PHARMACOGENOMICS AND ASTHMA E-bulletin No. 6: October 2, 2007 Eugene R. Bleecker, MD Thomas H. Davis Professor of Pulmonary Medicine and Public Health Sciences Section Head, Pulmonary, Critical Care, Allergy and Immunologic Diseases Co-director, Center for Human Genomics Wake Forest University School of Medicine Winston-Salem, NC

Take these CME-certified activities today! - Monographs - NEW! IMPLEMENTING THE NEW GUIDELINES FOR ASTHMA MANAGEMENT IN ADULTS Faculty: Leonard M. Fromer, MD ASTHMA: DISEASE CHARACTERIZATION Faculty: Eugene R. Bleecker, MD - Webinar - ASTHMA: DISEASE CHARACTERIZATION Faculty: William J. Calhoun, MD

Asthma treatment can be straightforward for some patients; however, an estimated 70-80% of patients have variable responses to common asthma medications.¹ In some cases, these variations are pronounced and can result in adverse reactions. In recent years, we have recognized that some of this variability may be due to genes and genetic variations that affect drug response. Pharmacogenomics examines these genetic variants, or polymorphisms, and their relation to key pathways for drug metabolism, delivery, excretion, site of action, and toxicity. (For a discussion of the terms used here, please see the box at the end of this article.)

Beta-2 adrenergic receptor (ADRβ2). The gene encoding the beta-2 adrenergic receptor (ADRβ2) is the most extensively studied gene in asthma pharmacogenomics and probably the best example for illustrating the relationship between polymorphisms and asthma treatment responses.² Analyses of several clinical studies reveal that ADRβ2 polymorphisms may alter a patient's response to short-acting beta-2 agonists. The Beta-agonist Genotype Study (BAGS) and the Beta-Adrenergic Response by Genotype (BARGE) trial examined whether responses to albuterol, a short-acting beta-2-agonist (SABA), were influenced by polymorphisms at codon 16 in the ADRβ2 gene.^3,4 Both trials noted that participants with the Arg/Arg genotype had better asthma control when using albuterol on an as-needed basis compared to regular albuterol treatment, while participants with the Gly/Gly genotype had improved asthma control with regular albuterol treatment. In addition, Arg/Arg participants on the regular dosing regimen in the BARGE study reported more symptoms, lower scores on a measurement of lung function, and more frequent use of rescue medication.⁴ The relationship between polymorphisms in the ADRβ2 gene and responses to a long-acting beta-2-agonist (LABA) is less clear. An analysis by Taylor et al. found that the pattern of major exacerbations and morning peak expiratory flow rate (PEFR) in patients treated with a LABA was unaffected by the genotype at position 16;⁵ however, a genotype analysis of the Salmeterol or Corticosteroid (SOCS) and Salmeterol ± Corticosteroid (SLIC) trials by Wechsler et al. concluded that Arg/Arg homozygotes had a substantially diminished therapeutic response to salmeterol monotherapy compared to Gly/Gly homozygotes.⁶ A recent study examined the effect of combination LABA/inhaled cortico-steroids (ICS) therapy on measures of asthma control according to ADRβ2 genotype and found that responses to the LABA did not vary between genotypes after chronic dosing with the ICS.⁷ In contrast, the Wechsler analysis previously reported genotype-specific differences in the response to combination therapy, with the Arg/Arg homozygotes having worse symptoms and more frequent rescue medication use compared to Gly/Gly participants.⁶ Therefore, it is clear that additional clinical investigation is required to resolve the impact of ADRβ2 polymorphisms on treatment response in patients with asthma.

Do these findings suggest more appropriate, individualized treatments for patients with the Arg/Arg genotype? Possibly. The Arg/Arg genotype occurs in about one-sixth of the US population and is more prevalent in certain ethnic groups, including African Americans—who have a high prevalence of asthma and variable treatment responses. However, regulation of the beta agonist response is complex and cannot be explained by a single ADRβ2 polymorphism or even a single pathway.² It is still unclear whether the findings can be generalized to all inhaled beta-2-agonists, and whether the same effects would be observed in patients on combined therapy with inhaled corticosteroids (ICS).

Looking ahead. Clearly, more studies are needed to examine genetic variability in other major pathways relevant to asthma, such as the glucocorticoid, cholinergic, and leukotriene pathways, and their interactions with the beta-2-agonist pathways. Any findings in these areas will need careful interpretation and replication in multiple studies. Developers of clinical genetic tests must also consider affordability and ease of use as well as the many legal, regulatory, and ethical issues that these new advances will raise.⁸ Although many challenges remain ahead, the future looks promising for employing individualized asthma therapy that offers simple dosing, improved efficacy, and enhanced safety.

References

This activity is supported by an educational grant from

This activity is sponsored by