Purpose of Review
Several genome-wide association studies (GWASs) of bronchodilator response (BDR) to albuterol have been published over the past decade. This review describes current knowledge gaps, including pharmacogenetic studies of albuterol response in minority populations, effect modification of pharmacogenetic associations by age, and relevance of BDR phenotype characterization to pharmacogenetic findings. New approaches, such as leveraging additional “omics” data to focus pharmacogenetic interrogation, as well as developing polygenic risk scores in asthma treatment responses, are also discussed.
Recent pharmacogenetic studies of albuterol response in minority populations have identified genetic polymorphisms in loci (DNAH5, NFKB1, PLCB1, ADAMTS3, COX18, and PRKG1), that are associated with BDR. Additional studies are needed to replicate these findings. Modification of the pharmacogenetic associations for SPATS2L and ASB3 polymorphisms by age has also been published. Evidence from metabolomic and epigenomic studies of BDR may point to new pharmacogenetic targets. Lastly, a polygenic risk score for response to albuterol has been developed but requires validation in additional cohorts.
In order to expand our knowledge of pharmacogenetics of BDR, additional studies in minority populations are needed. Consideration of effect modification by age and leverage of other “omics” data beyond genomics may also help uncover novel pharmacogenetic loci for use in precision medicine for asthma treatment.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price excludes VAT (USA)
Tax calculation will be finalised during checkout.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
GBD 2015 Chronic Respiratory Disease Collaborators. Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Respir Med. 2017.
Martinez FD, Vercelli D. Asthma Lancet. 2013;382(9901):1360–72.
Billington CK, Penn RB, Hall IP. β2 Agonists. Handb Exp Pharmacol. 2017;237:23–40.
• Beasley R, Braithwaite I, Semprini A, Kearns C, Weatherall M, Pavord ID. Optimal asthma control: time for a new target. Am J Respir Crit Care Med. 2020;201(12):1480–7. This review discusses the current limitations of pharmacological treatment of adult asthma, and proposes the development of practical methods to identify treatable traits contributing to respiratory symptoms in asthma.
McGeachie MJ, Stahl EA, Himes BE, Pendergrass SA, Lima JJ, Irvin CG, et al. Polygenic heritability estimates in pharmacogenetics: focus on asthma and related phenotypes. Pharmacogenet Genomics. 2013;23(6):324–8.
Nieminen MM, Kaprio J, Koskenvuo M. A population-based study of bronchial asthma in adult twin pairs. Chest. 1991;100(1):70–5.
Fagnani C, Annesi-Maesano I, Brescianini S, D’Ippolito C, Medda E, Nisticò L, et al. Heritability and shared genetic effects of asthma and hay fever: an Italian study of young twins. Twin Res Hum Genet. 2008;11(2):121–31.
Wu AC, Tantisira K, Li L, Schuemann B, Weiss S. Childhood asthma management program research group. Repeatability of response to asthma medications. J Allergy Clin Immunol. 2009;123(2):385–90.
Daya M, Ortega VE. Asthma genomics and pharmacogenomics. Curr Opin Immunol. 2020;66:136–42.
Figueiredo RG, Costa RS, Figueiredo CA, Cruz AA. Genetic determinants of poor response to treatment in severe asthma. Int J Mol Sci. 2021;22(8):4251.
Vijverberg SJH, Farzan N, Slob EMA, Neerincx AH and Maitland-van der Zee AH. Treatment response heterogeneity in asthma: the role of genetic variation. EXPERT REVIEW OF RESPIRATORY MEDICINE, 2018; 12 (1) 55–65
García-Menaya JM, Cordobés-Durán C, García-Martín E, Agúndez JAG. Pharmacogenetic factors affecting asthma treatment response. potential implications for drug therapy. Front Pharmacol. 2019;10:520.
Perez-Garcia J, Espuela-Ortiz A, Lorenzo-Diaz F, Pino-Yanes M. Pharmacogenetics of pediatric asthma: current perspectives. Pharmgenomics Pers Med. 2020;13:89–103.
Naqvi M, Thyne S, Choudhry S, Tsai H, Navarro D, Castro RA, et al. Ethnic-specific differences in bronchodilator responsiveness among African Americans, Puerto Ricans, and Mexicans with asthma. J Asthma. 2007;44(8):639–48.
Burchard EG, Avila PC, Nazario S, Casal J, Torres A, Rodriguez-Santana JR, et al. Lower bronchodilator responsiveness in Puerto Rican than in Mexican subjects with asthma. Am J Respir Crit Care Med. 2004;169(3):386–92.
