Treatment response heterogeneity in asthma: the role of genetic variation

Abstract

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

Genome‐wide association study of inhaled corticosteroid response in admixed children with asthma

“…For several decades, pharmacogenetic studies have utilized candidate‐gene approaches, which only evaluate a small portion of the genetic variation. More recently, these have evolved towards hypothesis‐free approaches by implementing genome‐wide association studies (GWAS) . Eight GWAS of ICS response have been performed to date, revealing an association between 14 genomic regions and this trait.…”

LTA4Hassociation with montelukast response in early and late-onset asthma

“…preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted October 6, 2020. ; https://doi.org/10.1101/2020.10.05.20206847 doi: medRxiv preprint Institute for Health and Clinical Excellence (NICE), highlighted leukotriene receptor antagonists (LTRA) as a key part of asthma management and recommended their use as the first line add-on therapy for persistent asthmatic patients who still show symptoms despite low dose of inhaled corticosteroids (ICS) (9). However, a range of 35 to 78 percent of the patients treated with leukotriene inhibitors such as montelukast were found unresponsive over independent studies (10)(11)(12)(13)(14).…”

“…We would like to thank all the participants from the different cohorts, the BREATHE, preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted October 6, 2020. ; https://doi.org/10.1101/2020. 10 Table 3. Association between rs2660845 and exacerbation in individuals with early-onset asthma in PAGES and BREATHE nonmontelukast users and in GoSHARE(b) individuals a year before being on montelukast.…”

“…preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted October 6, 2020. ; https://doi.org/10.1101/2020. 10 Leukotriene modifiers are pharmacological therapies for the treatment of asthma and allergic rhinitis. As established through numerous clinical trials, drugs such as montelukast have been shown to be effective in improving lung function, asthma control and quality of life, by reducing airway hyperresponsiveness and eosinophilia (8).…”

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

“…23,24 Pharmacogenomics effects related to asthma medication, such as inhaled corticosteroids (ICS), long-acting beta2-agonists (LABA), and leukotriene modifiers (LTMs), have been studied intensely in the last decades. 4,30 For LABA pharmacogenomics, the most clinically relevant variant seems to result in the substitution of amino-acid Glycine by Arginine at position 16 in the beta-2 receptor encoded by ADRB2. This variant was shown to be associated with poor response to LABA in children.…”