ARG1 Is a Novel Bronchodilator Response Gene: Screening and Replication in Four Asthma Cohorts

Channing Laboratory, Pulmonary Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 13). 08/2008; 178(7):688-94. DOI: 10.1164/rccm.200709-1363OC
Source: PubMed


Inhaled beta-agonists are one of the most widely used classes of drugs for the treatment of asthma. However, a substantial proportion of patients with asthma do not have a favorable response to these drugs, and identifying genetic determinants of drug response may aid in tailoring treatment for individual patients.
To screen variants in candidate genes in the steroid and beta-adrenergic pathways for association with response to inhaled beta-agonists.
We genotyped 844 single nucleotide polymorphisms (SNPs) in 111 candidate genes in 209 children and their parents participating in the Childhood Asthma Management Program. We screened the association of these SNPs with acute response to inhaled beta-agonists (bronchodilator response [BDR]) using a novel algorithm implemented in a family-based association test that ranked SNPs in order of statistical power. Genes that had SNPs with median power in the highest quartile were then taken for replication analyses in three other asthma cohorts.
We identified 17 genes from the screening algorithm and genotyped 99 SNPs from these genes in a second population of patients with asthma. We then genotyped 63 SNPs from four genes with significant associations with BDR, for replication in a third and fourth population of patients with asthma. Evidence for association from the four asthma cohorts was combined, and SNPs from ARG1 were significantly associated with BDR. SNP rs2781659 survived Bonferroni correction for multiple testing (combined P value = 0.00048, adjusted P value = 0.047).
These findings identify ARG1 as a novel gene for acute BDR in both children and adults with asthma.

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    • "We have previously demonstrated that the AHR in a chronic murine model of allergic airways inflammation to OVA is due to arginase 1 overexpression [16]. Furthermore, single nucleotide polymorphisms of arginase 1 have been specifically associated with responsiveness to bronchodilators, and L-arginine bioavailability can impact airflow in asthma [23,24]. "
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    ABSTRACT: Arginase overexpression contributes to airways hyperresponsiveness (AHR) in asthma. Arginase expression is further augmented in cigarette smoking asthmatics, suggesting that it may be upregulated by environmental pollution. Thus, we hypothesize that arginase contributes to the exacerbation of respiratory symptoms following exposure to air pollution, and that pharmacologic inhibition of arginase would abrogate the pollution-induced AHR. To investigate the role of arginase in the air pollution-induced exacerbation of airways responsiveness, we employed two murine models of allergic airways inflammation. Mice were sensitized to ovalbumin (OVA) and challenged with nebulized PBS (OVA/PBS) or OVA (OVA/OVA) for three consecutive days (sub-acute model) or 12 weeks (chronic model), which exhibit inflammatory cell influx and remodeling/AHR, respectively. Twenty-four hours after the final challenge, mice were exposed to concentrated ambient fine particles plus ozone (CAP+O₃), or HEPA-filtered air (FA), for 4 hours. After the CAP+O₃ exposures, mice underwent tracheal cannulation and were treated with an aerosolized arginase inhibitor (S-boronoethyl-L-cysteine; BEC) or vehicle, immediately before determination of respiratory function and methacholine-responsiveness using the flexiVent®. Lungs were then collected for comparison of arginase activity, protein expression, and immunohistochemical localization. Compared to FA, arginase activity was significantly augmented in the lungs of CAP+O₃-exposed OVA/OVA mice in both the sub-acute and chronic models. Western blotting and immunohistochemical staining revealed that the increased activity was due to arginase 1 expression in the area surrounding the airways in both models. Arginase inhibition significantly reduced the CAP+O₃-induced increase in AHR in both models. This study demonstrates that arginase is upregulated following environmental exposures in murine models of asthma, and contributes to the pollution-induced exacerbation of airways responsiveness. Thus arginase may be a therapeutic target to protect susceptible populations against the adverse health effects of air pollution, such as fine particles and ozone, which are two of the major contributors to smog.
    Full-text · Article · Feb 2011 · Respiratory research
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    • "However, another study evaluating the effects of variation in the β-2AR gene on clinical response to salmeterol administered with fluticasone propionate found no variation in response to salmeterol after chronic dosing with an inhaled corticosteroid.[23] Recently, ARG1 is identified as a new gene for acute bronchodilator response to β-2 agonist.[24] "
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    ABSTRACT: Asthma is a complex disease with multiple genetic and environmental factors contributing to it. A component of this complexity is a highly variable response to pharmacological therapy. Pharmacogenomics is the study of the role of genetic determinants in the variable response to therapy. A number of examples of possible pharmacogenomic approaches that may prove of value in the management of asthma are discussed below. A search of PubMed, Google scholar, E-Medicine, BMJ and Mbase was done using the key words "pharmacogenomics of asthma", "pharmacogenomics of β-agonist, glucocorticoids, leukotriene modifiers, theophylline, muscarinic antagonists in asthma". Presently, there are limited examples of gene polymorphism that can influence response to asthma therapy. Polymorphisms that alter response to asthma therapy include Arg16Gly, Gln27Glu, Thr164Ile for β-agonist receptor, polymorphism of glucocorticoid receptor gene, CRHR1 variants and polymorphism of LTC4S, ALOX5. Polymorphic variants of muscarinic receptors, PDE4 and CYP450 gene variants. It was concluded that genetic variation can improve the response to asthma therapy. However, no gene polymorphism has been associated with consistent results in different populations. Therefore, asthma pharmacogenomic studies in different populations with a large number of subjects are required to make possible tailoring the asthma therapy according to the genetic characteristic of individual patient.
    Full-text · Article · Sep 2010 · Indian Journal of Human Genetics
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    • "Thus, a significant association between SNPs in arginase 2 and increased risk of childhood asthma has been observed, whereas in the same population of children SNPs in both arginase 1 and arginase 2 were associated with atopy [117]. Quite remarkably, pharmacogenetic screening of 844 SNPs in 111 candidate genes for association with inhaled 2 -agonist-induced bronchodilation recently identified arginase 1 as a potential 2 -agonist response gene [118]. "

    Full-text · Article · Nov 2009
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