Review
Do genetic polymorphisms alter patient response to inhaled bronchodilators? 1.
Introduction
2.
Bronchodilator use in asthma
3.
Pharmacology of SABA and
John J Lima Center for Pharmacogenomics and Translational Research, Nemours Children’ s Clinic, Jacksonville, FL, USA
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LABA 4.
Bronchodilator heterogeneity
5.
Safety of bronchodilators
6.
Pharmacogenetic studies of SABA and LABA
7.
Summary and conclusion
8.
Expert opinion
Introduction: Short- and long-acting b agonists (SABA and LABA) are bronchodilators for treating asthma. Bronchodilator response (BDR) is quantified by measuring air expired in the first second during a forced expiratory maneuver, prior to and following inhalation of SABA. BDR has been associated with a significant degree of heterogeneity, in part attributable to genetic variation. Heritability, the proportion of phenotypic variability accounted for by genetic variation is estimated to account for 50% of pulmonary function and 28.5% for BDR. Areas covered: A MEDLINE search for English articles published from January 1990 to June 2014 was completed using the terms: bronchodilator, bronchodilator response, short-acting bronchodilator, long-acting bronchodilator, b2 adrenergic receptor gene (ADRB2), asthma and pharmacogenomics. The effects of ADRB2 variants on BDR and the safety of SABA and LABA + inhaled corticosteroids have been studied with equivocal results. Single and candidate gene studies have identified variants in other genes that alter response to bronchodilators. Associations were recently observed between hospital admission rates and two rare ADRB2 polymorphisms: Thr164Ile and a 25 base pair insertion-deletion at nucleotide -376. This was the first report of life-threatening events associated with LABA being linked to rare ADRB2 variants. Expert opinion: Pharmacogenomic studies over the last two decades clearly demonstrate that polymorphisms alter patient response to bronchodilators in patients with asthma. Keywords: adrenergic receptor, asthma, bronchodilator, drug, gene, heritability, heterogeneity, pharmacogenetic, polymorphisms, response Expert Opin. Drug Metab. Toxicol. [Early Online]
1.
Introduction
Bronchodilators are extensively used by patients with asthma, COPD or both. Most of the studies exploring the influence of genetic variation on patient response to bronchodilators have been performed in patients with asthma. Therefore, this review considers pharmacogenomic studies of asthma in order to address the question of whether genetic variation alters patient response to bronchodilators. This research topic is significant because of the importance of the clinical issues surrounding variable response including toxicity to inhaled bronchodilators. Asthma is a chronic, complex disease characterized by reversible airway obstruction, increased bronchial hyper-responsiveness and inflammation. Genome-wide studies have implicated several genes that associate with asthma signifying a substantial genetic component [1-6]. Recent studies have used cluster analyses to identify several distinct phenotypes suggesting that asthma is a markedly heterogeneous disease [7-12]. Gene--gene interactions, gene--environment [13] interactions and 10.1517/17425255.2014.939956 © 2014 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 All rights reserved: reproduction in whole or in part not permitted
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J. J. Lima
Article highlights. . . . .
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Bronchodilator response (BDR) is highly variable among patients with asthma. Heritability, the fraction of BDR attributable to genetic variation is 28.5%. Genetic associations between common b2 adrenergic receptor gene (ADRB2) SNPs and BDR are inconsistent. ADRB2 Arg16 alleles associate with asthma worsening in asthmatics receiving continuous short-acting b agonists and long-acting b agonists (LABA) monotherapy. Rare ADRB2 variants associate with serious adverse events associated with continuous LABA treatment. Candidate gene and genome-wide studies have identified common SNPs that associate with BDR in different ethnic and racial populations with asthma. Genome-wide association studies have identified rare SNPs in several genes that associate with BDR in patients with asthma. Genetic polymorphisms alter response to inhaled bronchodilators in patients with asthma.
This box summarizes key points contained in the article.
epigenetics are thought to contribute to asthma heterogeneity. Asthma imposes a significant worldwide burden comparable to that of diabetes mellitus or cirrhosis [14]. It affects 300 million individuals worldwide and is responsible for 180 thousand deaths and 15 million disability-adjusted life-years lost each year [15]. In 2011, CDC reported that asthma affects 1 in 12 Americans; its prevalence among children is 9.6% making asthma the most common chronic disease of childhood; and that 1 in 6 African Americans have asthma, which represents an increased prevalence of 50% since 2001. 2.
than SABA or LABA in patients with asthma. Methylxanthines, a third class of bronchodilators, are used little as bronchodilators in asthma owing to toxicity and the need for therapeutic drug monitoring. Consequently, this review will cover SABA and LABA pharmacogenomic studies in asthma in an effort to answer the question posed in this review: Do genetic polymorphisms alter patient response to inhaled bronchodilators? 3.
SABA and LABA relax bronchial smooth muscle by binding to and activating b2 adrenergic receptors (b2AR) expressed on the surface of airway smooth muscle. b2ARs are G-protein-coupled receptors, which can exist in an active (R*) form or inactive (R) form. Agonist ligands can be classified as partial or full agonists depending on the fraction b2ARs that they stabilize in their R* forms, which are coupled to Gs and stimulate adenylyl cyclase to form cAMP, the second messenger. cAMP stimulates protein kinase A (PKA) leading to phosphorylation of downstream proteins, inhibition of phosphoinositol hydrolysis, a reduction in intracellular Ca2 concentrations, and activation of large conductance K+ channels, which relaxes airway smooth muscle [17]. Full agonists have higher intrinsic efficacies than partial agonists, meaning that full b agonists stimulate more cAMP than partial agonists at equivalent receptor occupancies. Continuous stimulation of b2ARs results in receptor uncoupling from Gsa, receptor desensitization and agonist-promoted downregulation (i.e., loss of receptor number or density) [18]. In addition to being phosphorylated by PKA b2ARs can be phosphorylated by G-protein receptor kinases (GRK), which can also result in uncoupling of agonist-occupied b2ARs.
Bronchodilator use in asthma 4.