• Spear ML, Hu D, Pino-Yanes M, Huntsman S, Eng C, Levin AM, et al. A genome-wide association and admixture mapping study of bronchodilator drug response in African Americans with asthma. Pharmacogenomics J. 2019;19(3):249-59. GWAS study of bronchodilator response in minority populations (Latinos and African Americans) indicates that both population-specific and shared genetic variation contribute to differences in BDR phenotypes.
Finkelstein Y, Bournissen FG, Hutson JR, Shannon M. Polymorphism of the ADRB2 gene and response to inhaled beta-agonists in children with asthma: a meta-analysis. J Asthma. 2009;46(9):900–5.
• Mak ACY, White MJ, Eckalbar WL, Szpiech ZA, Oh SS, Pino-Yanes M, et al. Whole-genome sequencing of pharmacogenetic drug response in racially diverse children with asthma. Am J Respir Crit Care Med. 2018 15;197(12):1552–64. The first whole-genome sequencing pharmacogenetics study of children with asthma. The study focused on racially diverse children and used "responder" and "non-responder" status from the tails of the bronchodilator response distribution as the phenotype of interest.
• Jerome RN, Pulley JM, Sathe NA, Krishnaswami S, Dickerson AB, Worley KJ, et al. Uncovering Outcome Disparities of β2 Adrenergic Agonists in Blacks: A Systematic Review. J Natl Med Assoc. 2021;113(1):8-29. Systematic review of studies on β2 agonist response among Blacks, including pharmacogenetics studies.
Global Strategy for Asthma Management and Prevention. 2019. Date last accessed: 2 August 2021.
Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, et al. Interpretative strategies for lung function tests. Eur Respir J. 2005;26(5):948–68.
National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Summary Report 2007. J Allergy Clin Immunol. 2007;120(5 Suppl):S94-138.
Guezguez F, Ben SH. What constitutes a “clinically significant” bronchodilator response in children? Eur Respir J. 2020;55(5):2000207.
Waalkens HJ, Merkus PJ, van Essen-Zandvliet EE, Brand PL, Gerritsen J, Duiverman EJ, e al. Assessment of bronchodilator response in children with asthma. Dutch CNSLD Study Group. Eur Resp J. 1993;6(5):645-51.
• Ferreira MA, Mathur R, Vonk JM, Szwajda A, Brumpton B, Granell R, et al. Genetic architectures of childhood-and adult-onset asthma are partly distinct. The Am J Hum Genet. 2019;104(4):665-84. This study examined the extent to which genetic risk factors are shared between childhood-onset (COA) and adult-onset (AOA) asthma. Distinct loci for COA vs. AOA may be useful for differentiating pathophysiology and enhancing precision in treatments for asthma by age of onset.
Dunn RM, Lehman E, Chinchilli VM, Martin RJ, Boushey HA, Israel E, et al. Impact of age and sex on response to asthma therapy. Am J Respir Crit Care Med. 2015;192(5):551–8.
Gubbels Bupp MR, Potluri T, Fink AL, Klein SL. The confluence of sex hormones and aging on immunity. Front Immunol. 2018;9:1269.
van den Beld AW, Kaufman J-M, Zillikens MC, Lamberts SWJ, Egan JM, van der Lely AJ. The physiology of endocrine systems with ageing. Lancet Diabetes Endocrinol. 2018;6(8):647–58.
Litonjua AA, Lasky-Su J, Schneiter K, Tantisira KG, Lazarus R, Klanderman B, et al. ARG1 is a novel bronchodilator response gene: screening and replication in four asthma cohorts. Am J Respir Crit Care Med. 2008;178(7):688–94.
Lipworth BJ, Basu K, Donald HP, Tavendale R, Macgregor DF, Ogston SA, et al. Tailored second-line therapy in asthmatic children with the Arg(16) genotype. Clin Sci (Lond). 2013;124(8):521–8.
Palmer LJ, Celedón JC, Chapman HA, Speizer FE, Weiss ST, Silverman EK. Genome-wide linkage analysis of bronchodilator responsiveness and post-bronchodilator spirometric phenotypes in chronic obstructive pulmonary disease. Hum Mol Genet. 2003;12(10):1199–210.
Zuurhout MJL, Vijverberg SJH, Raaijmakers JAM, Koenderman L, Postma DS, Koppelman GH, et al. Arg16 ADRB2 genotype increases the risk of asthma exacerbation in children with a reported use of long-acting β2-agonists: results of the PACMAN cohort. Pharmacogenomics. 2013;14(16):1965–71.
Wechsler ME, Kunselman SJ, Chinchilli VM, Bleecker E, Boushey HA, Calhoun WJ, et al. Effect of beta2-adrenergic receptor polymorphism on response to long-acting beta2 agonist in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial. Lancet. 2009;374(9703):1754–64.
