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Asthma pharmacogenetics

Elin T G Kersten, Gerard H Koppelman
PURPOSE OF REVIEW: Although currently available drugs to treat asthma are effective in most patients, a proportion of patients do not respond or experience side-effects; which is partly genetically determined. Pharmacogenetics is the study of how genetic variations influence drug response. In this review, we summarize prior results and recent studies in pharmacogenetics to determine if we can use genetic profiles for personalized treatment of asthma. RECENT FINDINGS: The field of pharmacogenetics has moved from candidate gene studies in single populations toward genome-wide association studies and meta-analysis of multiple studies...
October 18, 2016: Current Opinion in Pulmonary Medicine
Amber Dahlin, Scott T Weiss
Aspirin-exacerbated respiratory disease (AERD) severity and its clinical phenotypes are characterized by genetic variation within pathways for arachidonic acid metabolism, inflammation, and immune responses. Epigenetic effects, including DNA methylation and histone protein modification, contribute to regulation of many genes that contribute to inflammatory states in AERD. The development of noninvasive, predictive clinical tests using data from genetic, epigenetic, pharmacogenetic, and biomarker studies will improve precision medicine efforts for AERD and asthma treatment...
November 2016: Immunology and Allergy Clinics of North America
Fariba Ahmadizar, Susanne J H Vijverberg, Hubertus G M Arets, Anthonius de Boer, Jason E Lang, Meyer Kattan, Colin N A Palmer, Somnath Mukhopadhyay, Steve Turner, Anke H Maitland-van der Zee
To estimate the association between obesity and poor asthma control or risk of exacerbations in asthmatic children and adolescents, and to assess whether these associations are different by sex.A meta-analysis was performed on unpublished data from three North-European paediatric asthma cohorts (BREATHE, PACMAN (Pharmacogenetics of Asthma medication in Children: Medication with Anti-inflammatory effects) and PAGES (Pediatric Asthma Gene Environment Study)) and 11 previously published studies (cross-sectional and longitudinal studies)...
October 2016: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
Michael Mosteller, Louise Hosking, Kay Murphy, Judong Shen, Kijoung Song, Matthew Nelson, Soumitra Ghosh
BACKGROUND: Inhaled corticosteroids (ICSs) are considered the most effective anti-inflammatory therapy for asthma control and management; however, there is substantial treatment response variability. OBJECTIVE: We sought to identify genetic markers of ICS response by conducting the largest pharmacogenetic investigation to date in 2672 ICS-treated patients with asthma. METHODS: Genotyping and imputation was performed in fluticasone furoate (FF) or fluticasone propionate-treated patients with asthma from 3 phase IIB and 4 phase IIIA randomized, double-blind, placebo-controlled, parallel group, multicenter studies...
July 5, 2016: Journal of Allergy and Clinical Immunology
Elin T G Kersten, Gerard H Koppelman, Bernard J Thio
Beta2-adrenoreceptor agonists (β2-agonists) are extensively used in the treatment of childhood asthma. However, there have been concerns regarding their adverse effects and safety. In 2005, the FDA commissioned a "Black Box Warning" communicating the potential for an increased risk for serious asthma exacerbations or asthma related deaths, with the regular use of LABAs. In a meta-analysis of controlled clinical trials, the incidence of severe adverse events appeared to be highest in the 4-11 year age group...
June 16, 2016: Paediatric Respiratory Reviews
Srinivas Bandaru, Pramod Tarigopula, Jyothy Akka, Vijaya Kumar Marri, Ramesh Kumar Kattamuri, Anuraj Nayarisseri, Madhavi Mangalarapu, Swetha Vinukonda, Hema Prasad Mundluru, Someswar Rao Sagurthi
BACKGROUND: Thr164Ile polymorphism in the ADRB2 gene encoding β2 adrenergic receptor (β2AR) has its functional consequence in declining ligand-receptor interactions and depressed coupling of β2AR to adenylcyclase. In the present study, we sought to evaluate the possible association of Thr164Ile polymorphism with asthma susceptibility, pharmacogenetic response to Salbutamol and varying degrees of severity. METHODS: Three hundred and ninety eight clinically diagnosed patients and four hundred and fifty six healthy controls were enrolled in the study...
October 30, 2016: Gene
Dan-Dan Guo, Xiang-Rong Zheng
The studies on gene polymorphisms in biological pathways of the drugs for the treatment of asthma refer to the studies in which pharmacogenetic methods, such as genome-wide association studies, candidate gene studies, genome sequencing, admixture mapping analysis, and linkage disequilibrium, are used to identify, determine, and repeatedly validate the effect of one or more single nucleotide polymorphisms on the efficacy of drugs. This can provide therapeutic strategies with optimal benefits, least side effects, and lowest costs to patients with asthma, and thus realize individualized medicine...
