Personalized management of asthma exacerbations: lessons from genetic studies

Wang, Alberta L.; Tantisira, Kelan G.

doi:10.1080/23808993.2016.1269600

Cited by 8 publications

(6 citation statements)

References 76 publications

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“…In a prior study, differential methylation of the glucocorticoid receptor gene ( NR3C1 ) was associated with dexamethasone sensitivity in endothelial cells, but we did not find an association of NR3C1 methylation with ICS response in peripheral blood . In addition, differential methylation of genetic loci previously associated with asthma exacerbations on ICS treatment ( ST13 , FCER2 , P2RX7 , CMTR1 ) was not detected . This absence of association may be due to phenotypic heterogeneity of the measured outcomes or a lack of methylation quantitative trait association at these genetic loci.…”

Section: Discussioncontrasting

confidence: 85%

“…14 In addition, differential methylation of genetic loci previously associated with asthma exacerbations on ICS treatment (ST13, FCER2, P2RX7, CMTR1) was not detected. 36 This absence of association may be due to phenotypic heterogeneity of the measured outcomes or a lack of methylation quantitative trait association at these genetic loci. Further research is needed to determine the association between genetic variation and quantitative changes in DNA methylation in asthma pharmacogenomics.…”

Section: Discussionmentioning

confidence: 99%

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DNA methylation is associated with inhaled corticosteroid response in persistent childhood asthmatics

Wang

Gruzieva

Qiu

et al. 2019

Clin Experimental Allergy

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Background Response to inhaled corticosteroids is highly variable, and the association between DNA methylation and treatment response is not known. Objective To examine the association between peripheral blood DNA methylation and inhaled corticosteroid response in children with persistent asthma. Methods Epigenome‐wide DNA methylation was analysed in individuals on inhaled corticosteroids in three independent and ethnically diverse cohorts—Childhood Asthma Management Program (CAMP); Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE); and Genetic Epidemiology of Asthma in Costa Rica Study (GACRS). Treatment response was evaluated using two definitions, the absence of emergency department visits and/or hospitalizations and the absence oral corticosteroid use while on inhaled corticosteroid therapy. CpG sites meeting nominal significance (P < 0.05) for each outcome were combined in a three‐cohort meta‐analysis with adjustment for multiple testing. DNA methylation was correlated with gene expression using Pearson and partial correlations. Results In 154 subjects from CAMP, 72 from BAMSE, and 168 from GACRS, relative hypomethylation of cg00066816 (171 bases upstream of IL12B) was associated with the absence of emergency department visits and/or hospitalizations (Q = 0.03) in all cohorts and lower IL12B expression (ρ = 0.34, P = 0.01) in BAMSE. Relative hypermethylation of cg04256470 (688 bases upstream of CORT) was associated with the absence of oral corticosteroid use (Q = 0.04) in all cohorts and higher CORT expression (ρ = 0.20, P = 0.045) in CAMP. Conclusion and Clinical Relevance Differential DNA methylation of IL12B and CORT are associated with inhaled corticosteroid treatment response in persistent childhood asthmatics. Pharmaco‐methylation can identify novel markers of treatment sensitivity in asthma.

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Section: Discussioncontrasting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

DNA methylation is associated with inhaled corticosteroid response in persistent childhood asthmatics

Wang

Gruzieva

Qiu

et al. 2019

Clin Experimental Allergy

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“…Nonetheless, given the deficiencies of supervised analysis to fully capture meaningful ontological associations, it is also likely that molecular endotyping can independently yield additional novel biology when used as an independent metric, as supported by our ontology enrichment analysis. Others and we previously cited the advantage of molecular endotyping for predicting therapeutic response in asthma 37. Fitzpatrick et al 35 noted that clinical features were of limited use for predicting triamcinolone response, whereas systemic mRNA expression of inflammatory cytokines and chemokines related to interleukin (IL)-2, IL-10 and tumour necrosis factor signalling pathways, including, AIMP1, CCR2, IL10RB, and IL5, strongly differentiated children who failed to achieve control with triamcinolone treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Others and we previously cited the advantage of molecular endotyping for predicting therapeutic response in asthma. 37 Fitzpatrick et al 35 noted that clinical features were of limited use for predicting triamcinolone response, whereas systemic mRNA expression of inflammatory cytokines and chemokines related to interleukin (IL)-2, IL-10 and tumour necrosis factor signalling pathways, including, AIMP1, CCR2, IL10RB, and IL5, strongly differentiated children who failed to achieve control with triamcinolone treatment. Our analysis also includes prediction of response using molecular features that were not noted using clinical biomarkers alone, 15 16 but in the context of molecular endotypes generated by genome-wide RNA-seq CS response data.…”

Section: Asthmamentioning

confidence: 99%

Lung function, airway and peripheral basophils and eosinophils are associated with molecular pharmacogenomic endotypes of steroid response in severe asthma

