional Hazards Models, Risk Assessment methods, Risk Factors, Time Factors, Vital Capacity, Gene Expression Profiling methods, Genetic Testing methods, Idiopathic Pulmonary Fibrosis genetics, Oligonucleotide Array Sequence Analysis methods
- Abstract
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 increase in up score and decrease in down score was predictive of decreased transplant-free survival (3·18, 1·16-8·76; p=0·025) in the Pittsburgh cohort. A simultaneous decrease in up score and increase in down score after initiation of antifibrotic drugs was associated with a significant (p=0·0050) improvement in FVC in the Yale cohort., Interpretation: The peripheral blood 52-gene expression signature is predictive of outcome in patients with IPF. The potential value of the 52-gene signature in predicting response to therapy should be determined in prospective studies., Funding: The Pulmonary Fibrosis Foundation, the Harold Amos Medical Faculty Development Program of the Robert Wood Johnson Foundation, and the National Heart, Lung, and Blood Institute of the US National Institutes of Health., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
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34. 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.
- Author
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Naeem AS, Tommasi C, Cole C, Brown SJ, Zhu Y, Way B, Willis Owen SA, Moffatt M, Cookson WO, Harper JI, Di WL, Brown SJ, Reinheckel T, and O'Shaughnessy RF
- Subjects
- Animals, Blotting, Western, Cathepsin H deficiency, Dermatitis, Atopic pathology, Filaggrin Proteins, Fluorescent Antibody Technique, Humans, Immunohistochemistry, Keratinocytes metabolism, Keratinocytes pathology, Male, Mice, Mice, Knockout, Microscopy, Electron, Transmission, Oligonucleotide Array Sequence Analysis, Rats, Real-Time Polymerase Chain Reaction, Regulatory-Associated Protein of mTOR, Skin metabolism, Skin pathology, Adaptor Proteins, Signal Transducing metabolism, Cathepsin H metabolism, Dermatitis, Atopic metabolism, Intermediate Filament Proteins metabolism, Proto-Oncogene Proteins c-akt metabolism
- Abstract
Background: Filaggrin, which is encoded by the filaggrin gene (FLG), is an important component of the skin's barrier to the external environment, and genetic defects in FLG strongly associate with atopic dermatitis (AD). However, not all patients with AD have FLG mutations., Objective: We hypothesized that these patients might possess other defects in filaggrin expression and processing contributing to barrier disruption and AD, and therefore we present novel therapeutic targets for this disease., Results: We describe the relationship between the mechanistic target of rapamycin complex 1/2 protein subunit regulatory associated protein of the MTOR complex 1 (RAPTOR), the serine/threonine kinase V-Akt murine thymoma viral oncogene homolog 1 (AKT1), and the protease cathepsin H (CTSH), for which we establish a role in filaggrin expression and processing. Increased RAPTOR levels correlated with decreased filaggrin expression in patients with AD. In keratinocyte cell cultures RAPTOR upregulation or AKT1 short hairpin RNA knockdown reduced expression of the protease CTSH. Skin of CTSH-deficient mice and CTSH short hairpin RNA knockdown keratinocytes showed reduced filaggrin processing, and the mouse had both impaired skin barrier function and a mild proinflammatory phenotype., Conclusion: Our findings highlight a novel and potentially treatable signaling axis controlling filaggrin expression and processing that is defective in patients with AD., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
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35. Adult onset asthma and interaction between genes and active tobacco smoking: The GABRIEL consortium.
