Summary Chronic obstructive pulmonary disease is mainly a smoking-related disorder and affects millions of people worldwide, with a large effect on individual patients and society as a whole. ...Although the disease becomes clinically apparent around the age of 40–50 years, its origins can begin very early in life. Different risk factors in very early life—ie, in utero and during early childhood—drive the development of clinically apparent chronic obstructive pulmonary disease in later life. In discussions of which risk factors drive chronic obstructive pulmonary disease, it is important to realise that the disease is very heterogeneous and at present is largely diagnosed by lung function only. In this Review, we will discuss the evidence for risk factors for the various phenotypes of chronic obstructive pulmonary disease during different stages of life.
Smoking is a leading cause of chronic obstructive pulmonary disease (COPD). It is known to have a significant impact on gene expression and (inflammatory) cell populations in the airways involved in ...COPD pathogenesis. In this study, we investigated the impact of smoking on the expression of miRNAs in healthy and COPD individuals. We aimed to elucidate the overall smoking-induced miRNA changes and those specific to COPD. In addition, we investigated the downstream effects on regulatory gene expression and the correlation to cellular composition. We performed a genome-wide miRNA expression analysis on a dataset of 40 current- and 22 ex-smoking COPD patients and a dataset of 35 current- and 38 non-smoking respiratory healthy controls and validated the results in an independent dataset. miRNA expression was then correlated with mRNA expression in the same patients to assess potential regulatory effects of the miRNAs. Finally, cellular deconvolution analysis was used to relate miRNAs changes to specific cell populations. Current smoking was associated with increased expression of three miRNAs in the COPD patients and 18 miRNAs in the asymptomatic smokers compared to respiratory healthy controls. In comparison, four miRNAs were lower expressed with current smoking in asymptomatic controls. Two of the three smoking-related miRNAs in COPD, miR-203a-3p and miR-375, were also higher expressed with current smoking in COPD patients and the asymptomatic controls. The other smoking-related miRNA in COPD patients, i.e. miR-31-3p, was not present in the respiratory healthy control dataset. miRNA-mRNA correlations demonstrated that miR-203a-3p, miR-375 and also miR-31-3p expression were negatively associated with genes involved in pro-inflammatory pathways and positively associated with genes involved in the xenobiotic pathway. Cellular deconvolution showed that higher levels of miR-203a-3p were associated with higher proportions of proliferating-basal cells and secretory (club and goblet) cells and lower levels of fibroblasts, luminal macrophages, endothelial cells, B-cells, amongst other cell types. MiR-375 expression was associated with lower levels of secretory cells, ionocytes and submucosal cells, but higher levels of endothelial cells, smooth muscle cells, and mast cells, amongst other cell types. In conclusion, we identified two smoking-induced miRNAs (miR-375 and miR-203a-3p) that play a role in regulating inflammation and detoxification pathways, regardless of the presence or absence of COPD. Additionally, in patients with COPD, we identified miR-31-3p as a miRNA induced by smoking. Our identified miRNAs should be studied further to unravel which smoking-induced inflammatory mechanisms are reactive and which are involved in COPD pathogenesis.
SARS-CoV-2 is responsible for the coronavirus disease 2019 (COVID-19) and the current health crisis. Despite intensive research efforts, the genes and pathways that contribute to COVID-19 remain ...poorly understood. We, therefore, used an integrative genomics (IG) approach to identify candidate genes responsible for COVID-19 and its severity
.
We used Bayesian colocalization (COLOC) and summary-based Mendelian randomization to combine gene expression quantitative trait loci (eQTLs) from the Lung eQTL (
n
= 1,038) and eQTLGen (
n
= 31,784) studies with published COVID-19 genome-wide association study (GWAS) data from the COVID-19 Host Genetics Initiative. Additionally, we used COLOC to integrate plasma protein quantitative trait loci (pQTL) from the INTERVAL study (
n
= 3,301) with COVID-19 loci. Finally, we determined any causal associations between plasma proteins and COVID-19 using multi-variable two-sample Mendelian randomization (MR). The expression of 18 genes in lung and/or blood co-localized with COVID-19 loci. Of these, 12 genes were in suggestive loci (
P
GWAS
< 5 × 10
–05
).
LZTFL1, SLC6A20, ABO, IL10RB and IFNAR2
and
OAS1
had been previously associated with a heightened risk of COVID-19 (
P
GWAS
< 5 × 10
–08
). We identified a causal association between
OAS1
and COVID-19 GWAS. Plasma ABO protein, which is associated with blood type in humans, demonstrated a significant causal relationship with COVID-19 in the MR analysis; increased plasma levels were associated with an increased risk of COVID-19 and, in particular, severe COVID-19. In summary, our study identified genes associated with COVID-19 that may be prioritized for future investigations. Importantly, this is the first study to demonstrate a causal association between plasma ABO protein and COVID-19.