Several drugs and drug classes are available to treat asthma symptoms in a step-wise fashion [16]. Inhaled bronchodilators are the most highly used asthma drug class and play a significant role in relieving and controlling asthma symptoms. Two classes of inhaled bronchodilators are used in asthma: b2 agonists and antimuscarinic agents. b2 agonists are classified according to their pharmacokinetic half-lives and duration of action as short-acting b agonists (SABA) or as long-acting b agonists (LABA). Inhaled SABAs are used by all patients virtually with asthma to provide quick relief of bronchoconstriction. SABA monotherapy is used in patients with mild, intermittent asthma (Step 1). Inhaled corticosteroids (ICS) are preferred in mild, persistent asthma along with SABA for rescue (Step 2); followed by the addition LABA or leukotriene receptor antagonist (LTRA) if asthma symptoms are poorly controlled (Step 3). High-dose ICS or additional add-on therapy (Step 4) and oral steroids (Step 5) are recommended for better control if necessary. Inhaled antimuscarinic agents are classified as short-acting antimuscarinic or as long-acting antimuscarinic agents and are used to a much lesser extent 2
Pharmacology of SABA and LABA
Bronchodilator heterogeneity
The bronchodilator response (BDR) (aka reversibility) is quantified by measuring the amount of air expired in the first second during a forced expiratory maneuver, just prior to and after inhalation of two or occasionally four puffs of SABA, generally albuterol. The resulting values of FEV1 are converted to per cent predicted FEV1 (FEV1% pred) [19], and BDR is often expressed as a percent by: (1)
(FEV1% pred post − FEV1% pred pre )
(FEV1% pred ) pre
× 100
where the terms pre and post refer to pre- and postbronchodilator inhalation. In general, a 12% or higher BDR is commonly used to aid in the diagnosis of asthma, although the validity of that value has been questioned, at least in children [20]. BDR has been associated with a significant degree of variability. Figure 1 shows that ~ 50% of patients who participated in three large clinical trials of asthma had BDR values ‡ 12%, 25 -- 30% had BDRs £ 5%, and a small
Expert Opin. Drug Metab. Toxicol. (2014) 10(9)
Do genetic polymorphisms alter patient response to inhaled bronchodilators?
Bronchodilator response distribution in ACRN, CARE and CAMP 30 ACRN CAMP CARE
25
Subjects (%)
15
10
5
35 to 40
Greater than 40
Bronchodilator response (%)
30 to 35
25 to 30
20 to 25
15 to 20
10 to 15
5 to 10
0 to 5
-5 to 0
-10 to -5
0 Less than-10
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20
Figure 1. Distribution of the bronchodilator response across three major asthma networks in SHARP. Despite highly varying enrollment criteria, the overall distribution of response is remarkably similar between the clinical trial networks. Reproduced with permission from [20]. ACRN: Asthma Clinical Research Network; CAMP: Children Asthma Management Program; CARE: Childhood Asthma Research and Education; SHARP: SNP Health Association Resources (SHARe) Asthma Resource project.
percentage of patients had negative BDR. BDR heterogeneity is attributable to several factors including asthma severity, poor medication adherence, non-responsive phenotypes, environmental exposure, drug interactions with ICS and genetic variation. Heritability, defined as the proportion of phenotypic variability that is accounted for by genetic variation has been estimated to be 70 -- 90% for asthma [21] and ~ 50% for pulmonary function [22]. The heritability of BDR to SABA is 28.5% [23]; however, we can account for only a small fraction of the heritability of the BDR. 5.
Safety of bronchodilators
The safety of bronchodilators in the treatment of asthma is relevant to this review because it is possible that genetic variation contributes to adverse events associated with bronchodilator use thereby altering patient response to this class of drugs. In the mid-fifties and early sixties Metered Dose Inhalers (MDI) containing the non-selective, full agonists epinephrine and isoproterenol were introduced and the popularity of bronchodilator inhaler treatment increased dramatically. Coincident with the increased sales of inhaled isoproterenol was an increase in asthma deaths in the UK -the so called ‘epidemic’ of asthma deaths, which reversed
following withdrawal from the market [24]. At about the same time, the b2 selective, partial agonist salbutamol (albuterol in the USA) MDI was introduced. A second ‘epidemic’ of asthma deaths was witnessed in New Zealand between 1976 and 1989, which was coincident with the introduction of fenoterol, a b2 selective, full agonist with a subsequent decline following removal of fenoterol from the market [25]. The safety of continuously inhaled albuterol (b2 selective partial agonist) use was established in the b agonist study (BAGS), but continuous use had no additional benefit over as-needed use [26], thus establishing SABA for rescue use only. It should be noted that increased use of both inhaled fenoterol and albuterol were associated with the risk of death or near death in a matched case-control study [27,28]. The first LABA, salmeterol was introduced into practice in the late 1980s and continues as a standard of therapy so long as it is administered with ICS. LABA monotherapy is associated with asthma worsening [29-38], which includes one or more of the following: decreases in morning and evening peak flow rates, decreased scores on symptom questionnaires, increased use of rescue SABA inhalation, requirement of short courses of oral steroids, decreases in lung function including BDR and increased airway hyper-responsiveness. LABA-associated serious adverse events include exacerbations
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J. J. Lima
requiring hospitalization, intubation, life-threatening asthma attacks and death. The Salmeterol Multi-centre Asthma Research Trial reported a rare, but significant increase in respiratory- or asthma- related deaths in individuals particularly African Americans taking salmeterol compared with placebo [39], which led to an FDA black-box warning regarding the use of LABA in asthma [40]. Consequently, the FDA recommended that LABAs not be used as monotherapy but should be combined with ICS [41,42]. A review of many studies concluded that LABA monotherapy worsens asthma symptoms, increases the risk of serious LABA-associated adverse events (hospitalizations, intubations, ER visits and death) and that concomitant use of ICS or the use of ICS + LABA in a single inhaler reduces these risks and is not associated with asthma-related deaths [43]. Recent reviews support the idea that compared to ICS alone the combination of ICS + LABA decreases risk of severe exacerbations [44] and are safe [45]. However, a recent meta-analysis reported that ICA + LABA increases catastrophic events by over threefold compared to ICS alone, and concluded that LABA increases the risk of asthma-related intubations and deaths, even when used in a controlled fashion with concomitant ICS [46]. In a thoughtful, expert review of LABA safety, Sears concluded that in patients taking ICS + LABA under-treatment with ICS may mask LABA-induced inflammation, which will lead to increased asthma worsening and mortality, and that withdrawal of LABA can result in loss of symptom control [47]. This is because LABA can mask worsening inflammation as a consequence of steroid reduction or withdrawal, although a direct adverse effect of LABA cannot be ruled out [30,47].
Pharmacogenetic studies of SABA and LABA 6.