- Author
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Vonk JM, Scholtens S, Postma DS, Moffatt MF, Jarvis D, Ramasamy A, Wjst M, Omenaas ER, Bouzigon E, Demenais F, Nadif R, Siroux V, Polonikov AV, Solodilova M, Ivanov VP, Curjuric I, Imboden M, Kumar A, Probst-Hensch N, Ogorodova LM, Puzyrev VP, Bragina EY, Freidin MB, Nolte IM, Farrall AM, Cookson WO, Strachan DP, Koppelman GH, and Boezen HM
- Subjects
- Adult, Cohort Studies, Genetic Predisposition to Disease genetics, Humans, Polymorphism, Single Nucleotide, Asthma chemically induced, Asthma genetics, Gene-Environment Interaction, Genome-Wide Association Study, Smoking adverse effects
- Abstract
Background: Genome-wide association studies have identified novel genetic associations for asthma, but without taking into account the role of active tobacco smoking. This study aimed to identify novel genes that interact with ever active tobacco smoking in adult onset asthma., Methods: We performed a genome-wide interaction analysis in six studies participating in the GABRIEL 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 and replicated our findings in an independent cohort (LifeLines Cohort Study), including 12,475 subjects., Results: First approach: 50 SNPs were selected based on an overall interaction effect at p<10-4. The most pronounced interaction effect was observed for rs9969775 on chromosome 9 (discovery meta-analysis: ORint = 0.50, p = 7.63*10-5, replication: ORint = 0.65, p = 0.02). Second approach: 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 chromosome 12 (discovery meta-analysis ORint = 1.50, p = 1.21*10-4; replication: ORint = 1.40, p = 0.03)., Conclusions: Using two genome-wide interaction approaches, we identified novel polymorphisms in non-annotated intergenic regions on chromosomes 9 and 12, that showed suggestive evidence for interaction with active tobacco smoking in the onset of adult asthma.
- Published
- 2017
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36. Bacterial microbiota of the upper respiratory tract and childhood asthma.
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Depner M, Ege MJ, Cox MJ, Dwyer S, Walker AW, Birzele LT, Genuneit J, Horak E, Braun-Fahrländer C, Danielewicz H, Maier RM, Moffatt MF, Cookson WO, Heederik D, von Mutius E, and Legatzki A
- Subjects
- Bacteria classification, Bacteria genetics, Bacteria isolation & purification, Child, DNA, Bacterial genetics, Farms, Female, Humans, Male, Microbiota, RNA, Ribosomal, 16S genetics, Asthma microbiology, Nose microbiology, Pharynx microbiology
- Abstract
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., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. All rights reserved.)
- Published
- 2017
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37. Longitudinal assessment of sputum microbiome by sequencing of the 16S rRNA gene in non-cystic fibrosis bronchiectasis patients.
- Author
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Cox MJ, Turek EM, Hennessy C, Mirza GK, James PL, Coleman M, Jones A, Wilson R, Bilton D, Cookson WO, Moffatt MF, and Loebinger MR
- Subjects
- Aged, Bronchiectasis diagnosis, Bronchiectasis etiology, Bronchitis physiopathology, Cross-Sectional Studies, Humans, Metagenomics methods, Middle Aged, Respiratory Function Tests, Risk Factors, Tomography, X-Ray Computed, Bronchiectasis complications, Bronchitis diagnosis, Bronchitis etiology, Microbiota, RNA, Ribosomal, 16S, Sputum microbiology
- Abstract
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 improved by therapy specific to their microbiome, taking into account pathogen load, community stability, and acute and chronic community responses to antibiotics., Competing Interests: DB received a grant from Novartis UK for sequencing costs. The funder had no involvement in study design, collection or analysis of data, or in the decision to publish. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
- Published
- 2017
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38. Changes in the respiratory microbiome during acute exacerbations of idiopathic pulmonary fibrosis.
- Author
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Molyneaux PL, Cox MJ, Wells AU, Kim HC, Ji W, Cookson WO, Moffatt MF, Kim DS, and Maher TM
- Subjects
- Acute Disease, Aged, Bacteria classification, Female, Humans, Male, Recurrence, Species Specificity, Bacteria genetics, Bacteria isolation & purification, Bronchoalveolar Lavage Fluid microbiology, Idiopathic Pulmonary Fibrosis microbiology, Lung microbiology, Microbiota genetics
- Abstract
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.