To identify candidate causal genes of asthma, we performed a genome-wide association study (GWAS) in UK Biobank on a broad asthma definition (n = 56,167 asthma cases and 352,255 controls). We then ...carried out functional mapping through transcriptome-wide association studies (TWAS) and Mendelian randomization in lung (n = 1,038) and blood (n = 31,684) tissues. The GWAS reveals 72 asthma-associated loci from 116 independent significant variants (P
< 5.0E-8). The most significant lung TWAS gene on 17q12-q21 is GSDMB (P
= 1.42E-54). Other TWAS genes include TSLP on 5q22, RERE on 1p36, CLEC16A on 16p13, and IL4R on 16p12, which all replicated in GTEx lung (n = 515). We demonstrate that the largest fold enrichment of regulatory and functional annotations among asthma-associated variants is in the blood. We map 485 blood eQTL-regulated genes associated with asthma and 50 of them are causal by Mendelian randomization. Prioritization of druggable genes reveals known (IL4R, TSLP, IL6, TNFSF4) and potentially new therapeutic targets for asthma.
Recent studies have demonstrated an association between high blood eosinophil counts and greater risk of asthma exacerbations. We sought to determine whether patients hospitalized for an asthma ...exacerbation were at greater risk of readmission if they had a high blood eosinophil count documented before the first hospitalization.
This historical cohort study drew on 2 years of medical record data (Clinical Practice Research Datalink with Hospital Episode Statistics linkage) of patients (aged ≥5 years) admitted to hospital in England for asthma, with recorded blood eosinophil count within 1 baseline year before admission. We analyzed the association between high blood eosinophil count (≥0.35x109 cells/L) and readmission risk during 1 year of follow-up after hospital discharge, with adjustment for predefined, relevant confounders using forward selection.
We identified 2,613 eligible patients with asthma-related admission, of median age 51 years (interquartile range, 36-69) and 76% women (1,997/2,613). Overall, 835/2,613 (32.0%) had a preadmission high blood eosinophil count. During the follow-up year, 130/2,613 patients (5.0%) were readmitted for asthma, including 55/835 (6.6%) with vs. 75/1,778 (4.2%) without high blood eosinophil count at baseline (adjusted hazard ratio HR 1.49; 95% CI 1.04-2.13, p = 0.029). The association was strongest in never-smokers (n = 1,296; HR 2.16, 95% CI 1.27-3.68, p = 0.005) and absent in current smokers (n = 547; HR 1.00, 95% CI 0.49-2.04, p = 0.997).
A high blood eosinophil count in the year before an asthma-related hospitalization is associated with increased risk of readmission within the following year. These findings suggest that patients with asthma and preadmission high blood eosinophil count require careful follow-up, with treatment optimization, after discharge.
Molecular phenotyping of chronic obstructive pulmonary disease (COPD) has been impeded in part by the difficulty in obtaining lung tissue samples from individuals with impaired lung function.
We ...sought to determine whether COPD-associated processes are reflected in gene expression profiles of bronchial airway epithelial cells obtained by bronchoscopy.
Gene expression profiling of bronchial brushings obtained from 238 current and former smokers with and without COPD was performed using Affymetrix Human Gene 1.0 ST Arrays.
We identified 98 genes whose expression levels were associated with COPD status, FEV1% predicted, and FEV1/FVC. In silico analysis identified activating transcription factor 4 (ATF4) as a potential transcriptional regulator of genes with COPD-associated airway expression, and ATF4 overexpression in airway epithelial cells in vitro recapitulates COPD-associated gene expression changes. Genes with COPD-associated expression in the bronchial airway epithelium had similarly altered expression profiles in prior studies performed on small-airway epithelium and lung parenchyma, suggesting that transcriptomic alterations in the bronchial airway epithelium reflect molecular events found at more distal sites of disease activity. Many of the airway COPD-associated gene expression changes revert toward baseline after therapy with the inhaled corticosteroid fluticasone in independent cohorts.
Our findings demonstrate a molecular field of injury throughout the bronchial airway of active and former smokers with COPD that may be driven in part by ATF4 and is modifiable with therapy. Bronchial airway epithelium may ultimately serve as a relatively accessible tissue in which to measure biomarkers of disease activity for guiding clinical management of COPD.
Traditionally, asthma has been considered a disease that predominantly involves the large airways. Today, this concept is being challenged, and increasing evidence has become available showing that ...abnormalities in the small airways also contribute to the clinical expression of asthma. The small airways can be affected by inflammation, remodeling, and changes in the surrounding tissue, all contributing to small-airways dysfunction. In this article we have performed a systematic review of the literature on the association between small-airways dysfunction and clinical signs and symptoms of asthma. This review shows that small-airways dysfunction associates with worse control of asthma, higher numbers of exacerbations, the presence of nocturnal asthma, more severe bronchial hyperresponsiveness, exercise-induced asthma, and the late-phase allergic response. Importantly, small-airways dysfunction can already be present in patients with mild asthma. Our review provides suggestive evidence that a better response of the small airways to inhaled steroids or montelukast associates with better asthma control. For this reason, an early recognition of small-airways dysfunction is important because it enables the physician to start timely treatment to target the small airways. It is important to develop simpler and more reliable tools (eg, questionnaires or bronchial provocation tests with small-particle stimuli) to assess the presence and extent of small-airways dysfunction in daily clinical practice.
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