ADRb2 gene Identifying genetic variants that predict beneficial and adverse events associated with the use of bronchodilators would aid in our understanding of the mechanisms underlying these associations and would enable us to personalize bronchodilator therapy in asthma and thus avoid adverse events in susceptible patients. Given the central role of b2ARs in regulating bronchodilator tone in patients with asthma, it is not surprising that initial efforts at identifying genetic variants that associate with response to SABA and LABA began with the b2 adrenergic receptor gene (ADRB2). The ADRB2 is a small, intronless gene, which has been resequenced in multiple ethnic populations to determine polymorphic variability and haplotype structure [48]. Of 80 polymorphisms identified, 45 SNPs and two insertion/deletion polymorphisms have been validated. Two common nonsynonomous variants at amino acid positions 16 (Gly16Arg) and 27 (Gln27Glu) have functional relevance in vitro [49,50]. Cells, including airway smooth muscle cells expressing the Gly16 allele were significantly more sensitive to agonist-promoted receptor down-regulation compared to the Arg16 allele. The Ile allele for an uncommon, nonsynonomous SNP at position 164 (Thr164Ile) 6.1
4
reduced agonist binding to the b2 AR and coupling to adenylyl cyclase [51]. Initial studies exploring associations between BDR to SABA and the Gly16Arg polymorphism in outpatients found Arg16 homozygotes had a greater BDR than Gly16 homozygotes [52-54], which were consistent in vitro studies [51]. Subsequent studies however, found opposite results or no association [48,55-59]. Interestingly, when the BAGS trial, which studied the safety of continuously inhaled albuterol [26] was analyzed by genotype, Arg16 homozygotes had worse asthma control on regularly scheduled albuterol compared to Gly16 homozygotes on regularly scheduled albuterol and to Arg16 homozygotes treated as-needed with albuterol [60]. The results of two additional retrospective trials were consistent with the BAGS trial [61,62], and the carefully designed prospective trial by Israel et al. of patients with mild asthma not taking controller medication found that morning peak flow rates in Arg16 homozygotes were lower than Gly16 homozygotes treated with regularly scheduled albuterol [60]. Taken together the results of these studies of continuous or regularly-scheduled SABA were encouraging because they supported the idea that bronchodilator therapy in patients with asthma could be personalized using Arg16Gly genotype as a genetic biomarker. An important question to answer is: do polymorphisms in the ADRB2 associate with asthma worsening and asthma deaths in patients with asthma taking LABA or, more relevantly, taking LABA + ICS? Two studies reported that compared to the Gly16 allele the Arg16 allele was associated with an impaired response to salmeterol in the absence or presence of inhaled corticosteroid [63] or with bronchoprotective subsensitivity to salmeterol or formoterol [64]. However, Bleecker et al. found no evidence of a pharmacogenetic effect in patients with asthma participating in two large retrospective clinical trials of LABA with or without ICS [65,66]. Similar findings were reported in a randomized, double-blind, placebo-controlled trial of LABA with ICS in patients with moderate asthma leading the authors to conclude that patients should continue to be treated with ICS + LABA irrespective of Gly16Arg genotype [67]. The Gly16Arg SNP was not associated with loss of in response to salmeterol [68]. Other ADRB2 variants also failed to associate with BDR to ICS + LABA [69]. Most pharmacogenetic studies of bronchodilators have been performed in adults. It is important to explore the pharmacogenetics of bronchodilators in children with asthma because they may be at greater risk of asthma exacerbations from LABA treatment alone or with ICS [33] and the efficacy of LABA as add-on to ICS has been questioned [70,71]. Moreover, since 2000, children with asthma are rapidly being switched from ICS monotherapy to ICS + LABA. [34]. Two studies have explored associations between ADRB2 SNPs and LABA-associated adverse events in children. Palmer et al. studied 546 children and young adults taking LABA (mean age 10.2 years old) and reported that the Arg16 genotype
Expert Opin. Drug Metab. Toxicol. (2014) 10(9)
Do genetic polymorphisms alter patient response to inhaled bronchodilators?
A.
Participants admitted to hospital in past year (%)
90
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B.
Non-hispanic white patients
90
Thr164Ile
n=6
Rare genotype (CT) Common genotype (CC)
80 70
OR 4.48 (95% CI 1.40 – 13.96) p = 0.01
Rare insertion Common genotype
70
OR 13.43 (95% CI 2.02 – 265.42) p = 0.006
60 50
n = 13
40
40
30
30
20
-376 In-Del
80
60 50
African-American patients
20
n = 384 n = 10
10
n = 179
n = 218
n=5
10
0
n = 119
0 LABA treatment
No LABA treatment
LABA treatment
No LABA treatment
Figure 2. Association between rare ADRB2 variants and hospital admissions for a severe asthma exacerbation in patients taking LABA. Dark bars show the percentage of patients with the Thr164Ile or with the -376 In-Del variant; light bars show the percentage in those without these rare variants. Thr164Ile was the only variant identified in non-Hispanic White patients and a 25-base pair promoter insertion deletion (-376 In-Del) was identified in African American but not in non-Hispanic White patients. Reproduced with permission from [74]. ADRB2: b2 adrenergic receptor gene; LABA: Long-acting b agonists.
predisposed children taking LABA to increased risk of asthma exacerbations even with ICS [72]. A more recent study reported that compared to Gly16 homozygotes Arg16 homozygotes taking ICS + LABA had an increased risk of exacerbations and oral corticosteroid use in the PACMAN cohort study (children 4 -- 12 year old) [73]. These studies support the idea that knowledge of the Arg16Gly genotype may predict asthma exacerbations in children taking LABA + ICS. More studies are warranted in children to replicate these studies. The frequency of the Gly16Arg SNP is common among different ethnic groups making it highly unlikely to account for rare, life-threatening events associated with LABA use, and which resulted in the boxed warning from the FDA. Oretga and colleagues [74] hypothesized that rare (< 5%) ADRB2 variants are associated with increased hospital admissions for asthma exacerbations in patients receiving LABA and ICS. These investigators sequenced a 5356 base pair (bp) region of the ADRB2 beginning at -3270 bp 5’ of the ATG start site to + 1886 bp after the ATG start site including the 1239 bp coding region in 461 non-Hispanic White, African American and Puerto Rican patients with asthma including many with severe asthma. Six rare variants were identified and genotyped in a primary cohort of 1165 patients with asthma; 659-nonHispanic White patients with asthma comprised the replicate cohort. Associations were observed between hospital admission rates and two ADRB2 polymorphisms: Thr164Ile (minor allele
frequencies: 0.02, 0.006 and 0.007 in non-Hispanic White, African American and Puerto Rican patients, respectively) and 25 bp insertion-deletion at nucleotide -376 relative to the ATG start site (Figure 2). The genetic effects of the Thr164Ile variant on symptom control were replicated. This study is the first to report that rare, potentially life-threatening events associated with LABA (in the presence of ICS)----those for which the FDA requires a box warning----is linked to rare ADRB2 variants. These findings require further replication in large multiethnic asthma populations and, as the authors point out, if replicated, these genetic variants could serve as important predictive biomarkers for these rare, serious side effects [74]. Two studies report a gene-gene interaction between variants on ADRB2-GSNOR could alter the BDR to SABA [75,76]. S-nitrosoglutathione (GSNO) is an endogenous brochodilator formed from interactions involving nitric oxide and glutathione that can regulate the activity of GRK2, which can phosphorylate and uncouple B2AR. GSNO reductase (GSNOR) metabolizes GSNO and variants that affect the activity of GSNOR can alter BDR [76]. Other genes In addition to ADRB2 polymorphisms, variants in other genes have been identified that alter BDR to SABA and these are summarized in Table 1. Single and candidate gene studies have identified variants on adenylyl cyclase (ADCY9) [77], 6.2
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J. J. Lima
Table 1. Summary of association studies between genetic variants and bronchodilator response to short-acting b agonists and long-acting b agonists.
