Pharmacogenomics of β₂-Agonist: Key Focus on Signaling Pathways

Abstract

Asthma is one of the most common respiratory diseases, where inhalation and exhalation are obstructed due to narrowing of the airways by broncho-constriction or by inflammation. Among all the available anti-asthma therapies, β₂-agonists are the most effective bronchodilators available, and give rapid relief of asthma symptoms. Evidence suggests that the degree of β₂-agonist response varies greatly between patients and genetic factors have a major role in it. Despite several studies on the β₂-agonist pharmacogenetics, significant gaps in knowledge still remain and need to be resolved before the pharmacotyping of β₂-agonist responsiveness comes to clinical practice. As we know, β₂-agonists show their influence by targeting β₂-adrenergic receptors, leading to the activation of β₂-adrenergic receptors and its downstream cascade. Signaling through β₂-adrenergic receptors mediates numerous airway functions by regulating broncho-constriction and dilation pathways. Therefore, it is an important prerequisite to understand these pathways, which will assist in defining the variability in therapeutic responses for β₂-agonists. Owing to the complexity of the action of a β₂-agonist and its therapeutic response, a broader genomics approach will help in optimizing therapy for the individual patient. This might be achieved by considering and focusing on receptor/s at which the drug binds directly, signal transduction cascades or downstream proteins and proteins involved in the relaxation and constriction of the airway smooth muscle. Considering that a drug response may involve a large number of proteins, it seems unlikely that a single polymorphism or haplotype in a single gene would explain a high degree of drug response variability in a consistent fashion. Thus, it shows that a polygenic approach will be more appropriate. In order to follow this, the mode of action of the β₂-agonist and its downstream signaling cascade should essentially be assessed to resolve the β₂-agonist enigma.

Keywords: :

• asthma
• drug response
• pharmacogenetics
• pharmacogenomics
• signaling pathways
• single nucleotide polymorphisms

Acknowledgement

The authors thank Prof. SK Brahmachari (Director, IGIB), Dr Balaram Ghosh (Scientist, IGIB) and Dr AB Singh (Scientist, IGIB) for their invaluable scientific suggestions.

Additional information

Funding

The authors thank Prof. SK Brahmachari (Director, IGIB), Dr Balaram Ghosh (Scientist, IGIB) and Dr AB Singh (Scientist, IGIB) for their invaluable scientific suggestions.