The Pharmacogenomics Journal (2006) 6, 311–326 & 2006 Nature Publishing Group All rights reserved 1470-269X/06 $30.00 www.nature.com/tpj REVIEW Overview of the pharmacogenetics of asthma treatment ST Weiss1, AA Litonjua1, Asthma affects approximately 300 million individuals worldwide. Medica- 2 1 tions comprise a substantial portion of asthma expenditures. Despite the C Lange , R Lazarus , availability of three primary therapeutic classes of medications, there are a 3 4 SB Liggett , ER Bleecker , significant number of nonresponders to therapy. Available data, as well as KG Tantisira1 previous pharmacogenetic studies, suggest that genetics may contribute as much as 60–80% to the interindividual variability in treatment response. In 1Channing Laboratory, Brigham and Women’s this methodologic review, after providing a broad overview of the asthma 2 Hospital, Boston, MA, USA; Harvard School of pharmacogenetics literature to date, we describe the application of a novel Public Health, Boston, MA, USA; 3Department of Medicine, University of Maryland, Baltimore, MD, family-based screening algorithm to the analysis of pharmacogenetic data USA and 4Division of Pulmonary and Critical Care and highlight our approach to identifying and verifying loci influencing Medicine and Center for Human Genomics, asthma treatment response. This approach seeks to address issues related to Wake Forest University School of Medicine, multiple comparisons, statistical power, population stratification, and failure Winston-Salem, NC, USA to replicate from which previous population-based or case–control pharma- Correspondence: cogenetic association studies may suffer. Identification of such replicable loci Dr K Tantisira, Channing Laboratory, Brigham is the next step towards the goal of ‘individualized therapy’ for asthma. and Women’s Hospital, 181 Longwood The Pharmacogenomics Journal (2006) 6, 311–326. doi:10.1038/sj.tpj.6500387; Avenue, Boston MA 02115, USA. E-mail: [email protected] published online 25 April 2006 Keywords: beta-agonist; leukotriene; corticosteroid; FEV1; genetics Introduction The 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 stratifica- tion, 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 rationale Pharmacogenetics is the study of the role of genetic determinants in the variable, Received 1 December 2005; revised 15 February 2006; accepted 16 February 2006; interindividual response to medications. Numerous examples of heritable published online 25 April 2006 differences in pharmacokinetics (drug distribution and metabolism) in Overview of the pharmacogenetics of asthma treatment ST Weiss et al 312 individuals resulting in varied clinical response to medica- 1 Growth Factors tions have been described. Other mechanisms underlying Endogenous GC Early Environmental Chronic Tissue the genetic response to drugs includes alterations in Factors Inflammation Remodeling Cytokines pharmacodynamics (changes in the drug target), idiosyn- Allergens Endogenous GC Allergens cratic associations (unintended side effects in predisposed Pollution TH2 Pollution Virus Immune Virus individuals), and genetic predisposition to the disease in Cigarettes Deviation Cigarettes which the treatment is to be instituted2,3 Overall, it is Stress Stress Acute estimated that genetics can account for 20–95% of varia- Susceptibility Inflammation Leukotrienes 2 Bronchoconstr Histamine bility in drug disposition and effects. In corticosteroid Genes Endothelins/Chemokines therapy, a number of family and twin studies have demon- ADAM33 Complement FcεRI Endogenous GC strated consistent evidence that endogenous levels of IL4Rα iction glucocorticoids (GC), usually measured as plasma cortisol TGFβ SYMPTOMS 4–8 GPRA Wheezing levels at certain times of the day, are heritable. We have GSTP1 Dyspnea generated similar heritability data for bronchodilator re- Cough 9 sponse in a Chinese population. As the initial sequence of Figure 1 Asthma pathobiology. Asthma is an inflammatory disorder of 10,11 the human genome was published, the concept that the airways influenced by multiple early life and genetic factors. The genetic variation will allow prediction of treatment response inflammatory response, as well as smooth muscle constriction, lead to has been seen as an important and achievable goal.12–14 airway narrowing and symptoms. Further, the food and drug administration has drafted guidelines requiring drug development companies to submit pharmacogenetic information when reporting clinical trial lymphocytes, epithelial cells, and airway smooth muscle results. Ideally, pharmacogenetics will allow for ‘individua- cells play a prominent role.25 Figure 1 shows important lized therapy’ that is tailored to an individual’s genetic pathobiologic features of asthma. Genetics in combination make-up to maximize the potential for therapeutic benefit, with early life environment modulate the development of while minimizing the risk of adverse effects. The potential CD4/lymphocytes towards a Th2 immunophenotype. These for cost savings and for decreasing morbidity and mortality lymphocytes then produce cytokines, such as interleukin is immense because the target therapies are so widely used. (IL)-3, IL-4, IL-5, IL-13, and granulocyte–macrophage col- ony-stimulating factor (GM-CSF) and thereby promote the Asthma – overview and rationale synthesis of IgE, an important allergic effector molecule, resulting in an inflammatory airway milieu. Chemokines, The burden of asthma such as eotaxin, RANTES, and IL-8 produced by epithelial Asthma is a complex disease affecting over 300 million and inflammatory cells, serve to amplify and perpetuate the individuals in the developed world.15 Of all asthma cases, inflammatory events. Several bronchoactive mediators, such 90%, including asthma in adults, has its origins in child- as histamine, LT, and neuropeptides are released into the hood. Of concern are the increases in asthma prevalence16 airways and precipitate an asthma attack by causing airway and hospitalization rates.17 Between 1980 and 1994, the self- smooth muscle constriction, mucus secretion, and edema. reported prevalence of asthma in the USA increased from Over time there is smooth muscle growth and the deposi- 30.7 to 53.8 per 1000, an increase of 75%.16 This increase tion of subepithelial connective tissue, a process referred to has been accompanied by a similar increase in health care as airway remodeling. This basic asthma pathobiology is utilization and mortality over the same time period.16 An important for asthma pharmacogenetics because many estimated 12.6 billion dollars were spent on the diagnosis genes associated with an altered treatment response are also and management of asthma in the US in 1998, of which associated with asthma or its intermediate phenotypes. 58% were direct medical expenditures (DMEs).18 Medication Clinically, asthmatics have difficulty exhaling air because of costs are currently the largest component of DMEs. Despite an increase in airway resistance that is a consequence of the availability of several classes of therapeutic agents for smooth muscle contraction, inflammation and remodeling asthma, it has been estimated that as many as one-half of (Figure 1). In clinical trials, the degree of resistance and asthmatic patients do not respond to treatment with b2- physiological impairment is quantitated most commonly by 3,19,20 agonists, LT antagonists, or inhaled corticosteroids. As the forced vital capacity in 1 s (FEV1) (Figure 2). Forced vital a whole, adverse drug reactions are estimated to cost the US capacity in 1 s is the volume of air a person can ‘blow out’ in $100 billion and over 100 000 deaths a year.21 Asthma one second and is very useful as a measurement of lung therapy has been associated with adverse drug reactions, function because it is easily obtained, reproducible, and 26 including serious and potentially fatal complications.22–24 correlated with asthma severity and therapeutic responses. Another commonly used measurement of the physiological Asthma: definition, clinical features, pathobiology impairment in asthmatics is the peak expiratory flow rate Asthma is a clinical syndrome of unknown etiology (PEFR). Peak expiratory flow rate is defined as the maximal characterized by reversible episodes of airflow obstruction, flow rate achieved during forced exhalation.27 airway hyperresponsiveness, and a chronic inflammatory During an asthma attack, patients experience shortness of process of the airways of which mast cells, eosinophils,