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SNP
Gene
Replication
Genetic study
Ethnicity or race
Ref.
rs2230739 rs7793837 rs2781659 Haplotypes rs295137 rs892940 Gene based
ADCY9 CRHR2 ARG1 ARG1 SPATS2L THRB SPATA13-AS1
No Yes Yes Not applicable Yes Yes Yes
Single Single Candidate Single GWAS Candidate GWAS
[77] [78] [79] [80] [82] [81] [83]
GWAS
Caucasian Caucasian Caucasian Caucasian Non-Hispanic White Non-Hispanic White African- and EuropeanAmericans Caucasian
rs11252394 rs6988229 rs8191725 rs77441273 rs77977790 rs77149876 rs115501901 rs116551936 rs74973995
Intergenic COL22A1 IGF2R SLC24A4 PAPPA2 SPON1 NCOA3 Intergenic Intergenic
Yes Yes Yes Yes Yes No No No No
GWAS*
Latino
[85]
[84]
*All SNPs were rare (allele frequencies < 5%). GWAS: Genome-wide association study.
corticotrophin hormone receptor 2 (CRHR2) [78], arginase 1 (ARG1) [79,80] and thyroid hormone receptor b 1 (THRB) [81] that associate with BDR. Genome-Wide Association Study (GWAS) identified common SNPs on Spermatogenesis Associated, Serine-Rich 2-Like (SPATS2L) [82], SPATA13-AS1 (an antisense RNA that overlaps SPATA13, also known as ASEF2) [83] and Collagen, Type XXII, a 1 (COL22A1) [84]. These SNPs were replicated. The GWAS by Drake et al. [85], (Table 1) identified seven rare variants (with frequencies < 5 %) that contribute to variability in the BDR to SABA in Latino children with asthma across American and Puerto Rico with replication among Mexicans and Puerto Ricans. No common SNPs that had been reported in earlier studies (Table 1) were found to associate with BDR and two rare variants were identified in ADCY9 and CRHR2 -- genes that had been previously reported to alter BDR (Table 1). GWAS of diseases (including asthma) have uncovered numerous genes yet explain only a small fraction of disease heritability and that genome-wide sequencing may uncover rare variants that could explain missing genetic variance [86]. Although a number of variants have been identified and replicated that associate with BDR, only a small fraction of bronchodilator heritability has been accounted for. The studies of Drake et al. [85], and Ortega et al. [74], highlight the potential for identifying rare variants that could contribute to variability in BDR among asthmatics. Taken together the results of numerous studies over the past two decades clearly support the notion that genetic polymorphisms alter the BDR to inhaled b agonists in patients with asthma. The substantial heterogeneity in BDR, the fact that about a third of inter-patient variability in BDR is attributable to genetic variability, and the demonstration 6
that several pharmacogenomic studies indentify variants in candidate genes and in genes whose link to BDR is not clear support this conclusion. 7.
Summary and conclusion
Common and rare variants in several genes have been identified that associate with BDR and with bronchodilator-linked adverse events thereby supporting the notion that genetic polymorphisms alter patient response to inhaled bronchodilators. 8.
Expert opinion
Pharmacogenomic studies of BDR in patients with asthma are important because they help us understand the mechanisms that underlie variable BDR. Knowledge of the mechanisms that underlie BDR response will enhance our search for novel drug targets and novel agents to use in patients. Currently b agonists (SABA and LABA) and antimuscarinic agents are the only drugs that are available for use as bronchodilators (antimuscarinic drug are not approved by the FDA for asthma). The field of respiratory medicine needs novel bronchodilators not only for their efficacy to rapidly and safely relax bronchial smooth muscle but also for use to diagnose asthma and asthma phenotypes. Currently, a BDR of 12% is used to facilitate the diagnosis of asthma. We know that many patients with asthma maximally reverse at 8% or less and that genetic variation has been associated with a poor BDR. It is likely that future studies will include a systems biology approach which encompasses genomics in order to elucidate the mechanisms responsible for BDR heterogeneity.
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Do genetic polymorphisms alter patient response to inhaled bronchodilators?
Pharmacogenomic studies of BDR are also important because they may hold the key to the development of genetic biomarkers that will enable us to personalize bronchodilator therapy. Although we have identified a number of variants that contribute to bronchodilator heterogeneity, we can only account for a small fraction of BDR heritability. Wu and colleagues [87] developed a Combined Clinical and Pharmacogenetic Predictive Test that predicted poor BDR (20th percentile of BDR values for each population) in a primary and two replicate populations using eight SNPs. The accuracy of the test to predict poor BDR ranged between 0.6 and 0.65 (1.0 is perfect), which is barely fair, but more importantly, supports the idea that an accurate test to predict BDR (predictability ‡ 0.8) may be possible by increasing the number of SNPs or selecting SNPs with larger effect sizes. Those patients responding poorly to b agonists might benefit from using an antimuscarinic bronchodilator. Undoubtedly, investigators will continue to explore associations between the Gly16Arg (and other common ADRB2 SNPs) genotype with BDR or with adverse events related to LABA. Asthma worsening associated with LABA monotherapy or with continuous SABA use may be related to the Arg16 allele but is probably not relevant because LABA must be used with ICS and regular SABA use is not recommended. So genotyping the Gly16Arg SNP for the purpose of avoiding
b agonist-associated asthma worsening is not recommended. Serious adverse events associated with LABA/inhaled corticosteroid combination are rare and not related to common ADRB2 variants. However, exacerbations requiring hospitalization, intubation, life-threatening asthma attacks and deaths associated with LABA, while rare, may be related to rare ADRB2 variants (and/or rare variants in other genes) [74]. If the work by Ortega and colleagues [74] can be replicated by other investigators in different populations then it makes sense to develop a genetic biomarker that is informative with respect to those individuals who are at risk of LABA-associated severe adverse events. These individuals should then be treated by either increasing the dose of inhaled corticosteroid or by adding on an LTRA.
Declaration of interest This paper has been supported by funding from Nemours Biomedical Research and grants from the American Lung Association and National Institutes of Health. The author has no other relevant affiliations or financial involvement with any other organization or entity with a financial interest in or financial conflict with the subject matter of material discussed in the manuscript apart from those disclosed.
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Do genetic polymorphisms alter patient response to inhaled bronchodilators?
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Wechsler ME, Lehman E, Lazarus SC, et al. beta-Adrenergic receptor polymorphisms and response to salmeterol. Am J Respir Crit Care Med 2006;173:519-26 Lee DK, Currie GP, Hall IP, et al. The arginine-16 beta2-adrenoceptor polymorphism predisposes to bronchoprotective subsensitivity in patients treated with formoterol and salmeterol. Br J Clin Pharmacol 2004;57:68-75
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Predictive Test in asthma: proof of concept. Pharmacogenet Genomics 2010;20:86-93
Affiliation John J Lima Pharm D Center for Pharmacogenomics and Translational Research, Nemours Children’s Clinic, 807 Children’s Way, Jacksonville, FL 32207, USA, Tel: +1 904 697 3683; Fax: +1 904 687 7988; E-mail: [email protected]
Do genetic polymorphisms alter patient response to inhaled bronchodilators? 1.
