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RATIONALE: Eosinophils are associated with airway inflammation in respiratory disease. Eosinophil production and survival is controlled partly by interleukin-5: anti-interleukin-5 agents reduce asthma and response correlates with baseline eosinophil counts. However, whether raised eosinophils are causally related to chronic obstructive pulmonary disease (COPD) and other respiratory phenotypes is not well understood. OBJECTIVES: We investigated causality between eosinophils and: lung function, acute exacerbations of COPD, asthma-COPD overlap (ACO), moderate-to-severe asthma and respiratory infections. METHODS: We performed Mendelian randomisation (MR) using 151 variants from genome-wide association studies of blood eosinophils in UK Biobank/INTERVAL, and respiratory traits in UK Biobank/SpiroMeta, using methods relying on different assumptions for validity. We performed multivariable analyses using eight cell types where there was possible evidence of causation by eosinophils. MEASUREMENTS AND MAIN RESULTS: Causal estimates derived from individual variants were highly heterogeneous, which may arise from pleiotropy. The average effect of raising eosinophils was to increase risk of ACO (weighted median OR per SD eosinophils, 1.44 (95%CI 1.19 to 1.74)), and moderate-severe asthma (weighted median OR 1.50 (95%CI 1.23 to 1.83)), and to reduce forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) and FEV1 (weighted median estimator, SD FEV1/FVC: -0.054 (95% CI -0.078 to -0.029), effect only prominent in individuals with asthma). CONCLUSIONS: Broad consistency across MR methods may suggest causation by eosinophils (although of uncertain magnitude), yet heterogeneity necessitates caution: other important mechanisms may be responsible for the impairment of respiratory health by these eosinophil-raising variants. These results could suggest that anti-IL5 agents (designed to lower eosinophils) may be valuable in treating other respiratory conditions, including people with overlapping features of asthma and COPD.
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Asma , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Eosinófilos , Estudio de Asociación del Genoma Completo , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Asma/complicaciones , Volumen Espiratorio Forzado , PulmónRESUMEN
INTRODUCTION: There is increasing interest in the relationship between acute infections and acute cardiovascular events. Most previous research has focused on understanding whether the risk of acute cardiovascular events increases following a respiratory tract infection. The relationship between urinary tract infections (UTIs) and acute cardiovascular events is less well studied. Therefore, the aim of this study is to determine whether there is a causal relationship between UTI and acute myocardial infarction (MI) or stroke. METHODS AND ANALYSIS: We will undertake a self-controlled case series study using linked anonymised general practice, hospital admission and microbiology data held within the Secure Anonymised Information Linkage (SAIL) Databank. Self-controlled case series is a relatively novel study design where individuals act as their own controls, thereby inherently controlling for time-invariant confounders. Only individuals who experience an exposure and outcome of interest are included.We will identify individuals in the SAIL Databank who have a hospital admission record for acute MI or stroke during the study period of 2010-2020. Individuals will need to be aged 30-100 during the study period and be Welsh residents for inclusion. UTI will be identified using general practice, microbiology and hospital admissions data. We will calculate the incidence of MI and stroke in predefined risk periods following an UTI and in 'baseline' periods (without UTI exposure) and use conditional Poisson regression models to derive incidence rate ratios. ETHICS AND DISSEMINATION: Data access, research permissions and approvals have been obtained from the SAIL independent Information Governance Review Panel, project number 0972. Findings will be disseminated through conferences, blogs, social media threads and peer-reviewed journals. Results will be of interest internationally to primary and secondary care clinicians who manage UTIs and may inform future clinical trials of preventative therapy.
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Infarto del Miocardio , Accidente Cerebrovascular , Infecciones Urinarias , Registros Electrónicos de Salud , Humanos , Missouri , Infarto del Miocardio/epidemiología , Infarto del Miocardio/etiología , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/epidemiología , Infecciones Urinarias/complicaciones , Infecciones Urinarias/tratamiento farmacológico , Infecciones Urinarias/epidemiologíaRESUMEN
BACKGROUND: Airway bacterial dysbiosis is a feature of chronic obstructive pulmonary disease (COPD). However, there is limited comparative data of the lung microbiome between healthy smokers, non-smokers and COPD. METHODS: We compared the 16S rRNA gene-based sputum microbiome generated from pair-ended Illumina sequencing of 124 healthy subjects (28 smokers and 96 non-smokers with normal lung function), with single stable samples from 218 COPD subjects collected from three UK clinical centres as part of the COPDMAP consortium. RESULTS: In healthy subjects Firmicutes, Bacteroidetes and Actinobacteria were the major phyla constituting 88% of the total reads, and Streptococcus, Veillonella, Prevotella, Actinomyces and Rothia were the dominant genera. Haemophilus formed only 3% of the healthy microbiome. In contrast, Proteobacteria was the most dominant phylum accounting for 50% of the microbiome in COPD subjects, with Haemophilus and Moraxella at genus level contributing 25 and 3% respectively. There were no differences in the microbiome profile within healthy and COPD subgroups when stratified based on smoking history. Principal coordinate analysis on operational taxonomic units showed two distinct clusters, representative of healthy and COPD subjects (PERMANOVA, p = 0·001). CONCLUSION: The healthy and COPD sputum microbiomes are distinct and independent of smoking history. Our results underline the important role for Gammaproteobacteria in COPD.
