The impact of genomic variants on patient response to inhaled bronchodilators: a comprehensive update

ABSTRACT

Introduction

The bronchodilator response (BDR) depends on many factors, including genetic ones. Numerous single nucleotide polymorphisms (SNPs) influencing BDR have been identified. However, despite several studies in this field, genetic variations are not currently being utilized to support the use of bronchodilators.

Areas covered

In this narrative review, the possible impact of genetic variants on BDR is discussed.

Expert opinion

Pharmacogenetic studies of β₂-agonists have mainly focused on ADRB2 gene. Three SNPs, A46G, C79G, and C491T, have functional significance. However, other uncommon variants may contribute to individual variability in salbutamol response. SNPs haplotypes in ADRB2 may have a role. Many variants in gene coding for muscarinic ACh receptor (mAChR) have been reported, particularly in the M₂ and, to a lesser degree, M₃ mAChRs, but no consistent evidence for a pharmacological relevance of these SNPs has been reported. Moreover, there is a link between SNPs and ethnic and/or age profiles regarding BDR. Nevertheless, replication of pharmacogenetic results is limited and often, BDR is dissociated from what is expected based on SNP identification. Pharmacogenetic studies on bronchodilators must continue. However, they must integrate data derived from a multi-omics approach with epigenetic factors that may modify BDR.

KEYWORDS:

• Age
• inhaled bronchodilators
• β₂-agonists
• multi-omics approach
• muscarinic receptor antagonists
• ethnicity
• single nucleotide polymorphisms

Article highlights

• Inhaled bronchodilators are crucial in treating airway disorders such as asthma and COPD, but they are not always successful for all patients also because genomic variants influence BDR.

• Numerous SNPs influencing BDR have been identified even in large populations, but they have only small effects on BDR.

• There are three SNPs in the ADRB2 gene, Gly¹⁶Arg (A46G, rs1042713), Gln²⁷Glu (C79G, rs1042714), and Thr¹⁶⁴Ile (C491T, rs1800888), that have functional significance.

• Many SNPs in mAChR subtype genes have been reported, particularly in the M₂ and, to a lesser degree, M₃ mAChRs, but no consistent evidence for a pharmacological relevance of these SNPs has been reported.

• Replication of pharmacogenetic results is limited. Therefore, their use in clinical practice has not yet been validated.

• Pharmacogenetic studies focusing on bronchodilators should continue, but it will be necessary for them to integrate multi-omics data and also consider epigenetic factors that may modify BDR.

Declaration of interest

G Novelli’s laboratory is supported by grants of ’Piano Sviluppo e Coesione Salute’ (FSC 2014–2020, T3- AN-04 GENERA) and European Union – NextGenerationEU PNRR M4-C2-1.4 (CN00000041). 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.

Additional information

Funding

This paper was not funded