Introduction
2.
Bronchodilator use in asthma
3.
Pharmacology of SABA and
John J Lima Center for Pharmacogenomics and Translational Research, Nemours Children’ s Clinic, Jacksonville, FL, USA
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LABA 4.
Bronchodilator heterogeneity
5.
Safety of bronchodilators
6.
Pharmacogenetic studies of SABA and LABA
7.
Summary and conclusion
8.
Expert opinion
Introduction: Short- and long-acting b agonists (SABA and LABA) are bronchodilators for treating asthma. Bronchodilator response (BDR) is quantified by measuring air expired in the first second during a forced expiratory maneuver, prior to and following inhalation of SABA. BDR has been associated with a significant degree of heterogeneity, in part attributable to genetic variation. Heritability, the proportion of phenotypic variability accounted for by genetic variation is estimated to account for 50% of pulmonary function and 28.5% for BDR. Areas covered: A MEDLINE search for English articles published from January 1990 to June 2014 was completed using the terms: bronchodilator, bronchodilator response, short-acting bronchodilator, long-acting bronchodilator, b2 adrenergic receptor gene (ADRB2), asthma and pharmacogenomics. The effects of ADRB2 variants on BDR and the safety of SABA and LABA + inhaled corticosteroids have been studied with equivocal results. Single and candidate gene studies have identified variants in other genes that alter response to bronchodilators. Associations were recently observed between hospital admission rates and two rare ADRB2 polymorphisms: Thr164Ile and a 25 base pair insertion-deletion at nucleotide -376. This was the first report of life-threatening events associated with LABA being linked to rare ADRB2 variants. Expert opinion: Pharmacogenomic studies over the last two decades clearly demonstrate that polymorphisms alter patient response to bronchodilators in patients with asthma. Keywords: adrenergic receptor, asthma, bronchodilator, drug, gene, heritability, heterogeneity, pharmacogenetic, polymorphisms, response Expert Opin. Drug Metab. Toxicol. [Early Online]
1.
Introduction
Bronchodilators are extensively used by patients with asthma, COPD or both. Most of the studies exploring the influence of genetic variation on patient response to bronchodilators have been performed in patients with asthma. Therefore, this review considers pharmacogenomic studies of asthma in order to address the question of whether genetic variation alters patient response to bronchodilators. This research topic is significant because of the importance of the clinical issues surrounding variable response including toxicity to inhaled bronchodilators. Asthma is a chronic, complex disease characterized by reversible airway obstruction, increased bronchial hyper-responsiveness and inflammation. Genome-wide studies have implicated several genes that associate with asthma signifying a substantial genetic component [1-6]. Recent studies have used cluster analyses to identify several distinct phenotypes suggesting that asthma is a markedly heterogeneous disease [7-12]. Gene--gene interactions, gene--environment [13] interactions and 10.1517/17425255.2014.939956 © 2014 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 All rights reserved: reproduction in whole or in part not permitted
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Article highlights. . . . .
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Bronchodilator response (BDR) is highly variable among patients with asthma. Heritability, the fraction of BDR attributable to genetic variation is 28.5%. Genetic associations between common b2 adrenergic receptor gene (ADRB2) SNPs and BDR are inconsistent. ADRB2 Arg16 alleles associate with asthma worsening in asthmatics receiving continuous short-acting b agonists and long-acting b agonists (LABA) monotherapy. Rare ADRB2 variants associate with serious adverse events associated with continuous LABA treatment. Candidate gene and genome-wide studies have identified common SNPs that associate with BDR in different ethnic and racial populations with asthma. Genome-wide association studies have identified rare SNPs in several genes that associate with BDR in patients with asthma. Genetic polymorphisms alter response to inhaled bronchodilators in patients with asthma.
This box summarizes key points contained in the article.
epigenetics are thought to contribute to asthma heterogeneity. Asthma imposes a significant worldwide burden comparable to that of diabetes mellitus or cirrhosis [14]. It affects 300 million individuals worldwide and is responsible for 180 thousand deaths and 15 million disability-adjusted life-years lost each year [15]. In 2011, CDC reported that asthma affects 1 in 12 Americans; its prevalence among children is 9.6% making asthma the most common chronic disease of childhood; and that 1 in 6 African Americans have asthma, which represents an increased prevalence of 50% since 2001. 2.
than SABA or LABA in patients with asthma. Methylxanthines, a third class of bronchodilators, are used little as bronchodilators in asthma owing to toxicity and the need for therapeutic drug monitoring. Consequently, this review will cover SABA and LABA pharmacogenomic studies in asthma in an effort to answer the question posed in this review: Do genetic polymorphisms alter patient response to inhaled bronchodilators? 3.
SABA and LABA relax bronchial smooth muscle by binding to and activating b2 adrenergic receptors (b2AR) expressed on the surface of airway smooth muscle. b2ARs are G-protein-coupled receptors, which can exist in an active (R*) form or inactive (R) form. Agonist ligands can be classified as partial or full agonists depending on the fraction b2ARs that they stabilize in their R* forms, which are coupled to Gs and stimulate adenylyl cyclase to form cAMP, the second messenger. cAMP stimulates protein kinase A (PKA) leading to phosphorylation of downstream proteins, inhibition of phosphoinositol hydrolysis, a reduction in intracellular Ca2 concentrations, and activation of large conductance K+ channels, which relaxes airway smooth muscle [17]. Full agonists have higher intrinsic efficacies than partial agonists, meaning that full b agonists stimulate more cAMP than partial agonists at equivalent receptor occupancies. Continuous stimulation of b2ARs results in receptor uncoupling from Gsa, receptor desensitization and agonist-promoted downregulation (i.e., loss of receptor number or density) [18]. In addition to being phosphorylated by PKA b2ARs can be phosphorylated by G-protein receptor kinases (GRK), which can also result in uncoupling of agonist-occupied b2ARs.
Bronchodilator use in asthma 4.