- Published
- 2017
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39. A functional AT/G polymorphism in the 5'-untranslated region of SETDB2 in the IgE locus on human chromosome 13q14.
- Author
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Holt RJ, Vandiedonck C, Willis-Owen SA, Knight JC, Cookson WO, Moffatt MF, and Zhang Y
- Published
- 2017
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40. Global gene regulation during activation of immunoglobulin class switching in human B cells.
- Author
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Zhang Y, Fear DJ, Willis-Owen SA, Cookson WO, and Moffatt MF
- Subjects
- B-Lymphocytes immunology, Cells, Cultured, Germinal Center immunology, Humans, Immunoglobulin Class Switching immunology, Lymphocyte Activation immunology, B-Lymphocytes metabolism, Gene Expression Regulation, Germinal Center metabolism, Immunoglobulin Class Switching genetics, Immunoglobulin Isotypes genetics, Lymphocyte Activation genetics
- Abstract
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.
- Published
- 2016
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41. LILRA6 copy number variation correlates with susceptibility to atopic dermatitis.
- Author
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López-Álvarez MR, Jiang W, Jones DC, Jayaraman J, Johnson C, Cookson WO, Moffatt MF, Trowsdale J, and Traherne JA
- Subjects
- Child, DNA analysis, Female, Humans, Male, Polymerase Chain Reaction, DNA genetics, DNA Copy Number Variations genetics, Dermatitis, Atopic genetics, Dermatitis, Atopic pathology, Disease Susceptibility, Receptors, Immunologic genetics
- Abstract
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., Competing Interests: The authors declare they have no conflict of interest.
- Published
- 2016
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42. DNA methylation within melatonin receptor 1A (MTNR1A) mediates paternally transmitted genetic variant effect on asthma plus rhinitis.
- Author
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Sarnowski C, Laprise C, Malerba G, Moffatt MF, Dizier MH, Morin A, Vincent QB, Rohde K, Esparza-Gordillo J, Margaritte-Jeannin P, Liang L, Lee YA, Bousquet J, Siroux V, Pignatti PF, Cookson WO, Lathrop M, Pastinen T, Demenais F, and Bouzigon E
- Subjects
- Alleles, Asthma epidemiology, Comorbidity, DNA Methylation, Genetic Variation, Genotype, Humans, Rhinitis, Allergic epidemiology, Asthma genetics, CpG Islands, Paternal Inheritance, Receptor, Melatonin, MT1 genetics, Rhinitis, Allergic genetics
- Abstract
Background: Asthma and allergic rhinitis (AR) are common allergic comorbidities with a strong genetic component in which epigenetic mechanisms might be involved., Objective: We aimed to identify novel risk loci for asthma and AR while accounting for parent-of-origin effect., Methods: We performed a series of genetic analyses, taking into account the parent-of-origin effect in families ascertained through asthma: (1) genome-wide linkage scan of asthma and AR in 615 European families, (2) association analysis with 1233 single nucleotide polymorphisms (SNPs) covering the significant linkage region in 162 French Epidemiological Study on the Genetics and Environment of Asthma families with replication in 154 Canadian Saguenay-Lac-Saint-Jean asthma study families, and (3) association analysis of disease and significant SNPs with DNA methylation (DNAm) at CpG sites in 40 Saguenay-Lac-Saint-Jean asthma study families., Results: We detected a significant paternal linkage of the 4q35 region to asthma and allergic rhinitis comorbidity (AAR; P = 7.2 × 10(-5)). Association analysis in this region showed strong evidence for the effect of the paternally inherited G allele of rs10009104 on AAR (P = 1.1 × 10(-5), reaching the multiple-testing corrected threshold). This paternally inherited allele was also significantly associated with DNAm levels at the cg02303933 site (P = 1.7 × 10(-4)). Differential DNAm at this site was found to mediate the identified SNP-AAR association., Conclusion: By integrating genetic and epigenetic data, we identified that a differentially methylated CpG site within the melatonin receptor 1A (MTNR1A) gene mediates the effect of a paternally transmitted genetic variant on the comorbidity of asthma and AR. This study provides a novel insight into the role of epigenetic mechanisms in patients with allergic respiratory diseases., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. All rights reserved.)
