Developing and utilising longitudinal population studies to investigate genetic architecture of asthma and COPD

Chronic respiratory diseases, particularly asthma and COPD, cause substantial morbidity and mortality. Some individuals have features of both asthma and COPD (sometimes described as asthma-COPD overlap or ACO), and genetic risk factors for this are not fully understood. Genetic studies can identify underlying mechanisms to develop and target treatments, but require large cohorts with genotype data and phenotypic data such as self-reported diagnoses, spirometry and/or linked electronic health records (EHR). This project develops and utilises such cohorts to explore the epidemiology of asthma, COPD and ACO, and to study genetic associations with ACO. I developed recruitment to the Extended Cohort for E-health, Environment and DNA (EXCEED), a study of over 11,000 participants, and undertook descriptive analyses to produce a cohort profile paper. I undertook epidemiological analyses of linked EHR, which demonstrated the feasibility and utility of defining ACO and acute exacerbations of COPD using this data. Alongside this, I led quality control of spirometry data in the AWI-Gen-XHALE pilot study in South Africa, contributing to establishing an additional resource for respiratory genetic epidemiology in an underserved region. I identified eight signals reaching genome-wide significance (P<5x10-8) in a genome-wide association study of ACO. None of the signals were previously associated with ACO, and one intergenic signal on chromosome 5 was not previously associated with either asthma or COPD (rs80101740). The signals suggested a spectrum of genetic influences, some predominantly influencing asthma (signals in/near FAM105A, GLB1, PHB, TSLP), others predominantly influencing COPD (IL17RD), and others intermediate (C5orf56, HLA-DQB1). Subgroup analyses suggested that the associations were not driven by smoking or age at asthma diagnosis. I showed shared genetic influences between asthma, COPD, ACO and eosinophils at the level of individual loci and genome-wide, and highlighted pathways implicating innate and adaptive immunity and potentially bone development.</p

Mendelian randomization of eosinophils and other cell types in relation to lung function and disease

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.</p

Additional file 1 of Respiratory health among adolescents living in the Highveld Air Pollution Priority Area in South Africa

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United Kingdom Research study into Ethnicity And COVID-19 outcomes in Healthcare workers (UK-REACH): a retrospective cohort study using linked routinely collected data, study protocol.

Introduction: COVID-19 has spread rapidly worldwide, causing significant morbidity and mortality. People from ethnic minorities, particularly those working in healthcare settings, have been disproportionately affected. Current evidence of the association between ethnicity and COVID-19 outcomes in people working in healthcare settings is insufficient to inform plans to address health inequalities. Methods and analysis: This study combines anonymised human resource databases with professional registration and National Health Service data sets to assess associations between ethnicity and COVID-19 diagnosis, hospitalisation and death in healthcare workers in the UK. Adverse COVID-19 outcomes will be assessed between 1 February 2020 (date following first confirmed COVID-19 case in UK) and study end date (31 January 2021), allowing 1-year of follow-up. Planned analyses include multivariable Poisson, logistic and flexible parametric time-to-event regression within each country, adjusting for core predictors, followed by meta-analysis of country-specific results to produce combined effect estimates for the UK. Mediation analysis methods will be explored to examine the direct, indirect and mediated interactive effects between ethnicity, occupational group and COVID-19 outcomes. Ethics and dissemination: Ethical approval for the UK-REACH programme has been obtained via the expedited HRA COVID-19 processes (REC ref: 20/HRA/4718, IRAS ID: 288316). Research information will be anonymised via the Secure Anonymised Information Linkage Databank before release to researchers. Study results will be submitted for publication in an open access peer-reviewed journal and made available on our dedicated website (https://uk-reach.org/). Trial registration number: ISRCTN11811602.</p

Resistome analyses of sputum from COPD and healthy subjects reveals bacterial load-related prevalence of target genes

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 (r 2 =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 Î 3Proteobacteria 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

Multi-ancestry genome-wide association study improves resolution of genes, pathways and pleiotropy for lung function and chronic obstructive pulmonary disease