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Pulmón/microbiología , No Fumadores , Enfermedad Pulmonar Obstructiva Crónica/microbiología , Fumadores , Esputo/microbiología , Anciano , Estudios de Casos y Controles , Disbiosis , Inglaterra , Femenino , Estado de Salud , Humanos , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , RibotipificaciónRESUMEN
BACKGROUND: Antibiotic resistance is a major global threat. We hypothesised that the chronic obstructive pulmonary disease (COPD) airway is a reservoir of antimicrobial resistance genes (ARGs) that associate with microbiome-specific COPD subgroups. OBJECTIVE: To determine the resistance gene profiles in respiratory samples from COPD patients and healthy volunteers. METHODS: Quantitative PCR targeting 279 specific ARGs was used to profile the resistomes in sputum from subjects with COPD at stable, exacerbation and recovery visits (n=55; COPD-BEAT study), healthy controls with (n=7) or without (n=22) exposure to antibiotics in the preceding 12 months (EXCEED study) and in bronchial brush samples from COPD (n=8) and healthy controls (n=7) (EvA study). RESULTS: ARG mean (SEM) prevalence was greater in stable COPD samples (35.2 (1.6)) than in healthy controls (27.6 (1.7); p=0.004) and correlated with total bacterial abundance (r2=0.23; p<0.001). Prevalence of ARG positive signals in individuals was not related to COPD symptoms, lung function or their changes at exacerbation. In the COPD subgroups designated High γProteobacteria and High Firmicutes, ARG prevalence was not different at stable state but significantly declined from stable through exacerbation to recovery in the former (p=0.011) without changes in total bacterial abundance. The ARG patterns were similar in COPD versus health, COPD microbiome-subgroups and between sputum and bronchoscopic samples independent of antibiotic exposure in the last 12 months. CONCLUSIONS: ARGs are highly prevalent in sputum, broadly in proportion to bacterial abundance in both healthy and COPD subjects. Thus, COPD appears to be an ARG reservoir due to high levels of bacterial colonisation.
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Farmacorresistencia Bacteriana/genética , Enfermedad Pulmonar Obstructiva Crónica/microbiología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Esputo/microbiología , Anciano , Carga Bacteriana , Femenino , Genes Bacterianos , Humanos , Masculino , Microbiota , Persona de Mediana Edad , Reacción en Cadena de la PolimerasaRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Ambiente , Estado de Salud , Estilo de Vida , Enfermedad Pulmonar Obstructiva Crónica , Telemedicina , Adulto , Anciano , Estudios de Cohortes , ADN , Femenino , Interacción Gen-Ambiente , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Fumar , Medio Social , Reino UnidoRESUMEN
Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function-associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.
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Predisposición Genética a la Enfermedad/genética , Pulmón/fisiopatología , Enfermedad Pulmonar Obstructiva Crónica/genética , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Estudio de Asociación del Genoma Completo/métodos , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Fumar/genéticaRESUMEN
Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P < 5 × 10-8; 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.
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Predisposición Genética a la Enfermedad/genética , Enfermedad Pulmonar Obstructiva Crónica/genética , Adulto , Anciano , Asma/genética , Estudios de Casos y Controles , Femenino , Expresión Génica/genética , Sitios Genéticos/genética , Estudio de Asociación del Genoma Completo/métodos , Humanos , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Fibrosis Pulmonar/genética , Fumar/genéticaRESUMEN
OBJECTIVES: To assess whether residential proximity to industrial incinerators in England is associated with increased risk of cancer incidence and mortality. DESIGN: Retrospective study using matched case-control areas. SETTING: Five circular regions of radius 10 km near industrial incinerators in England (case regions) and five matched control regions, 1998-2008. PARTICIPANTS: All cases of diseases of interest within the circular areas. PRIMARY AND SECONDARY OUTCOME MEASURES: Counts of childhood cancer incidence (<15 years); childhood leukaemia incidence (<15 years); leukaemia incidence; liver cancer incidence; lung cancer incidence; non-Hodgkin's lymphoma incidence; all-cause mortality; infant mortality (<1 year) and liver cancer mortality. RESULTS: The estimated relative risks for case circles versus control circles for the nine outcomes considered range from 0.94 to 1.14, and show neither elevated risk in case circles compared to control areas nor elevated risk with proximity to incinerators within case circles. CONCLUSIONS: This study applies statistical methods for analysing spatially referenced health outcome data in regions with a hypothesised exposure relative to matched regions with no such exposure. There is no evidence of elevated risk of cancer incidence or mortality in the vicinity of large industrial incinerators in England.