Several drugs and drug classes are available to treat asthma symptoms in a step-wise fashion [16]. Inhaled bronchodilators are the most highly used asthma drug class and play a significant role in relieving and controlling asthma symptoms. Two classes of inhaled bronchodilators are used in asthma: b2 agonists and antimuscarinic agents. b2 agonists are classified according to their pharmacokinetic half-lives and duration of action as short-acting b agonists (SABA) or as long-acting b agonists (LABA). Inhaled SABAs are used by all patients virtually with asthma to provide quick relief of bronchoconstriction. SABA monotherapy is used in patients with mild, intermittent asthma (Step 1). Inhaled corticosteroids (ICS) are preferred in mild, persistent asthma along with SABA for rescue (Step 2); followed by the addition LABA or leukotriene receptor antagonist (LTRA) if asthma symptoms are poorly controlled (Step 3). High-dose ICS or additional add-on therapy (Step 4) and oral steroids (Step 5) are recommended for better control if necessary. Inhaled antimuscarinic agents are classified as short-acting antimuscarinic or as long-acting antimuscarinic agents and are used to a much lesser extent 2
Pharmacology of SABA and LABA
Bronchodilator heterogeneity
The bronchodilator response (BDR) (aka reversibility) is quantified by measuring the amount of air expired in the first second during a forced expiratory maneuver, just prior to and after inhalation of two or occasionally four puffs of SABA, generally albuterol. The resulting values of FEV1 are converted to per cent predicted FEV1 (FEV1% pred) [19], and BDR is often expressed as a percent by: (1)
(FEV1% pred post − FEV1% pred pre )
(FEV1% pred ) pre
× 100
where the terms pre and post refer to pre- and postbronchodilator inhalation. In general, a 12% or higher BDR is commonly used to aid in the diagnosis of asthma, although the validity of that value has been questioned, at least in children [20]. BDR has been associated with a significant degree of variability. Figure 1 shows that ~ 50% of patients who participated in three large clinical trials of asthma had BDR values ‡ 12%, 25 -- 30% had BDRs £ 5%, and a small
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Do genetic polymorphisms alter patient response to inhaled bronchodilators?
Bronchodilator response distribution in ACRN, CARE and CAMP 30 ACRN CAMP CARE
25
Subjects (%)
15
10
5
35 to 40
Greater than 40
Bronchodilator response (%)
30 to 35
25 to 30
20 to 25
15 to 20
10 to 15
5 to 10
0 to 5
-5 to 0
-10 to -5
0 Less than-10
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20
Figure 1. Distribution of the bronchodilator response across three major asthma networks in SHARP. Despite highly varying enrollment criteria, the overall distribution of response is remarkably similar between the clinical trial networks. Reproduced with permission from [20]. ACRN: Asthma Clinical Research Network; CAMP: Children Asthma Management Program; CARE: Childhood Asthma Research and Education; SHARP: SNP Health Association Resources (SHARe) Asthma Resource project.
percentage of patients had negative BDR. BDR heterogeneity is attributable to several factors including asthma severity, poor medication adherence, non-responsive phenotypes, environmental exposure, drug interactions with ICS and genetic variation. Heritability, defined as the proportion of phenotypic variability that is accounted for by genetic variation has been estimated to be 70 -- 90% for asthma [21] and ~ 50% for pulmonary function [22]. The heritability of BDR to SABA is 28.5% [23]; however, we can account for only a small fraction of the heritability of the BDR. 5.
Safety of bronchodilators
The safety of bronchodilators in the treatment of asthma is relevant to this review because it is possible that genetic variation contributes to adverse events associated with bronchodilator use thereby altering patient response to this class of drugs. In the mid-fifties and early sixties Metered Dose Inhalers (MDI) containing the non-selective, full agonists epinephrine and isoproterenol were introduced and the popularity of bronchodilator inhaler treatment increased dramatically. Coincident with the increased sales of inhaled isoproterenol was an increase in asthma deaths in the UK -the so called ‘epidemic’ of asthma deaths, which reversed
following withdrawal from the market [24]. At about the same time, the b2 selective, partial agonist salbutamol (albuterol in the USA) MDI was introduced. A second ‘epidemic’ of asthma deaths was witnessed in New Zealand between 1976 and 1989, which was coincident with the introduction of fenoterol, a b2 selective, full agonist with a subsequent decline following removal of fenoterol from the market [25]. The safety of continuously inhaled albuterol (b2 selective partial agonist) use was established in the b agonist study (BAGS), but continuous use had no additional benefit over as-needed use [26], thus establishing SABA for rescue use only. It should be noted that increased use of both inhaled fenoterol and albuterol were associated with the risk of death or near death in a matched case-control study [27,28]. The first LABA, salmeterol was introduced into practice in the late 1980s and continues as a standard of therapy so long as it is administered with ICS. LABA monotherapy is associated with asthma worsening [29-38], which includes one or more of the following: decreases in morning and evening peak flow rates, decreased scores on symptom questionnaires, increased use of rescue SABA inhalation, requirement of short courses of oral steroids, decreases in lung function including BDR and increased airway hyper-responsiveness. LABA-associated serious adverse events include exacerbations
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J. J. Lima
requiring hospitalization, intubation, life-threatening asthma attacks and death. The Salmeterol Multi-centre Asthma Research Trial reported a rare, but significant increase in respiratory- or asthma- related deaths in individuals particularly African Americans taking salmeterol compared with placebo [39], which led to an FDA black-box warning regarding the use of LABA in asthma [40]. Consequently, the FDA recommended that LABAs not be used as monotherapy but should be combined with ICS [41,42]. A review of many studies concluded that LABA monotherapy worsens asthma symptoms, increases the risk of serious LABA-associated adverse events (hospitalizations, intubations, ER visits and death) and that concomitant use of ICS or the use of ICS + LABA in a single inhaler reduces these risks and is not associated with asthma-related deaths [43]. Recent reviews support the idea that compared to ICS alone the combination of ICS + LABA decreases risk of severe exacerbations [44] and are safe [45]. However, a recent meta-analysis reported that ICA + LABA increases catastrophic events by over threefold compared to ICS alone, and concluded that LABA increases the risk of asthma-related intubations and deaths, even when used in a controlled fashion with concomitant ICS [46]. In a thoughtful, expert review of LABA safety, Sears concluded that in patients taking ICS + LABA under-treatment with ICS may mask LABA-induced inflammation, which will lead to increased asthma worsening and mortality, and that withdrawal of LABA can result in loss of symptom control [47]. This is because LABA can mask worsening inflammation as a consequence of steroid reduction or withdrawal, although a direct adverse effect of LABA cannot be ruled out [30,47].
Pharmacogenetic studies of SABA and LABA 6.
