Childhood asthma exacerbations and the Arg16 β2-receptor polymorphism: A meta-analysis stratified by treatment

Turner, Steve; Francis, Ben; Vijverberg, Susanne J. H.; Pino-Yanes, María; Zee, Anke‐Hilse Maitland‐van der; Basu, K; Bignell, Lauren; Mukhopadhyay, Somnath; Tavendale, Roger; Palmer, Colin N.A.; Hawcutt, Daniel B; Pirmohamed, Munir; Burchard, Esteban G.; Lipworth, Brian J.

doi:10.1016/j.jaci.2015.10.045

Cited by 77 publications

(64 citation statements)

References 45 publications

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“…This hypothesis is supported by a recent large meta-analysis of observational studies gathered in Pharmacogenomics in Childhood Asthma Consortium (PiCA). Turner et al performed a meta-analysis of 4226 children and young adults and showed that patients treated with LABA had a 52% increased risk of exacerbations per copy of the Arg16 risk allele (Figure 3) [25]. Remarkably, patients solely treated with ICS did not have an increased risk.…”

Section: Long-acting Beta-2 Agonistsmentioning

confidence: 99%

Treatment response heterogeneity in asthma: the role of genetic variation

Vijverberg

Farzan

Slob

et al. 2017

Expert Review of Respiratory Medicine

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Introduction: Asthmatic patients show a large heterogeneity in response to asthma medication. Rapidly evolving genotyping technologies have led to the identification of various genetic variants associated with treatment outcomes. Areas covered: This review focuses on the current knowledge of genetic variants influencing treatment response to the most commonly used asthma medicines: short-and long-acting beta-2 agonists (SABA/ LABA), inhaled corticosteroids (ICS) and leukotriene modifiers. This review shows that various genetic variants have been identified, but none are currently used to guide asthma treatment. One of the most promising genetic variants is the Arg16 variant in the ADRB2 gene to guide LABA treatment in asthmatic children. Expert commentary: Poor replication of initially promising results and the low fraction of variability accounted for by single genetic variants inhibit pharmacogenetic findings to reach the asthma clinic. Nevertheless, the identification of genetic variation influencing treatment response does provide more insights in the complex processes underlying response and might identify novel targets for treatment. There is a need to report measures of clinical validity, to perform precision-medicine guided trials, as well as to understand how genetic variation interacts with environmental factors. In addition, systems biology approaches might be able to show a more complete picture of these complex interactions.ARTICLE HISTORY

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Section: Long-acting Beta-2 Agonistsmentioning

confidence: 99%

Treatment response heterogeneity in asthma: the role of genetic variation

Vijverberg

Farzan

Slob

et al. 2017

Expert Review of Respiratory Medicine

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“…For this reason, pharmacogenetics studies on heterogeneity in response to inhaled β 2 -agonists have mostly focused on ADRB2 . A recent meta-analysis stratified by treatment showed that the use of a long acting β 2 -agonist (LABA), but not an leukotriene receptor antagonist, as an add-on controller is associated with increased risk of AE in children carrying 1 or 2 A alleles at rs1042713 (Arg16 amino acid) in ADRB2 47. In this study, data from 4,226 children of white Northern European and Latino origin was analyzed, and both severe and non-severe AEs were included.…”

Section: Pharmacogeneticsmentioning

confidence: 99%

Genetic Signatures of Asthma Exacerbation

Park

Tantisira

2017

Allergy Asthma Immunol Res

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Asthma exacerbation (AE) usually denotes worsening of asthma symptoms that requires intense management to prevent further deterioration. AE has been reported to correlate with clinical and demographic factors, such as race, gender, and treatment compliance as well as environmental factors, such as viral infection, smoking, and air pollution. In addition, recent observations suggest that there are likely to be genetic factors specific to AE. Understanding genetic factors specific to AE is essential to develop therapy tailored for exacerbation-prone asthma. Here, we summarize the results of studies involving genetic risk factors for AE. To simplify and enhance understanding, we reviewed the studies according to the following categories: hypothesis-driven approaches, hypothesis-free approaches, gene-environment interactions, and pharmacogenetics.

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“…This variant was shown to be associated with poor response to LABA in children . In a recent meta‐analysis of 4226 asthmatic children included in the multi‐ethnic Pharmacogenomics in Childhood Asthma (PiCA) consortium, patients treated with ICS plus LABA showed an increased risk of asthma exacerbations for each copy of the ADRB2 risk allele (OR 1.52, 95%CI 1.17‐1.99; P = 0.002) . These findings suggest that ADRB2 genotype‐guided treatment can improve disease management.…”

Section: Introductionmentioning

confidence: 97%

The use of pharmacogenomics, epigenomics, and transcriptomics to improve childhood asthma management: Where do we stand?

Farzan

Vijverberg

Kabesch

et al. 2018

Pediatric Pulmonology

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Asthma is a complex multifactorial disease and it is the most common chronic disease in children. There is a high variability in response to asthma treatment, even in patients with good adherence to maintenance treatment, and a correct inhalation technique. Distinct underlying disease mechanisms in childhood asthma might be the reason of this heterogeneity. A deeper knowledge of the underlying molecular mechanisms of asthma has led to the recent development of advanced and mechanism-based treatments such as biologicals. However, biologicals are recommended only for patients with specific asthma phenotypes who remain uncontrolled despite high dosages of conventional asthma treatment. One of the main unmet needs in their application is lack of clinically available biomarkers to individualize pediatric asthma management and guide treatment. Pharmacogenomics, epigenomics, and transcriptomics are three omics fields that are rapidly advancing and can provide tools to identify novel asthma mechanisms and biomarkers to guide treatment. Pharmacogenomics focuses on variants in the DNA, epigenomics studies heritable changes that do not involve changes in the DNA sequence but lead to alteration of gene expression, and transcriptomics investigates gene expression by studying the complete set of mRNA transcripts in a cell or a population of cells. Advances in high-throughput technologies and statistical tools together with well-phenotyped patient inclusion and collaborations between different centers will expand our knowledge of underlying molecular mechanisms involved in disease onset and progress. Furthermore, it could help to select and stratify appropriate therapeutic strategies for subgroups of patients and hopefully bring precision medicine to daily practice.

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Childhood asthma exacerbations and the Arg16 β2-receptor polymorphism: A meta-analysis stratified by treatment

Cited by 77 publications

References 45 publications

Treatment response heterogeneity in asthma: the role of genetic variation

Treatment response heterogeneity in asthma: the role of genetic variation

Genetic Signatures of Asthma Exacerbation

The use of pharmacogenomics, epigenomics, and transcriptomics to improve childhood asthma management: Where do we stand?

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