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ARG1 is a novel bronchodilator response gene: screening and replication in four asthma cohorts.

ABSTRACT: 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.

SUBMITTER: Litonjua AA

PROVIDER: S-EPMC2556451 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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ARG1 is a novel bronchodilator response gene: screening and replication in four asthma cohorts.

Litonjua Augusto A AA Lasky-Su Jessica J Schneiter Kady K Tantisira Kelan G KG Lazarus Ross R Klanderman Barbara B Lima John J JJ Irvin Charles G CG Peters Stephen P SP Hanrahan John P JP Liggett Stephen B SB Hawkins Gregory A GA Meyers Deborah A DA Bleecker Eugene R ER Lange Christoph C Weiss Scott T ST

American journal of respiratory and critical care medicine 20080710 7

<h4>Rationale</h4>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.<h4>Objectives</h4>To screen variants in candidate genes in the steroid and beta-adrenergic pathways for association with response to inhaled beta-agonists.<h4>Method ...[more]

PMID: 18617639

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Project description:RationaleBronchodilator response (BDR) is a measure of improvement in airway smooth muscle tone, inhibition of liquid accumulation and mucus section into the lumen in response to short-acting beta-2 agonists that varies among asthmatic patients. MicroRNAs (miRNAs) are well-known post-translational regulators. Identifying miRNAs associated with BDR could lead to a better understanding of the underlying complex pathophysiology.ObjectiveThe purpose of this study is to identify circulating miRNAs associated with bronchodilator response in asthma and decipher possible mechanism of bronchodilator response variation.MethodsWe used available small RNA sequencing on blood serum from 1,134 asthmatic children aged 6 to 14 years who participated in the Genetics of Asthma in Costa Rica Study (GACRS). We filtered the participants into high and low bronchodilator response (BDR) quartiles and used DeSeq2 to identify miRNAs with differential expression (DE) in high (N= 277) vs low (N= 278) BDR group. Replication was carried out in the Leukotriene modifier Or Corticosteroids or Corticosteroid-Salmeterol trial (LOCCS), an adult asthma cohort. The putative target genes of DE miRNAs were identified, and pathway enrichment analysis was performed.ResultsWe identified 10 down-regulated miRNAs having odds ratios (OR) between 0.37 and 0.76 for a doubling of miRNA counts and one up-regulated miRNA (OR=2.26) between high and low BDR group. These were assessed for replication in the LOCCS cohort, where two miRNAs (miR-200b-3p and miR-1246) were associated. Further, functional annotation of 11 DE miRNAs were performed as well as of two replicated miRs. Target genes of these miRs were enriched in regulation of cholesterol biosynthesis by SREBPs, ESR-mediated signaling, G1/S transition, RHO GTPase cycle, and signaling by TGFB family pathways.ConclusionMiRNAs miR-1246 and miR-200b-3p are associated with both childhood and adult asthma BDR. Our findings add to the growing body of evidence that miRNAs play a significant role in the difference of asthma treatment response among patients as it points to genomic regulatory machinery underlying difference in bronchodilator response among patients.Trial registrationLOCCS cohort [ClinicalTrials.gov number: NCT00156819], GACRS cohort [ClinicalTrials.gov number: NCT00021840].

Dataset Information

ARG1 is a novel bronchodilator response gene: screening and replication in four asthma cohorts.

Publications

ARG1 is a novel bronchodilator response gene: screening and replication in four asthma cohorts.

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