- Published
- 2016
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43. Effects of different antibiotic classes on airway bacteria in stable COPD using culture and molecular techniques: a randomised controlled trial.
- Author
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Brill SE, Law M, El-Emir E, Allinson JP, James P, Maddox V, Donaldson GC, McHugh TD, Cookson WO, Moffatt MF, Nazareth I, Hurst JR, Calverley PM, Sweeting MJ, and Wedzicha JA
- Subjects
- Aged, Bacterial Load, Female, Humans, Male, Middle Aged, Moxifloxacin, Outcome Assessment, Health Care, Pulmonary Disease, Chronic Obstructive complications, Single-Blind Method, Sputum microbiology, Anti-Bacterial Agents therapeutic use, Azithromycin therapeutic use, Doxycycline therapeutic use, Fluoroquinolones therapeutic use, Pulmonary Disease, Chronic Obstructive microbiology, Respiratory System microbiology
- Abstract
Background: Long-term antibiotic therapy is used to prevent exacerbations of COPD but there is uncertainty over whether this reduces airway bacteria. The optimum antibiotic choice remains unknown. We conducted an exploratory trial in stable patients with COPD comparing three antibiotic regimens against placebo., Methods: This was a single-centre, single-blind, randomised placebo-controlled trial. Patients aged ≥45 years with COPD, FEV1<80% predicted and chronic productive cough were randomised to receive either moxifloxacin 400 mg daily for 5 days every 4 weeks, doxycycline 100 mg/day, azithromycin 250 mg 3 times a week or one placebo tablet daily for 13 weeks. The primary outcome was the change in total cultured bacterial load in sputum from baseline; secondary outcomes included bacterial load by 16S quantitative PCR (qPCR), sputum inflammation and antibiotic resistance., Results: 99 patients were randomised; 86 completed follow-up, were able to expectorate sputum and were analysed. After adjustment, there was a non-significant reduction in bacterial load of 0.42 log10 cfu/mL (95% CI -0.08 to 0.91, p=0.10) with moxifloxacin, 0.11 (-0.33 to 0.55, p=0.62) with doxycycline and 0.08 (-0.38 to 0.54, p=0.73) with azithromycin from placebo, respectively. There were also no significant changes in bacterial load measured by 16S qPCR or in airway inflammation. More treatment-related adverse events occurred with moxifloxacin. Of note, mean inhibitory concentrations of cultured isolates increased by at least three times over placebo in all treatment arms., Conclusions: Total airway bacterial load did not decrease significantly after 3 months of antibiotic therapy. Large increases in antibiotic resistance were seen in all treatment groups and this has important implications for future studies., Trial Registration Number: clinicaltrials.gov (NCT01398072)., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)
- Published
- 2015
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44. A functional AT/G polymorphism in the 5'-untranslated region of SETDB2 in the IgE locus on human chromosome 13q14.
- Author
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Holt RJ, Vandiedonck C, Willis-Owen SA, Knight JC, Cookson WO, Moffatt MF, and Zhang Y
- Subjects
- Adolescent, Adult, Asthma enzymology, Asthma genetics, Child, Electrophoretic Mobility Shift Assay, Exons, Female, Humans, Immunoglobulin E blood, Male, Middle Aged, Polymorphism, Single Nucleotide, White People, 5' Untranslated Regions, Chromosomes, Human, Pair 13, Histone-Lysine N-Methyltransferase genetics, Immunoglobulin E genetics, Protein Methyltransferases genetics
- Abstract
The immunoglobulin E (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 ungenotyped mutation (AT/G, rs386770867) in the 5'-untranslated region 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 revealed that the transcription factor Ying Yang 1 binds to the AT allele, whereas SRY (Sex determining Region Y) 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 overexpressed in these individuals (P=1.26×10(-21)). A dual-luciferase assay with the pGL3 luciferase reporter gene showed that the AT allele significantly affects transcriptional activities. Our results indicate that the IgE-associated AT/G polymorphism (rs386770867) regulates transcription of SETDB2.