Dahlin A, Sordillo JE, McGeachie M, Kelly RS, Tantisira KG, Lutz SM, et al. Genome-wide interaction study reveals age-dependent determinants of responsiveness to inhaled corticosteroids in individuals with asthma. PLoS One. 2020;15(3):e0229241.
Kelly RS, Sordillo JE, Lutz SM, Avila L, Soto-Quiros M, Celedón JC, et al. Pharmacometabolomics of bronchodilator response in asthma and the role of age-metabolite interactions. Metabolites. 2019;9(9):E179.
Sordillo JE, Lutz SM, Kelly RS, McGeachie MJ, Dahlin A, Tantisira K, et al. Plasmalogens mediate the effect of age on bronchodilator response in individuals with asthma. Front Med (Lausanne). 2020;7:38.
Voorhies K, Sordillo JE, McGeachie M, Ampleford E, Wang AL, Lasky-Su J, et al. Age by single nucleotide polymorphism interactions on bronchodilator response in asthmatics. J Pers Med. 2021;11(1):59.
Sordillo JE, McGeachie M, Lutz SM, Lasky-Su J, Tantisira K, Tsai CH, et al. Longitudinal analysis of bronchodilator response in asthmatics and effect modification of age-related trends by genotype. Pediatr Pulmonol. 2019;54(2):158–64.
Gaugg MT, Engler A, Nussbaumer-Ochsner Y, Bregy L, Stöberl AS, Gaisl T, et al. Metabolic effects of inhaled salbutamol determined by exhaled breath analysis. J Breath Res. 2017;11(4):046004.
Nowadly CD, Liao S-Y, Rose JS. Effects of continuous albuterol inhalation on serum metabolome in healthy subjects: more than just lactic acid. J Clin Pharmacol. 2021;61(5):649–55.
Cascorbi I, Schwab M. Epigenetics in drug response. Clin Pharmacol Ther. 2016;99(5):468–70.
Olivier M, Asmis R, Hawkins GA, Howard TD, Cox LA. The need for multi-omics biomarker signatures in precision medicine. Int J Mol Sci. 2019;20(19):E4781.
Cardenas A, Sordillo JE, Rifas-Shiman SL, Chung W, Liang L, Coull BA, et al. The nasal methylome as a biomarker of asthma and airway inflammation in children. Nat Commun. 2019 12;10(1):3095.
Moll M, Sakornsakolpat P, Shrine N, Hobbs BD, DeMeo DL, John C, et al. Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts. Lancet Respir Med. 2020;8(7):696–708.
Li JH, Szczerbinski L, Dawed AY, Kaur V, Todd JN, Pearson ER, et al. A polygenic score for type 2 diabetes risk is associated with both the acute and sustained response to sulfonylureas. Diabetes. 2021;70(1):293–300.
Lewis JP, Backman JD, Reny J-L, Bergmeijer TO, Mitchell BD, Ritchie MD, et al. Pharmacogenomic polygenic response score predicts ischaemic events and cardiovascular mortality in clopidogrel-treated patients. Eur Heart J Cardiovasc Pharmacother. 2020;6(4):203–10.
Chasman DI, Giulianini F, Demler OV, Udler MS. Pleiotropy-based decomposition of genetic risk scores: association and interaction analysis for type 2 diabetes and CAD. Am J Hum Genet. 2020;106(5):646–58.
Sordillo JE, Lutz SM, McGeachie MJ, Lasky-Su J, Weiss ST, Celedón JC, et al. Pharmacogenetic polygenic risk score for bronchodilator response in children and adolescents with asthma: proof-of-concept. J Pers Med. 2021;11(4):319.
This work was funded by National Institutes of Health (NIH) grants: R01HD085993 and K01HL125858.
Conflict of Interest
Joanne Sordillo, Sharon Lutz, Jessica Lasky-Su, and Rachel Kelly declare that they have no conflict of interest. Ann Chen Wu reports grants from GlaxoSmithKline, outside the submitted work.
Human and Animal Rights and Informed Consent
All reported studies/experiments with human subjects mentioned in this review that were performed by the authors were performed in accordance with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This article is part of the Topical Collection on Asthma
Rights and permissions
About this article
Cite this article
Sordillo, J.E., Kelly, R.S., Lutz, S.M. et al. Pharmacogenetics of Bronchodilator Response: Future Directions. Curr Allergy Asthma Rep 21, 47 (2021). https://doi.org/10.1007/s11882-021-01023-w
- Bronchodilator response
- Polygenic risk score
- Effect modification by age