Kho

McGeachie

Jiang

et al. 2021

Thorax

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IntroductionAsthma is a complex disease with heterogeneous expression/severity. There is growing interest in defining asthma endotypes consistently associated with different responses to therapy, focusing on type 2 inflammation (Th2) as a key pathological mechanism. Current asthma endotypes are defined primarily by clinical/laboratory criteria. Each endotype is likely characterised by distinct molecular mechanisms that identify optimal therapies.MethodsWe applied unsupervised (without a priori clinical criteria) principal component analysis on sputum airway cells RNA-sequencing transcriptomic data from 19 asthmatics from the Severe Asthma Research Program at baseline and 6–8 weeks follow-up after a 40 mg dose of intramuscular corticosteroids. We investigated principal components PC1, PC3 for association with 55 clinical variables.ResultsPC3 was associated with baseline Th2 clinical features including blood (rank-sum p=0.0082) and airway (rank-sum p=0.0024) eosinophilia, FEV1 change (Kendall tau-b R=−0.333 (−0.592 to −0.012)) and follow-up FEV1 albuterol response (Kendall tau-b R=0.392 (0.079 to 0.634)). PC1 with blood basophlia (rank-sum p=0.0191). The top 5% genes contributing to PC1, PC3 were enriched for distinct immune system/inflammation ontologies suggesting distinct subject-specific clusters of transcriptomic response to corticosteroids. PC3 association with FEV1 change was reproduced in silico in a comparable independent 14-subject (baseline, 8 weeks after daily inhaled corticosteroids (ICS)) airway epithelial cells microRNAome dataset.ConclusionsTranscriptomic PCs from this unsupervised methodology define molecular pharmacogenomic endotypes that may yield novel biology underlying different subject-specific responses to corticosteroid therapy in asthma, and optimal personalised asthma care. Top contributing genes to these PCs may suggest new therapeutic targets.

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“…As recently as two decades ago, there were very few options for patients with severe asthma exacerbations beyond systemic corticosteroids, which were associated with significant treatment toxicity and morbidity. 7 , 9 Within the past 10 years, there have been substantial efforts made to understand the phenotypic heterogeneity of the disease, particularly among those patients with severe asthma and who are refractory to front-line therapies. 7 , 10 As more focus has been placed on defining phenotypic biomarkers, there has also been a rapid influx of targeted biologic therapies approved for severe asthma, including monoclonal antibodies that target immunoglobulin E (IgE) (omalizumab), interleukin-5 (IL-5) (mepolizumab/reslizumab), the receptor IL-5Ra (benralizumab), and anti-IL-4Ra (dupilumab).…”

Section: Introductionmentioning

confidence: 99%

Cost Utility of Bronchial Thermoplasty for Severe Asthma: Implications for Future Cost-Effectiveness Analyses Based on Phenotypic Heterogeneity

Keim‐Malpass¹,

Malpass²

2022

CEOR

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Background Asthma is a disease with tremendous phenotypic heterogeneity, and the patients who are most severely impacted by the disease are high utilizers of the United States healthcare system. In the past decade, there has been many advances in asthma therapy for those with severe disease, including the use of a procedure called bronchial thermoplasty (BT) and the use of biologic therapy for certain phenotypes, but questions remain regarding the long-term durability and cost effectiveness of these therapies. The purpose of this analysis was (1) to assess the cost utility of BT relative to usual care (base case) and (2) to assess the cost utility of BT relative to usual care plus biologic therapy (omalizumab) (scenario analysis) based on updated 10-year clinical trial outcomes. Methods A Markov cohort model was developed and used to estimate the cost utility of BT to estimate the costs and quality-of-life impact of BT versus the comparisons over a 10-year time frame using a limited societal perspective, which included both direct health utilization costs and indirect costs associated with missed days of work, among those with severe persistent asthma. Results In the base case and the scenario analysis, BT was the dominant treatment strategy compared to usual care alone and usual care plus biologic therapy. The net monetary benefit for BT was $483,555.49 over a 10-year time horizon. Conclusion Cost-utility models are central to policy decisions dictating coverage, and can be extended to inform the patient and provider, during clinical decision-making, of the relative trade-offs of therapy, assessing long-term clinical and cost outcomes. Phenotypic classification of severe asthma is central to patient management and should also be integrated into economic analysis frameworks, particularly as new biologic agents are developed that are specific to a phenotype. Despite a larger upfront cost of BT therapy, there is a durable clinical and economic benefit over time for those with severe asthma.

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Personalized management of asthma exacerbations: lessons from genetic studies

Cited by 8 publications

References 76 publications

DNA methylation is associated with inhaled corticosteroid response in persistent childhood asthmatics

DNA methylation is associated with inhaled corticosteroid response in persistent childhood asthmatics

Lung function, airway and peripheral basophils and eosinophils are associated with molecular pharmacogenomic endotypes of steroid response in severe asthma

Cost Utility of Bronchial Thermoplasty for Severe Asthma: Implications for Future Cost-Effectiveness Analyses Based on Phenotypic Heterogeneity

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