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- 2015
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45. Outside In: Sequencing the Lung Microbiome.
- Author
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Cox MJ, Moffatt MF, and Cookson WO
- Subjects
- Female, Humans, Male, Microbiota, Pulmonary Disease, Chronic Obstructive microbiology, Pulmonary Disease, Chronic Obstructive pathology
- Published
- 2015
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46. Late-Onset Bloodstream Infection and Perturbed Maturation of the Gastrointestinal Microbiota in Premature Infants.
- Author
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Shaw AG, Sim K, Randell P, Cox MJ, McClure ZE, Li MS, Donaldson H, Langford PR, Cookson WO, Moffatt MF, and Kroll JS
- Subjects
- Feces microbiology, Female, Humans, Infant, Newborn, Male, Microbiota, Sepsis microbiology, Gastrointestinal Tract microbiology, Infant, Premature, Sepsis diagnosis
- Abstract
Background: Late-onset bloodstream infection (LO-BSI) is a common complication of prematurity, and lack of timely diagnosis and treatment can have life-threatening consequences. We sought to identify clinical characteristics and microbial signatures in the gastrointestinal microbiota preceding diagnosis of LO-BSI in premature infants., Method: Daily faecal samples and clinical data were collected over two years from 369 premature neonates (<32 weeks gestation). We analysed samples from 22 neonates who developed LO-BSI and 44 matched control infants. Next-generation sequencing of 16S rRNA gene regions amplified by PCR from total faecal DNA was used to characterise the microbiota of faecal samples preceding diagnosis from infants with LO-BSI and controls. Culture of selected samples was undertaken, and bacterial isolates identified using MALDI-TOF. Antibiograms from bloodstream and faecal isolates were compared to explore strain similarity., Results: From the week prior to diagnosis, infants with LO-BSI had higher proportions of faecal aerobes/facultative anaerobes compared to controls. Risk factors for LO-BSI were identified by multivariate analysis. Enterobacteriaceal sepsis was associated with antecedent multiple lines, low birth weight and a faecal microbiota with prominent Enterobacteriaceae. Staphylococcal sepsis was associated with Staphylococcus OTU faecal over-abundance, and the number of days prior to diagnosis of mechanical ventilation and of the presence of centrally-placed lines. In 12 cases, the antibiogram of the bloodstream isolate matched that of a component of the faecal microbiota in the sample collected closest to diagnosis., Conclusions: The gastrointestinal tract is an important reservoir for LO-BSI organisms, pathogens translocating across the epithelial barrier. LO-BSI is associated with an aberrant microbiota, with abundant staphylococci and Enterobacteriaceae and a failure to mature towards predominance of obligate anaerobes.
- Published
- 2015
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47. iGWAS: Integrative Genome-Wide Association Studies of Genetic and Genomic Data for Disease Susceptibility Using Mediation Analysis.
