Overview of the pharmacogenetics of asthma treatment

Abstract

Asthma affects approximately 300 million individuals worldwide. Medications comprise a substantial portion of asthma expenditures. Despite the availability of three primary therapeutic classes of medications, there are a significant number of nonresponders to therapy. Available data, as well as previous pharmacogenetic studies, suggest that genetics may contribute as much as 60-80% to the interindividual variability in treatment response. In this methodologic review, after providing a broad overview of the asthma pharmacogenetics literature to date, we describe the application of a novel family-based screening algorithm to the analysis of pharmacogenetic data and highlight our approach to identifying and verifying loci influencing asthma treatment response. This approach seeks to address issues related to multiple comparisons, statistical power, population stratification, and failure to replicate from which previous population-based or case-control pharmacogenetic association studies may suffer. Identification of such replicable loci is the next step towards the goal of 'individualized therapy' for asthma. The Pharmacogenomics Journal (2006) 6, 311-326. doi:10.1038/sj.tpj.6500387; published online 25 April 2006Keywords: beta-agonist; leukotriene; corticosteroid; FEV 1 ; genetics IntroductionThe goal of this review is to give a comprehensive assessment of asthma pharmacogenetics and highlight the scientific approach being taken by the pharmacogenetics of asthma treatment (PHAT) research group (http:// www.pharmgat.org/) to this research area. Our approach strives to address many of the potential problems inherent in genetic association studies, including those related to multiple comparisons, lack of statistical power, population stratification, and failure to replicate. Moreover, our group of collaborative investigators is well positioned to investigate the molecular biology and functional genomics of identified candidate gene associations. In this review, we will cover some aspects of asthma health care, pathobiology, and review the available pharmacogenetics literature on the important types and pathways of asthma medications: b-agonists, leukotriene (LT) antagonists, methylxanthines, and corticosteroids. We will then present details of our research approach to finding replicated pharmacogenetic associations and suggest what the future may hold for this research area. Pharmacogenetics -definition and rationalePharmacogenetics is the study of the role of genetic determinants in the variable, interindividual response to medications. Numerous examples of heritable differences in pharmacokinetics (drug distribution and metabolism) in The Pharmacogenomics Journal (2006) 6, 311-326 & 2006 Nature Publishing Group All rights reserved 1470-269X/06 $30.00 www.nature.com/tpj individuals resulting in varied clinical response to medications have been described. 1 Other mechanisms underlying the genetic response to drugs includes alterations in pharmacodynamics (changes in the drug target), idiosyncratic associations (unin...

Combined pharmacogenetic effect of ADCY9 and ADRB2 gene polymorphisms on the bronchodilator response to inhaled combination therapy

“…However, degrees of responsiveness to b2-agonist plus ICS vary and approximately 60-80% of inter-individual variations may be due to genetic factors, and thus, several pharmacogenetic studies have been conducted to investigate the genetic basis of therapeutic response heterogeneity (8,9). Several clinical investigations have demonstrated that ADRB2 gene polymorphisms contribute to different bronchodilator responses to LABA (10)(11)(12)(13).…”

ARG1 Is a Novel Bronchodilator Response Gene

“…To date, asthma pharmacogenetic studies in general (7), and response to inhaled bronchodilators in particular (8), have been based on one or more polymorphisms in a single gene. Recent studies from the Asthma Clinical Research Network, for instance, have reported adverse effects of regular albuterol treatment among patients with asthma who were homozygous for the 149 A allele (Arg16) of the ADRB2 gene (9,10).…”

Interpatient variability in rates of asthma progression: Can genetics provide an answer?

“…109 Therefore interpatient genetic variability is likely to be an important determinant of the effectiveness of treatment strategies in preventing progression. For example, a number of studies have examined the potential for desensitization immunotherapy to reduce the later occurrence of asthma.…”