Lung function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry GWAS meta-analysis of lung function to date, comprising 580,869 participants, 1020 independent association signals identified 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score (GRS) showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies (PheWAS) for selected associated variants, and trait and pathway-specific GRS to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.</p

The sputum microbiome is distinct between COPD and health, independent of smoking history

BackgroundAirway 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.MethodsWe 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.ResultsIn 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).ConclusionThe healthy and COPD sputum microbiomes are distinct and independent of smoking history. Our results underline the important role for Gammaproteobacteria in COPD.</div

Astegolimab, an anti-ST2, in chronic obstructive pulmonary disease - COPD-ST2OP : a phase IIa, placebo-controlled trial

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Healthcare workers' views on mandatory SARS-CoV-2 vaccination in the UK: A cross-sectional, mixed-methods analysis from the UK-REACH study.

Several countries now have mandatory SARS-CoV-2 vaccination for healthcare workers (HCWs) or the general population. HCWs' views on this are largely unknown. Using data from the nationwide UK-REACH study we aimed to understand UK HCW's views on improving SARS-CoV-2 vaccination coverage, including mandatory vaccination.Between 21st April and 26th June 2021, we administered an online questionnaire via email to 17 891 UK HCWs recruited as part of a longitudinal cohort from across the UK who had previously responded to a baseline questionnaire (primarily recruited through email) as part of the United Kingdom Research study into Ethnicity And COVID-19 outcomes in Healthcare workers (UK-REACH) nationwide prospective cohort study. We categorised responses to a free-text question "What should society do if people do not get vaccinated against COVID-19?" using qualitative content analysis. We collapsed categories into a binary variable: favours mandatory vaccination or not, using logistic regression to calculate its demographic predictors, and its occupational, health, and attitudinal predictors adjusted for demographics.Of 5633 questionnaire respondents, 3235 answered the free text question. Median age of free text responders was 47 years (IQR 36-56) and 2705 (74.3%) were female. 18% (n = 578) favoured mandatory vaccination (201 [6%] participants for HCWs and others working with vulnerable populations; 377 [12%] for the general population), but the most frequent suggestion was education (32%, n = 1047). Older HCWs (OR 1.84; 95% CI 1.44-2.34 [≥55 years vs 16 years to <40 years]), HCWs vaccinated against influenza (OR 1.49; 95% CI 1.11-2.01 [2 vaccines vs none]), and with more positive vaccination attitudes generally (OR 1.10; 95% CI 1.06-1.15) were more likely to favour mandatory vaccination, whereas female HCWs (OR= 0.79, 95% CI 0.63-0.96, vs male HCWs) and Black HCWs (OR=0.46, 95% CI 0.25-0.85, vs white HCWs) were less likely to.Only one in six of the HCWs in this large, diverse, UK-wide sample favoured mandatory vaccination. Building trust, educating, and supporting HCWs who are hesitant about vaccination may be more acceptable, effective, and equitable.</p

Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts

Background: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes.Methods: We constructed a polygenic risk score using a genome wide association study of lung function (FEV1 and FEV1/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV1/FVC Findings: The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1·81 [95% CI 1·74–1·88] and non-European (1·42 [1·34–1·51]) populations. Compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD, with an OR of 7·99 (6·56–9·72) in European ancestry and 4·83 (3·45–6·77) in non-European ancestry cohorts. The polygenic risk score was superior to previously described genetic risk scores and, when combined with clinical risk factors (ie, age, sex, and smoking pack-years), showed improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0·80 [0·79–0·81] vs 0·76 [0·75 0·76]). The polygenic risk score was associated with CT imaging phenotypes, including wall area percent, quantitative and qualitative measures of emphysema, local histogram emphysema patterns, and destructive emphysema subtypes. The polygenic risk score was associated with a reduced lung growth pattern. Interpretation: A risk score comprised of genetic variants can identify a small subset of individuals at markedly increased risk for moderate-to-severe COPD, emphysema subtypes associated with cigarette smoking, and patterns of reduced lung growth.</div