- Author
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Huang YT, Liang L, Moffatt MF, Cookson WO, and Lin X
- Subjects
- Child, Chromosome Mapping, Computer Simulation, Family, Genetic Linkage, Genome, Human, Genomics methods, Humans, Phenotype, Algorithms, Asthma genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Models, Genetic, Polymorphism, Single Nucleotide genetics, Quantitative Trait Loci genetics
- Abstract
Genome-wide association studies (GWAS) have been a standard practice in identifying single nucleotide polymorphisms (SNPs) for disease susceptibility. We propose a new approach, termed integrative GWAS (iGWAS) that exploits the information of gene expressions to investigate the mechanisms of the association of SNPs with a disease phenotype, and to incorporate the family-based design for genetic association studies. Specifically, the relations among SNPs, gene expression, and disease are modeled within the mediation analysis framework, which allows us to disentangle the genetic effect on a disease phenotype into two parts: an effect mediated through a gene expression (mediation effect, ME) and an effect through other biological mechanisms or environment-mediated mechanisms (alternative effect, AE). We develop omnibus tests for the ME and AE that are robust to underlying true disease models. Numerical studies show that the iGWAS approach is able to facilitate discovering genetic association mechanisms, and outperforms the SNP-only method for testing genetic associations. We conduct a family-based iGWAS of childhood asthma that integrates genetic and genomic data. The iGWAS approach identifies six novel susceptibility genes (MANEA, MRPL53, LYCAT, ST8SIA4, NDFIP1, and PTCH1) using the omnibus test with false discovery rate less than 1%, whereas no gene using SNP-only analyses survives with the same cut-off. The iGWAS analyses further characterize that genetic effects of these genes are mostly mediated through their gene expressions. In summary, the iGWAS approach provides a new analytic framework to investigate the mechanism of genetic etiology, and identifies novel susceptibility genes of childhood asthma that were biologically meaningful., (© 2015 WILEY PERIODICALS, INC.)
- Published
- 2015
- Full Text
- View/download PDF
48. eQTL mapping identifies insertion- and deletion-specific eQTLs in multiple tissues.
- Author
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Huang J, Chen J, Esparza J, Ding J, Elder JT, Abecasis GR, Lee YA, Mark Lathrop G, Moffatt MF, Cookson WO, and Liang L
- Subjects
- Child, Epigenesis, Genetic, Genetic Association Studies, Genome-Wide Association Study, Humans, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Chromosome Mapping, INDEL Mutation genetics, Organ Specificity genetics, Quantitative Trait Loci genetics
- Abstract
Genome-wide gene expression quantitative trait loci (eQTL) mapping have been focused on single-nucleotide polymorphisms and have helped interpret findings from diseases mapping studies. The functional effect of structure variants, especially short insertions and deletions (indel) has not been well investigated. Here we impute 1,380,133 indels based on the latest 1,000 Genomes Project panel into three eQTL data sets from multiple tissues. Imputation of indels increased 9.9% power and identifies indel-specific eQTLs for 325 genes. We find introns and vicinities of UTRs are more enriched of indel eQTLs and 3.6 (single-tissue)-9.2%(multi-tissue) of previous identified eSNPs were taggers of eindels. Functional analyses identifies epigenetics marks, gene ontology categories and disease GWAS loci affected by SNPs and indels eQTLs showing tissue-consistent or tissue-specific effects. This study provides new insights into the underlying genetic architecture of gene expression across tissues and new resource to interpret function of diseases and traits associated structure variants.