June 2016: Zhongguo Dang Dai Er Ke za Zhi, Chinese Journal of Contemporary Pediatrics
Almudena Sánchez-Martín, Asunción García-Sánchez, María Isidoro-García
Nearly one-half of asthmatic patients do not respond to the most common therapies. Evidence suggests that genetic factors may be involved in the heterogeneity in therapeutic response and adverse events to asthma therapies. We focus on the three major classes of asthma medication: β-adrenergic receptor agonist, inhaled corticosteroids, and leukotriene modifiers. Pharmacogenetics and pharmacogenomics studies have identified several candidate genes associated with drug response.In this chapter, the main pharmacogenetic and pharmacogenomic studies in addition to the future perspectives in personalized medicine will be reviewed...
2016: Methods in Molecular Biology
M T Reinartz, M Wetzke, C Happle, S Kälble, R Scherer, M Kabesch, R Seifert
Asthma can be controlled well in most patients by inhaled β-adrenoreceptor (β2 AR) agonists and steroids. Poor response to β2 AR agonists is difficult to predict, especially in young children and by lung function testing, which may be affected by multiple influences. As an alternative approach, we analyzed ex vivo neutrophilic superoxide inhibition in response to β2 AR stimulation. In 60 healthy volunteers, this assay was unaffected by sex, age, smoking, atopy or asthma status. Furthermore, we assessed effects of genetic variants in β2 AR by sequencing the ADRB2 gene in our cohort and relating genotypes to β2 AR-mediated neutrophilic superoxide inhibition...
August 2016: Allergy
Steve Turner, Ben Francis, Susanne Vijverberg, Maria Pino-Yanes, Anke H Maitland-van der Zee, Kaninika Basu, Lauren Bignell, Somnath Mukhopadhyay, Roger Tavendale, Colin Palmer, Daniel Hawcutt, Munir Pirmohamed, Esteban G Burchard, Brian Lipworth
BACKGROUND: The Gly-to-Arg substitution at the 16 position (rs1042713) in the β2-adrenoceptor gene (ADRB2) is associated with enhanced downregulation and uncoupling of β2-receptors. OBJECTIVES: We sought to undertake a meta-analysis to test the hypothesis that there is an interaction between the A allele of rs1042713 (Arg16 amino acid) and long-acting β-agonist (LABA) exposure for asthma exacerbations in children. METHODS: Children with diagnosed asthma were recruited in 5 populations (BREATHE, Genes-Environments and Admixture in Latino Americans II, PACMAN, the Paediatric Asthma Gene Environment Study, and the Pharmacogenetics of Adrenal Suppression with Inhaled Steroid Study)...
July 2016: Journal of Allergy and Clinical Immunology
Kathryn Blake, John Lima
INTRODUCTION: Long-acting β2-agonists are an effective class of drugs, when combined with inhaled corticosteroids, for reducing symptoms and exacerbations in patients with asthma that is not adequately controlled by inhaled corticosteroids alone. However, because this class of drugs has been associated with severe adverse events, including hospitalization and death in small numbers of patients, efforts to identify a pharmacogenetic profile for patients at risk has been diligently investigated...
2015: Expert Opinion on Drug Metabolism & Toxicology
Puneet Kaur Sahi, Neerja Gupta
No abstract text is available yet for this article.
September 2015: Indian Journal of Pediatrics
Joshua S Davis, Scott T Weiss, Kelan G Tantisira
There is evidence that genetic factors are implicated in the observed differences in therapeutic responses to the common classes of asthma therapy such as β2-agonists, corticosteroids, and leukotriene modifiers. Pharmacogenomics explores the roles of genetic variation in drug response and continues to be a field of great interest in asthma therapy. Prior studies have focused on candidate genes and recently emphasized genome-wide association analyses. Newer integrative omics and system-level approaches have recently revealed novel understanding of drug response pathways...
July 2015: Current Allergy and Asthma Reports
Amber Dahlin, Augusto Litonjua, John J Lima, Mayumi Tamari, Michiaki Kubo, Charles G Irvin, Stephen P Peters, Kelan G Tantisira
BACKGROUND: Genome-wide association study (GWAS) is a powerful tool to identify novel pharmacogenetic single nucleotide polymorphisms (SNPs). Leukotriene receptor antagonists (LTRAs) are a major class of asthma medications, and genetic factors contribute to variable responses to these drugs. We used GWAS to identify novel SNPs associated with the response to the LTRA, montelukast, in asthmatics. METHODS: Using genome-wide genotype and phenotypic data available from American Lung Association - Asthma Clinical Research Center (ALA-ACRC) cohorts, we evaluated 8-week change in FEV1 related to montelukast administration in a discovery population of 133 asthmatics...
