SummaryBackgroundFew genetic studies that focus on moderate-to-severe asthma exist. We aimed to identity novel genetic variants associated with moderate-to-severe asthma, see whether previously identified genetic variants for all types of asthma contribute to moderate-to-severe asthma, and provide novel mechanistic insights using expression analyses in patients with asthma.MethodsIn this genome-wide association study, we used a two-stage case-control design. In stage 1, we genotyped patient-level data from two UK cohorts (the Genetics of Asthma Severity and Phenotypes [GASP] initiative and the Unbiased BIOmarkers in PREDiction of respiratory disease outcomes [U-BIOPRED] project) and used data from the UK Biobank to collect patient-level genomic data for cases and controls of European ancestry in a 1:5 ratio. Cases were defined as having moderate-to-severe asthma if they were taking appropriate medication or had been diagnosed by a doctor. Controls were defined as not having asthma, rhinitis, eczema, allergy, emphysema, or chronic bronchitis as diagnosed by a doctor. For stage 2, an independent cohort of cases and controls (1:5) was selected from the UK Biobank only, with no overlap with stage 1 samples. In stage 1 we undertook a genome-wide association study of moderate-to-severe asthma, and in stage 2 we followed up independent variants that reached the significance threshold of p less than 1 × 10−6 in stage 1. We set genome-wide significance at p less than 5 × 10−8. For novel signals, we investigated their effect on all types of asthma (mild, moderate, and severe). For all signals meeting genome-wide significance, we investigated their effect on gene expression in patients with asthma and controls.FindingsWe included 5135 cases and 25 675 controls for stage 1, and 5414 cases and 21 471 controls for stage 2. We identified 24 genome-wide significant signals of association with moderate-to-severe asthma, including several signals in innate or adaptive immune-response genes. Three novel signals were identified: rs10905284 in GATA3 (coded allele A, odds ratio [OR] 0·90, 95% CI 0·88–0·93; p=1·76 × 10−10), rs11603634 in the MUC5AC region (coded allele G, OR 1·09, 1·06–1·12; p=2·32 × 10−8), and rs560026225 near KIAA1109 (coded allele GATT, OR 1·12, 1·08–1·16; p=3·06 × 10−9). The MUC5AC signal was not associated with asthma when analyses included mild asthma. The rs11603634 G allele was associated with increased expression of MUC5AC mRNA in bronchial epithelial brush samples via proxy SNP rs11602802; (p=2·50 × 10−5) and MUC5AC mRNA was increased in bronchial epithelial samples from patients with severe asthma (in two independent analyses, p=0·039 and p=0·022).InterpretationWe found substantial shared genetic architecture between mild and moderate-to-severe asthma. We also report for the first time genetic variants associated with the risk of developing moderate-to-severe asthma that regulate mucin production. Finally, we identify candidate causal genes in these loci and provide increased insight into this difficult to tr...

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Background Bronchial thermoplasty (BT) has previously been shown to improve asthma control out to 2 years in patients with severe persistent asthma. Objective To assess effectiveness and safety of BT in asthma patients 5 years post therapy. Methods BT-treated subjects from the Asthma Intervention Research 2 (AIR2) Trial (ClinicalTrials.gov NCT01350414) were evaluated annually for 5 years to assess long-term safety of BT and durability of treatment effect. Outcomes assessed post-BT included severe exacerbations, adverse events, healthcare utilization, spirometry data, and high resolution computed tomography (HRCT) scans. Results 162/190 BT-treated subjects (85.3%) from the AIR2 Trial completed 5 years of follow-up. The proportion of subjects experiencing severe exacerbations and Emergency Room visits, and the rates of events in each of years 1 to 5 remained low and were less than those observed in the 12 months prior to BT treatment (average 5 year reduction in proportions: 44% for exacerbations and 78% for ER visits). Respiratory adverse events and respiratory-related hospitalizations remained unchanged in Years 2 through 5 as compared to the first year after BT. Pre-BD FEV1 values remained stable between years 1 and 5 after BT, despite a 17% reduction in average daily inhaled corticosteroid dose. HRCT scans from baseline to 5 years after BT showed no structural abnormalities that could be attributed to BT. Conclusions These data demonstrate the 5-year durability of the benefits of BT with regard to both asthma control (based on maintained reduction in severe exacerbations and ER visits for respiratory symptoms) and safety. BT has become an important addition to our treatment armamentarium and should be considered for patients with severe persistent asthma who remain symptomatic despite taking ICS (inhaled corticosteroids) and LABA (long-acting-β2-agonists).

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Severe refractory asthma poses a substantial burden in terms of healthcare costs but relatively little is known about the factors which drive these costs. This study uses data from the British Thoracic Society Difficult Asthma Registry (n=596) to estimate direct healthcare treatment costs from an National Health Service perspective and examines factors that explain variations in costs. Annual mean treatment costs among severe refractory asthma patients were £2912 (SD £2212) to £4217 (SD £2449). Significant predictors of costs were FEV1% predicted, location of care, maintenance oral corticosteroid treatment and body mass index. Treating individuals with severe refractory asthma presents a substantial cost to the health service.

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Research Impact-These data demonstrate that profiling the FeNO and blood eosinophil response to inhaled corticosteroids (ICS) in subjects with difficult-to-control severe asthma using remote monitoring technology is useful for clinical phenotyping. It differentiates subjects who will respond well with better adherence to high dose ICS/LABA therapy from those subjects who may require progression to additional treatment. This strategy will be of value in identifying ICS-responsive subjects prior to recruitment to clinical trials investigating interventions which are "add-on" treatments to standard care, and to mechanistic studies investigating "true" inhaled steroid-resistant asthma.