- Published
- 2015
- Full Text
- View/download PDF
49. Dysbiosis anticipating necrotizing enterocolitis in very premature infants.
- Author
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Sim K, Shaw AG, Randell P, Cox MJ, McClure ZE, Li MS, Haddad M, Langford PR, Cookson WO, Moffatt MF, and Kroll JS
- Subjects
- Clostridium perfringens genetics, Clostridium perfringens isolation & purification, Continuous Positive Airway Pressure, Enterocolitis, Necrotizing therapy, Female, Humans, Infant, Infant, Newborn, Infant, Premature, Infant, Premature, Diseases therapy, Klebsiella genetics, Klebsiella isolation & purification, Male, Pregnancy, RNA, Ribosomal, 16S genetics, Sequence Analysis, DNA, Dysbiosis, Enterocolitis, Necrotizing microbiology, Infant, Premature, Diseases microbiology
- Abstract
Background: Necrotizing enterocolitis (NEC) is a devastating inflammatory bowel disease of premature infants speculatively associated with infection. Suspected NEC can be indistinguishable from sepsis, and in established cases an infant may die within hours of diagnosis. Present treatment is supportive. A means of presymptomatic diagnosis is urgently needed. We aimed to identify microbial signatures in the gastrointestinal microbiota preceding NEC diagnosis in premature infants., Methods: Fecal samples and clinical data were collected from a 2-year cohort of 369 premature neonates. Next-generation sequencing of 16S ribosomal RNA gene regions was used to characterize the microbiota of prediagnosis fecal samples from 12 neonates with NEC, 8 with suspected NEC, and 44 controls. Logistic regression was used to determine clinical characteristics and operational taxonomic units (OTUs) discriminating cases from controls. Samples were cultured and isolates identified using matrix-assisted laser desorption/ionization-time of flight. Clostridial isolates were typed and toxin genes detected., Results: A clostridial OTU was overabundant in prediagnosis samples from infants with established NEC (P = .006). Culture confirmed the presence of Clostridium perfringens type A. Fluorescent amplified fragment-length polymorphism typing established that no isolates were identical. Prediagnosis samples from NEC infants not carrying profuse C. perfringens revealed an overabundance of a Klebsiella OTU (P = .049). Prolonged continuous positive airway pressure (CPAP) therapy with supplemental oxygen was also associated with increased NEC risk., Conclusions: Two fecal microbiota signatures (Clostridium and Klebsiella OTUs) and need for prolonged CPAP oxygen signal increased risk of NEC in presymptomatic infants. These biomarkers will assist development of a screening tool to allow very early diagnosis of NEC. Clinical Trials Registration. NCT01102738., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2015
- Full Text
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50. Functional analysis of a novel ENU-induced PHD finger 11 (Phf11) mouse mutant.
- Author
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Zhang Y, Dean C, Chessum L, Nguyen D, Stewart M, Taylor M, Cookson WO, and Moffatt MF
- Subjects
- Amino Acid Sequence, Animals, Chromosomes, Mammalian, DNA-Binding Proteins metabolism, Ethylnitrosourea pharmacology, Female, Lipopolysaccharides pharmacology, Lung immunology, Lung metabolism, Lung pathology, Male, Mice, Inbred BALB C, Mice, Inbred C3H, Molecular Sequence Data, Mutagenesis, Mutagens pharmacology, Organ Specificity, Transcription Factors metabolism, DNA-Binding Proteins genetics, Point Mutation, Transcription Factors genetics
- Abstract
Previously, human genetic studies have shown association between polymorphisms within the gene encoding plant homeodomain zinc finger protein 11 (PHF11) and asthma-related phenotypes. Initial functional studies have suggested that PHF11 may be involved in the immune response through regulation of T cell activities. In order to study further the gene's functions, we have investigated the mouse Phf11 locus. We have established and characterised a mouse line harbouring a point mutation in the PHD domain of Phf11. Full-length mouse cDNA for Phf11 was obtained by applying rapid amplification of cDNA ends (RACE). All five exons encoding the PHD domain of Phf11 were directly sequenced in 3840 mouse DNA samples from the UK MRC Harwell ENU (N-ethyl-N-nitrosourea)-mutagenised DNA archive. Mice harbouring a valine to alanine substitution, predicted to have a significant functional impact on the PHD zinc finger domain, were re-derived. These Phf11 mutant mice were outcrossed to C3H mice and then backcrossed for ten generations in order to establish a congenic line harbouring the single point mutation in Phf11. Macroscopic examination, haematology and histological examination of lung structure revealed no significant differences between mutant and wild-type mice. After administration of lipopolysaccharide, the level of expression of Il2, NF-kB and Setdb2 were significantly increased in Phf11 mutant homozygous lungs compared to control littermates. Our results provide evidence that Phf11 can operate as a Th1 cell regulator in immune responses. Moreover, our data indicate that these mice may provide a useful model for future studies on Phf11.
- Published
- 2014
- Full Text
- View/download PDF
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