ADRb2 gene Identifying genetic variants that predict beneficial and adverse events associated with the use of bronchodilators would aid in our understanding of the mechanisms underlying these associations and would enable us to personalize bronchodilator therapy in asthma and thus avoid adverse events in susceptible patients. Given the central role of b2ARs in regulating bronchodilator tone in patients with asthma, it is not surprising that initial efforts at identifying genetic variants that associate with response to SABA and LABA began with the b2 adrenergic receptor gene (ADRB2). The ADRB2 is a small, intronless gene, which has been resequenced in multiple ethnic populations to determine polymorphic variability and haplotype structure [48]. Of 80 polymorphisms identified, 45 SNPs and two insertion/deletion polymorphisms have been validated. Two common nonsynonomous variants at amino acid positions 16 (Gly16Arg) and 27 (Gln27Glu) have functional relevance in vitro [49,50]. Cells, including airway smooth muscle cells expressing the Gly16 allele were significantly more sensitive to agonist-promoted receptor down-regulation compared to the Arg16 allele. The Ile allele for an uncommon, nonsynonomous SNP at position 164 (Thr164Ile) 6.1
4
reduced agonist binding to the b2 AR and coupling to adenylyl cyclase [51]. Initial studies exploring associations between BDR to SABA and the Gly16Arg polymorphism in outpatients found Arg16 homozygotes had a greater BDR than Gly16 homozygotes [52-54], which were consistent in vitro studies [51]. Subsequent studies however, found opposite results or no association [48,55-59]. Interestingly, when the BAGS trial, which studied the safety of continuously inhaled albuterol [26] was analyzed by genotype, Arg16 homozygotes had worse asthma control on regularly scheduled albuterol compared to Gly16 homozygotes on regularly scheduled albuterol and to Arg16 homozygotes treated as-needed with albuterol [60]. The results of two additional retrospective trials were consistent with the BAGS trial [61,62], and the carefully designed prospective trial by Israel et al. of patients with mild asthma not taking controller medication found that morning peak flow rates in Arg16 homozygotes were lower than Gly16 homozygotes treated with regularly scheduled albuterol [60]. Taken together the results of these studies of continuous or regularly-scheduled SABA were encouraging because they supported the idea that bronchodilator therapy in patients with asthma could be personalized using Arg16Gly genotype as a genetic biomarker. An important question to answer is: do polymorphisms in the ADRB2 associate with asthma worsening and asthma deaths in patients with asthma taking LABA or, more relevantly, taking LABA + ICS? Two studies reported that compared to the Gly16 allele the Arg16 allele was associated with an impaired response to salmeterol in the absence or presence of inhaled corticosteroid [63] or with bronchoprotective subsensitivity to salmeterol or formoterol [64]. However, Bleecker et al. found no evidence of a pharmacogenetic effect in patients with asthma participating in two large retrospective clinical trials of LABA with or without ICS [65,66]. Similar findings were reported in a randomized, double-blind, placebo-controlled trial of LABA with ICS in patients with moderate asthma leading the authors to conclude that patients should continue to be treated with ICS + LABA irrespective of Gly16Arg genotype [67]. The Gly16Arg SNP was not associated with loss of in response to salmeterol [68]. Other ADRB2 variants also failed to associate with BDR to ICS + LABA [69]. Most pharmacogenetic studies of bronchodilators have been performed in adults. It is important to explore the pharmacogenetics of bronchodilators in children with asthma because they may be at greater risk of asthma exacerbations from LABA treatment alone or with ICS [33] and the efficacy of LABA as add-on to ICS has been questioned [70,71]. Moreover, since 2000, children with asthma are rapidly being switched from ICS monotherapy to ICS + LABA. [34]. Two studies have explored associations between ADRB2 SNPs and LABA-associated adverse events in children. Palmer et al. studied 546 children and young adults taking LABA (mean age 10.2 years old) and reported that the Arg16 genotype
Expert Opin. Drug Metab. Toxicol. (2014) 10(9)
Do genetic polymorphisms alter patient response to inhaled bronchodilators?
A.
Participants admitted to hospital in past year (%)
90
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B.
Non-hispanic white patients
90
Thr164Ile
n=6
Rare genotype (CT) Common genotype (CC)
80 70
OR 4.48 (95% CI 1.40 – 13.96) p = 0.01
Rare insertion Common genotype
70
OR 13.43 (95% CI 2.02 – 265.42) p = 0.006
60 50
n = 13
40
40
30
30
20
-376 In-Del
80
60 50
African-American patients
20
n = 384 n = 10
10
n = 179
n = 218
n=5
10
0
n = 119
0 LABA treatment
No LABA treatment
LABA treatment
No LABA treatment
Figure 2. Association between rare ADRB2 variants and hospital admissions for a severe asthma exacerbation in patients taking LABA. Dark bars show the percentage of patients with the Thr164Ile or with the -376 In-Del variant; light bars show the percentage in those without these rare variants. Thr164Ile was the only variant identified in non-Hispanic White patients and a 25-base pair promoter insertion deletion (-376 In-Del) was identified in African American but not in non-Hispanic White patients. Reproduced with permission from [74]. ADRB2: b2 adrenergic receptor gene; LABA: Long-acting b agonists.
predisposed children taking LABA to increased risk of asthma exacerbations even with ICS [72]. A more recent study reported that compared to Gly16 homozygotes Arg16 homozygotes taking ICS + LABA had an increased risk of exacerbations and oral corticosteroid use in the PACMAN cohort study (children 4 -- 12 year old) [73]. These studies support the idea that knowledge of the Arg16Gly genotype may predict asthma exacerbations in children taking LABA + ICS. More studies are warranted in children to replicate these studies. The frequency of the Gly16Arg SNP is common among different ethnic groups making it highly unlikely to account for rare, life-threatening events associated with LABA use, and which resulted in the boxed warning from the FDA. Oretga and colleagues [74] hypothesized that rare (< 5%) ADRB2 variants are associated with increased hospital admissions for asthma exacerbations in patients receiving LABA and ICS. These investigators sequenced a 5356 base pair (bp) region of the ADRB2 beginning at -3270 bp 5’ of the ATG start site to + 1886 bp after the ATG start site including the 1239 bp coding region in 461 non-Hispanic White, African American and Puerto Rican patients with asthma including many with severe asthma. Six rare variants were identified and genotyped in a primary cohort of 1165 patients with asthma; 659-nonHispanic White patients with asthma comprised the replicate cohort. Associations were observed between hospital admission rates and two ADRB2 polymorphisms: Thr164Ile (minor allele
frequencies: 0.02, 0.006 and 0.007 in non-Hispanic White, African American and Puerto Rican patients, respectively) and 25 bp insertion-deletion at nucleotide -376 relative to the ATG start site (Figure 2). The genetic effects of the Thr164Ile variant on symptom control were replicated. This study is the first to report that rare, potentially life-threatening events associated with LABA (in the presence of ICS)----those for which the FDA requires a box warning----is linked to rare ADRB2 variants. These findings require further replication in large multiethnic asthma populations and, as the authors point out, if replicated, these genetic variants could serve as important predictive biomarkers for these rare, serious side effects [74]. Two studies report a gene-gene interaction between variants on ADRB2-GSNOR could alter the BDR to SABA [75,76]. S-nitrosoglutathione (GSNO) is an endogenous brochodilator formed from interactions involving nitric oxide and glutathione that can regulate the activity of GRK2, which can phosphorylate and uncouple B2AR. GSNO reductase (GSNOR) metabolizes GSNO and variants that affect the activity of GSNOR can alter BDR [76]. Other genes In addition to ADRB2 polymorphisms, variants in other genes have been identified that alter BDR to SABA and these are summarized in Table 1. Single and candidate gene studies have identified variants on adenylyl cyclase (ADCY9) [77], 6.2
Expert Opin. Drug Metab. Toxicol. (2014) 10(9)
5
J. J. Lima
Table 1. Summary of association studies between genetic variants and bronchodilator response to short-acting b agonists and long-acting b agonists.
