Pharmacogenetics of childhood uncontrolled asthma

ABSTRACT

Introduction

Asthma is a heterogeneous, multifactorial disease with multiple genetic and environmental risk factors playing a role in pathogenesis and therapeutic response. Understanding of pharmacogenetics can help with matching individualized treatments to specific genotypes of asthma to improve therapeutic outcomes especially in uncontrolled or severe asthma.

Areas covered

In this review, we outline novel information about biology, pathways, and mechanisms related to interindividual variability in drug response (corticosteroids, bronchodilators, leukotriene modifiers, and biologics) for childhood asthma. We discuss candidate gene, genome-wide association studies and newer omics studies including epigenomics, transcriptomics, proteomics, and metabolomics as well as integrative genomics and systems biology methods related to childhood asthma. The articles were obtained after a series of searches, last updated November 2022, using database PubMed/CINAHL DB.

Expert opinion

Implementation of pharmacogenetic algorithms can improve therapeutic targeting in children with asthma, particularly with severe or uncontrolled asthma who typically have challenges in clinical management and carry considerable financial burden. Future studies focusing on potential biomarkers both clinical and pharmacogenetic can help formulate a prognostic test for asthma treatment response that would represent true bench to bedside clinical implementation.

KEYWORD:

• Asthma
• children with asthma
• genes
• GWAS
• omics
• pediatric
• pharmacogenetics
• precision medicine

Article highlights

• Combining omics and clinical characteristics may be the most effective personalized medicine approach in asthma management.

• Single variant pharmacogenetic studies have been described for most commonly prescribed asthma medications like ICS (genes CRHR1, CHRM2, HSP8A, COL2A1, CYP3A4, GLCCI1, FBXL7, TBX21, CTNNA3, CRISPLD2, SPATA20, VEGF, TSC22D3) and bronchodilators (genes ADRB2, THRB, SPATA13-AS1, SLC22A15, NOS1, TBX3, EPHA7); however, polygenic risk scores assessment may more accurately predict greater proportion of pharmacogenetic variance.

• Transcriptomics studies investigating the role of gene expression and genetics in asthma treatment response identified potential pharmacogenetic variants and candidate genes, such as CRISPLD2 and LTBP1.

• Proteomics studies in children with asthma have revealed variations in the levels, activity, and interactions of proteins involved in the immune response, inflammation, and airway remodeling.

• Metabolomics research has discovered that metabolites such as 2-hydroxyglutarate, cholesterol esters, GABA, and ribothymidine may influence the age-related reduction in bronchodilator response (BDR) in asthmatic children. Asthma is best represented as endotypes (like T2 high and T2 low asthma, neutrophilic and eosinophilic asthma, and obese and non-obese asthma); pharmacogenetic studies comparing these endotypes may reveal differences in treatment response.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors K Tantisira and S Piparia are funded by NIH R01 HL161362 and R01 HL162570 grants. The author M Khare is supported by UC San Diego Department of Pediatrics Seed Grant.