The genetics of asthma and the promise of genomics-guided drug target discovery

El‐Husseini, Zaid W.; Gosens, Reinoud; Dekker, Frank J.; Koppelman, Gerard H.

doi:10.1016/s2213-2600(20)30363-5

Cited by 121 publications

(118 citation statements)

References 116 publications

Supporting

Mentioning

112

Contrasting

Unclassified

Order By: Relevance

“…9 . Notably, 101 of them overlapped with the recent list of 161 possible asthma drug targets summarized by El-Husseini et al 20 , which were derived from eQTL and non-synonymous analysis of independent variants associated with asthma in previous GWAS (Supplementary Data 17 ). According to the Open Targets Platform 21 , 13 out of 806 are the targets of investigational or approved asthma drugs (Supplementary Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

Prioritization of candidate causal genes for asthma in susceptibility loci derived from UK Biobank

et al. 2021

View full text Add to dashboard Cite

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 (PGWAS < 5.0E-8). The most significant lung TWAS gene on 17q12-q21 is GSDMB (PTWAS = 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.

show abstract

Section: Resultsmentioning

confidence: 99%

Prioritization of candidate causal genes for asthma in susceptibility loci derived from UK Biobank

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Over the past 3 years, the number of independent asthma‐associated genetic loci has increased to 128 according to well‐powered genetic studies. 81 In a post hoc analysis of the DREAM and MENSA study, genetic markers were tested in patients with severe asthma and found no genetic associations related to response to mepolizumab, even though it cannot be excluded the possibility of the existence of rare genetic variants not yet explored predictive of response. 80 Further studies are needed to establish the functional significance of gene variants associated with asthma and potential genetic biomarkers indicators of response to anti‐IL5/IL5R mAbs still need to be explored.…”

Section: Discussionmentioning

confidence: 99%

Treating severe asthma: Targeting the IL‐5 pathway

Principe

Porsbjerg

Ditlev

et al. 2021

Clin Experimental Allergy

View full text Add to dashboard Cite

Severe asthma is a heterogeneous disease with different phenotypes based on clinical, functional or inflammatory parameters. In particular, the eosinophilic phenotype is associated with type 2 inflammation and increased levels of interleukin (IL)‐4, IL‐5 and IL‐13). Monoclonal antibodies that target the eosinophilic inflammatory pathways (IL‐5R and IL‐5), namely mepolizumab, reslizumab, and benralizumab, are effective and safe for severe eosinophilic asthma. Eosinophils threshold represents the most indicative biomarker for response to treatment with all three monoclonal antibodies. Improvement in asthma symptoms scores, lung function, the number of exacerbations, history of late‐onset asthma, chronic rhinosinusitis with nasal polyposis, low oral corticosteroids use and low body mass index represent predictive clinical markers of response. Novel Omics studies are emerging with proteomics data and exhaled breath analyses. These may prove useful as biomarkers of response and non‐response biologics. Moreover, future biomarker studies need to be undertaken in paediatric patients affected by severe asthma. The choice of appropriate biologic therapy for severe asthma remains challenging. The importance of finding biomarkers that can predict response continuous an open issue that needs to be further explored. This review describes the clinical effects of targeting the IL‐5 pathway in severe asthma in adult and paediatric patients, focusing on predictors of response and non‐response.

show abstract

“…GPP65 encodes the chief acid-sensing receptor, G protein-coupled receptor 65 (GPR65), which increased the cellular viability of eosinophils in allergic airway inflammatory settings in mice [ 134 ]. Interestingly, the GWAS study for ACO and COPD failed to identify known asthma-associated genetic loci such as ORMDL3 , IL1RL1 and IL4R [ 135 ], indicating that ACO was not just an overlapping condition of asthma and COPD but was associated with a specific genetic background independent of asthma or COPD.…”

Section: Discussionmentioning

confidence: 99%

ACO (Asthma–COPD Overlap) Is Independent from COPD, a Case in Favor: A Systematic Review

Fujino

Sugiura

2021

Diagnostics

View full text Add to dashboard Cite

Asthma and chronic obstructive pulmonary disease (COPD) are now recognized to be able to co-exist as asthma–COPD overlap (ACO). It is clinically relevant to evaluate whether patients with COPD concurrently have components of asthma in primary care. This is because: (i) ACO is a relatively common condition among asthma (over 40 years of age) or COPD irrespective of its diagnosis criteria; (ii) patients with ACO can have higher frequency of exacerbation and more rapid decline in lung function than those with asthma or COPD; and (iii) asthmatic features such as eosinophilic airway inflammation are promising indicators for prediction of inhaled corticosteroid-responsiveness in COPD. The aim of this review to evaluate diagnostic markers for ACO. We searched PubMed for articles related to ACO published until 2020. Articles associated with diagnostic biomarkers were included. We identified a total of 25 studies, some of which have revealed that a combination of biomarkers such as fractional exhaled nitric oxide and serum immunoglobulin E is useful to discern type 2 inflammation in the airways of COPD. Here, we review the current understanding of the clinical characteristics, biomarkers and molecular pathophysiology of ACO in the context of how ACO can be differentiated from COPD.

show abstract

The genetics of asthma and the promise of genomics-guided drug target discovery

Cited by 121 publications

References 116 publications

Prioritization of candidate causal genes for asthma in susceptibility loci derived from UK Biobank

Prioritization of candidate causal genes for asthma in susceptibility loci derived from UK Biobank

Treating severe asthma: Targeting the IL‐5 pathway

ACO (Asthma–COPD Overlap) Is Independent from COPD, a Case in Favor: A Systematic Review

Contact Info

Product

Resources

About