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SNP
Gene
Replication
Genetic study
Ethnicity or race
Ref.
rs2230739 rs7793837 rs2781659 Haplotypes rs295137 rs892940 Gene based
ADCY9 CRHR2 ARG1 ARG1 SPATS2L THRB SPATA13-AS1
No Yes Yes Not applicable Yes Yes Yes
Single Single Candidate Single GWAS Candidate GWAS
[77] [78] [79] [80] [82] [81] [83]
GWAS
Caucasian Caucasian Caucasian Caucasian Non-Hispanic White Non-Hispanic White African- and EuropeanAmericans Caucasian
rs11252394 rs6988229 rs8191725 rs77441273 rs77977790 rs77149876 rs115501901 rs116551936 rs74973995
Intergenic COL22A1 IGF2R SLC24A4 PAPPA2 SPON1 NCOA3 Intergenic Intergenic
Yes Yes Yes Yes Yes No No No No
GWAS*
Latino
[85]
[84]
*All SNPs were rare (allele frequencies < 5%). GWAS: Genome-wide association study.
corticotrophin hormone receptor 2 (CRHR2) [78], arginase 1 (ARG1) [79,80] and thyroid hormone receptor b 1 (THRB) [81] that associate with BDR. Genome-Wide Association Study (GWAS) identified common SNPs on Spermatogenesis Associated, Serine-Rich 2-Like (SPATS2L) [82], SPATA13-AS1 (an antisense RNA that overlaps SPATA13, also known as ASEF2) [83] and Collagen, Type XXII, a 1 (COL22A1) [84]. These SNPs were replicated. The GWAS by Drake et al. [85], (Table 1) identified seven rare variants (with frequencies < 5 %) that contribute to variability in the BDR to SABA in Latino children with asthma across American and Puerto Rico with replication among Mexicans and Puerto Ricans. No common SNPs that had been reported in earlier studies (Table 1) were found to associate with BDR and two rare variants were identified in ADCY9 and CRHR2 -- genes that had been previously reported to alter BDR (Table 1). GWAS of diseases (including asthma) have uncovered numerous genes yet explain only a small fraction of disease heritability and that genome-wide sequencing may uncover rare variants that could explain missing genetic variance [86]. Although a number of variants have been identified and replicated that associate with BDR, only a small fraction of bronchodilator heritability has been accounted for. The studies of Drake et al. [85], and Ortega et al. [74], highlight the potential for identifying rare variants that could contribute to variability in BDR among asthmatics. Taken together the results of numerous studies over the past two decades clearly support the notion that genetic polymorphisms alter the BDR to inhaled b agonists in patients with asthma. The substantial heterogeneity in BDR, the fact that about a third of inter-patient variability in BDR is attributable to genetic variability, and the demonstration 6
that several pharmacogenomic studies indentify variants in candidate genes and in genes whose link to BDR is not clear support this conclusion. 7.
Summary and conclusion
Common and rare variants in several genes have been identified that associate with BDR and with bronchodilator-linked adverse events thereby supporting the notion that genetic polymorphisms alter patient response to inhaled bronchodilators. 8.
Expert opinion
Pharmacogenomic studies of BDR in patients with asthma are important because they help us understand the mechanisms that underlie variable BDR. Knowledge of the mechanisms that underlie BDR response will enhance our search for novel drug targets and novel agents to use in patients. Currently b agonists (SABA and LABA) and antimuscarinic agents are the only drugs that are available for use as bronchodilators (antimuscarinic drug are not approved by the FDA for asthma). The field of respiratory medicine needs novel bronchodilators not only for their efficacy to rapidly and safely relax bronchial smooth muscle but also for use to diagnose asthma and asthma phenotypes. Currently, a BDR of 12% is used to facilitate the diagnosis of asthma. We know that many patients with asthma maximally reverse at 8% or less and that genetic variation has been associated with a poor BDR. It is likely that future studies will include a systems biology approach which encompasses genomics in order to elucidate the mechanisms responsible for BDR heterogeneity.
Expert Opin. Drug Metab. Toxicol. (2014) 10(9)
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Do genetic polymorphisms alter patient response to inhaled bronchodilators?
Pharmacogenomic studies of BDR are also important because they may hold the key to the development of genetic biomarkers that will enable us to personalize bronchodilator therapy. Although we have identified a number of variants that contribute to bronchodilator heterogeneity, we can only account for a small fraction of BDR heritability. Wu and colleagues [87] developed a Combined Clinical and Pharmacogenetic Predictive Test that predicted poor BDR (20th percentile of BDR values for each population) in a primary and two replicate populations using eight SNPs. The accuracy of the test to predict poor BDR ranged between 0.6 and 0.65 (1.0 is perfect), which is barely fair, but more importantly, supports the idea that an accurate test to predict BDR (predictability ‡ 0.8) may be possible by increasing the number of SNPs or selecting SNPs with larger effect sizes. Those patients responding poorly to b agonists might benefit from using an antimuscarinic bronchodilator. Undoubtedly, investigators will continue to explore associations between the Gly16Arg (and other common ADRB2 SNPs) genotype with BDR or with adverse events related to LABA. Asthma worsening associated with LABA monotherapy or with continuous SABA use may be related to the Arg16 allele but is probably not relevant because LABA must be used with ICS and regular SABA use is not recommended. So genotyping the Gly16Arg SNP for the purpose of avoiding
b agonist-associated asthma worsening is not recommended. Serious adverse events associated with LABA/inhaled corticosteroid combination are rare and not related to common ADRB2 variants. However, exacerbations requiring hospitalization, intubation, life-threatening asthma attacks and deaths associated with LABA, while rare, may be related to rare ADRB2 variants (and/or rare variants in other genes) [74]. If the work by Ortega and colleagues [74] can be replicated by other investigators in different populations then it makes sense to develop a genetic biomarker that is informative with respect to those individuals who are at risk of LABA-associated severe adverse events. These individuals should then be treated by either increasing the dose of inhaled corticosteroid or by adding on an LTRA.
Declaration of interest This paper has been supported by funding from Nemours Biomedical Research and grants from the American Lung Association and National Institutes of Health. The author has no other relevant affiliations or financial involvement with any other organization or entity with a financial interest in or financial conflict with the subject matter of material discussed in the manuscript apart from those disclosed.
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Affiliation John J Lima Pharm D Center for Pharmacogenomics and Translational Research, Nemours Children’s Clinic, 807 Children’s Way, Jacksonville, FL 32207, USA, Tel: +1 904 697 3683; Fax: +1 904 687 7988; E-mail: [email protected]