2015: PloS One
Srinivas Bandaru, Jyothy Akka, Vijaya Kumar Marri, Mallika Alvala, Deepika Ponnala, Hema Prasad Mundluru
β2-Adrenergic receptor (β2-AR) plays a crucial role in asthma pathophysiology by regulating, processes of the lung function, and clinical response to bronchodilators. The +46G>A- Gly16Arg polymorphism in the gene encoding β2 adrenergic receptor (ADRB2) has been associated with receptor non-responsiveness after β2-agonist exposure. In the present study, we sought to evaluate the possible association of Gly16Arg polymorphism with asthma susceptibility, pharmacogenetic response to Salbutamol, and varying degrees of disease severity...
December 2015: Inflammation
A Dahlin, A Litonjua, C G Irvin, S P Peters, J J Lima, M Kubo, M Tamari, K G Tantisira
Heterogeneous therapeutic responses to leukotriene modifiers (LTMs) are likely due to variation in patient genetics. Although prior candidate gene studies implicated multiple pharmacogenetic loci, to date, no genome-wide association study (GWAS) of LTM response was reported. In this study, DNA and phenotypic information from two placebo-controlled trials (total N=526) of zileuton response were interrogated. Using a gene-environment (G × E) GWAS model, we evaluated 12-week change in forced expiratory volume in 1 second (ΔFEV1) following LTM treatment...
April 2016: Pharmacogenomics Journal
Victor E Ortega, Deborah A Meyers, Eugene R Bleecker
Human genetics research will be critical to the development of genetic profiles for personalized or precision medicine in asthma. Genetic profiles will consist of gene variants that predict individual disease susceptibility and risk for progression, predict which pharmacologic therapies will result in a maximal therapeutic benefit, and predict whether a therapy will result in an adverse response and should be avoided in a given individual. Pharmacogenetic studies of the glucocorticoid, leukotriene, and β2-adrenergic receptor pathways have focused on candidate genes within these pathways and, in addition to a small number of genome-wide association studies, have identified genetic loci associated with therapeutic responsiveness...
2015: Pharmacogenomics and Personalized Medicine
Merritt L Fajt, Sally E Wenzel
Traditionally, asthma and allergic diseases have been defined by broad definitions and treated with nonspecific medications, including corticosteroids and bronchodilators. There is an increasing appreciation of heterogeneity within asthma and allergic diseases based primarily on recent cluster analyses, molecular phenotyping, biomarkers, and differential responses to targeted and nontargeted therapies. These pioneering studies have led to successful therapeutic trials of molecularly targeted therapies in defined phenotypes...
February 2015: Journal of Allergy and Clinical Immunology
S J H Vijverberg, E S Koster, R Tavendale, M Leusink, L Koenderman, J A M Raaijmakers, D S Postma, G H Koppelman, S W Turner, S Mukhopadhyay, S M Tse, K G Tantisira, D B Hawcutt, B Francis, M Pirmohamed, M Pino-Yanes, C Eng, E G Burchard, C N A Palmer, A H Maitland-van der Zee
BACKGROUND: The clinical response to inhaled corticosteroids (ICS) is associated with single nucleotide polymorphisms (SNPs) in various genes. This study aimed to relate variations in genes in the steroid pathway and asthma susceptibility genes to exacerbations in children and young adults treated with ICS. METHODS: We performed a meta-analysis of three cohort studies: Pharmacogenetics of Asthma Medication in Children: Medication with Anti-Inflammatory effects (n = 357, age: 4-12 years, the Netherlands), BREATHE (n = 820, age: 3-22 years, UK) and Paediatric Asthma Gene Environment Study (n = 391, age: 2-16 years, UK)...
June 2015: Clinical and Experimental Allergy: Journal of the British Society for Allergy and Clinical Immunology
Elliot Israel, Jessica Lasky-Su, Amy Markezich, Amy Damask, Stanley J Szefler, Brooke Schuemann, Barbara Klanderman, Jody Sylvia, Shamsah Kazani, Rongling Wu, Fernando Martinez, Homer A Boushey, Vernon M Chinchilli, Dave Mauger, Scott T Weiss, Kelan G Tantisira
RATIONALE: β2-Agonists are the most common form of treatment of asthma, but there is significant variability in response to these medications. A significant proportion of this responsiveness may be heritable. OBJECTIVES: To investigate whether a genome-wide association study (GWAS) could identify novel pharmacogenetic loci in asthma. METHODS: We performed a GWAS of acute bronchodilator response (BDR) to inhaled β2-agonists. A total of 444,088 single-nucleotide polymorphisms (SNPs) were examined in 724 individuals from the SNP Health Association Resource (SHARe) Asthma Resource Project (SHARP)...
March 1, 2015: American Journal of Respiratory and Critical Care Medicine
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