Reviews and feature articleNew approaches to personalized medicine for asthma: Where are we?
Section snippets
Magnitude of the health care burden related to asthma care
There are more than 300 million subjects with doctor-diagnosed current asthma worldwide, with more than 24.6 million in the United States alone.2 These 24.6 million asthmatic patients incur $56 billion in direct health care costs related to the disease on a yearly basis.3 The greatest costs relate to 4 areas: the cost of the medications themselves and the costs of office visits, hospitalizations, and emergency department (ED) visits. Roughly half of all asthma costs are related to medication
Modern pharmacotherapy for asthma: Issues complicating personalized care
The most recent version of the National Asthma Education and Prevention Program (NAEPP) guidelines had several innovations, the most important being the distinction between severity and control.9 Clinicians traditionally divide asthma into 4 severity groups: mild, mild persistent, moderate, and severe. Severity is defined as the symptoms that occur off all medication and that reflect the natural intrinsic intensity of the disease process. Control is the degree to which the manifestations of
Organization to find genes for asthma drug treatment response
Given all of the difficulties in advancing personalized care for asthma, what is the best approach to finding genes that predict drug treatment response, and how can this search be accelerated? Fig 1 outlines the basic approach.13 Complexity resides at every step of the process. Initial approaches have used first candidate genes and then genome-wide association studies (GWASs) for step 1. However, most pharmacogenomic studies have populations an order of magnitude smaller than those for other
Promise of genetics and genomics in improving and predicting asthma care response
What specific genes have been identified that significantly predict response to β-agonists, ICSs, leukotriene antagonists, and anti-IgE therapy? Table II15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42 provides a summary of the variants and phenotypes for the genes identified as associated with the various classes of asthma medications. In these studies one is looking for replication of results from at least 2 genetic association
β-Agonists
β-Agonists are the most common medication for asthma. Short-acting β2-agonists (SABAs) are the preferred treatment for acute asthma attacks. LABAs are only used in combination with ICS therapy to provide long-term asthma control. This is because of concern about the long-term adverse effects of unopposed LABA use, especially in African American patients.
The β2-adrenergic receptor is a G protein–coupled receptor the activation of which leads to an increase in levels of adenylyl cyclase, an
Inhaled steroids
ICSs are the most common and most effective anti-inflammatory controller medications for the treatment of asthma of all severity classes.9 Glucocorticoids act by first forming a complex with the intracellular glucocorticoid α receptor. This complex translocates to the nucleus and acts as a transcription factor for genes involved in stress responses through directly binding with DNA or indirectly by interacting with other transcription factors.46
Three pharmacogenomic phenotypes have been
Lung function
A candidate gene study of 14 corticosteroid pathway genes identified the corticotropin-releasing hormone receptor 1 (CRHR1) genotype (homozygous for the minor allele of rs242941) as a significant predictor of FEV1 after 8 weeks of ICS treatment in clinical trials of both adult and childhood asthma.28 CRHRI is one of the receptors for corticotropin-releasing hormone. Corticotropin-releasing hormone is secreted by the pituitary gland and controls the release of adrenocorticotropic hormone from
Airway hyperresponsiveness
Relatively few studies have looked at the change in airway responsiveness with ICS medication. The one gene that has been examined for this phenotype is TBX21. TBX21 is a T-cell transcription factor responsible for T-cell differentiation, maturity, and lineage commitment. An increase in T-box transcription factor expression leads to differentiation of naive T lymphocytes into TH1 cells while simultaneously repressing TH2 cells.31 TBX21 is directly related to the immune aspects of the asthma
Asthma exacerbations
Increased total serum IgE levels are associated with asthma exacerbations. The FCER2 gene encodes for CD23, a low-affinity IgE receptor. Although glucocorticoids have been shown to decrease FCER2 expression and CD23 production,50 an SNP variant in FCER2, T2206C, has been associated with increased IgE levels and severe asthma exacerbations in asthmatic children despite ICS use.50 White children homozygous for the T2206C mutant allele were more likely (odds ratio, 3.95; 95% CI, 1.64-0.51) to have
Leukotriene antagonists
The leukotrienes are a potent class of inflammatory mediators that derive from arachidonic acid. Leukotriene antagonists block key steps in the inflammatory cascade and are used for the treatment of asthma. There are 2 biochemical types of antagonists: cysteinyl leukotriene receptor blockers (eg, montelukast, zafirlukast, and pranlukast) and inhibitors of 5-lipoxygenase (5-LO; eg, zileuton). Because leukotriene antagonists are less effective than ICSs, they are mostly used as adjunctive therapy
Lung function
ALOX5, the gene coding for the enzyme 5-LO, has a tandem repeat polymorphism (factor Sp1-binding motif) within its promoter region that has been associated with diminished promoter-reporter activity.35 This polymorphism is associated with improvement in FEV1 in subjects taking the 5-LO inhibitor, ABT-761, who were homozygous or heterozygous for the wild-type allele (5 repeats).36 A more recent study of montelukast also showed improvement of FEV1 in asthmatic patients with at least 1 wild-type
Exacerbations
A study of montelukast reported decreased number of asthma exacerbations and decreased use of β2-agonists after treatment with montelukast in asthmatic patients with at least 1 wild-type allele of the promotor polymorphism of ALOX5.37
In the previously cited study of Klotsman et al, when looking at montelukast, the authors found variants in ALOX5 (rs4986832) associated with reduced asthma exacerbations.37
Lima et al’s previously cited study of montelukast38 found a variant in LTA4H (rs2660845)
Drug levels
Leukotriene modifiers are not endogenously produced compounds, such as β-agonists and corticosteroids, and because they are administered orally and the drugs are metabolized in the liver, they are subject to first-pass kinetics. Variants in SLCO2B1, a gene that encodes the organic anion transporter OATP2B1, might partly mediate this effect. A nonsynonymous SNP in SLCO2B1 has been associated with plasma concentrations of montelukast after 1 and 6 months of treatment.42 Heterozygotes for the
Anti-IgE
To date, no pharmacogenomics studies of omalizumab have been performed.
Vitamin D
Sometimes genomic discovery has unusual applications. The identification of the VDR gene as a gene associated with asthma first identified by means of positional cloning55, 56 began to stimulate interest in the role of vitamin D in influencing steroid resistance in asthmatic patients already taking ICSs. The theoretic basis for this idea comes from in vitro studies. Vitamin D is associated with reduced airway smooth muscle proliferation.57, 58 In addition, vitamin D enhanced IL-10 levels at the
Summary
In summary, the number of genes identified for the various asthma drug response phenotypes remains small. In addition, there remain a number of barriers to personalized asthma care. The most important of these are greater dissemination of the electronic medical record, appropriate application of the NAEPP guidelines, a greater number of genes identified for each asthma drug response pathway, and the ability to use this genomic information for predicting drug treatment response in individual
Conclusions
In 1950, before the discovery of DNA, there were only 1 type of leukemia and 3 types of lymphoma described based on pathologic classification. By 1990, 40 years later but still before the human genome project, there were 31 types of leukemia and 51 types of lymphoma, all of which had specific treatments. Today, cancer genomics leads the revolution in personalized medicine. It seems likely that such a revolution as occurred for leukemia and lymphoma will not take 40 years for asthma. Increasing
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Disclosure of potential conflict of interest: S. T. Weiss has consulted for GlaxoSmithKline, Genentech, Novartis, Merck, and Schering-Plough; received research support from GlaxoSmithKline; and collaborated with Genome Network Sciences (GNS).