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Stress and Bronchodilator Response in Children with Asthma.

ABSTRACT: Stress is associated with asthma morbidity in Puerto Ricans (PRs), who have reduced bronchodilator response (BDR).To examine whether stress and/or a gene regulating anxiety (ADCYAP1R1) is associated with BDR in PR and non-PR children with asthma.This was a cross-sectional study of stress and BDR (percent change in FEV1 after BD) in 234 PRs ages 9-14 years with asthma. We assessed child stress using the Checklist of Children's Distress Symptoms, and maternal stress using the Perceived Stress Scale. Replication analyses were conducted in two cohorts. Polymorphisms in ADCYAP1R1 were genotyped in our study and six replication studies. Multivariable models of stress and BDR were adjusted for age, sex, income, environmental tobacco smoke, and use of inhaled corticosteroids.High child stress was associated with reduced BDR in three cohorts. PR children who were highly stressed (upper quartile, Checklist of Children's Distress Symptoms) and whose mothers had high stress (upper quartile, Perceived Stress Scale) had a BDR that was 10.2% (95% confidence interval, 6.1-14.2%) lower than children who had neither high stress nor a highly stressed mother. A polymorphism in ADCYAP1R1 (rs34548976) was associated with reduced BDR. This single-nucleotide polymorphism is associated with reduced expression of the gene for the ?2-adrenergic receptor (ADRB2) in CD4(+) lymphocytes of subjects with asthma, and it affects brain connectivity of the amygdala and the insula (a biomarker of anxiety).High child stress and an ADCYAP1R1 single-nucleotide polymorphism are associated with reduced BDR in children with asthma. This is likely caused by down-regulation of ADRB2 in highly stressed children.

SUBMITTER: Brehm JM

PROVIDER: S-EPMC4511425 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Stress and Bronchodilator Response in Children with Asthma.

Brehm John M JM Ramratnam Sima K SK Tse Sze Man SM Croteau-Chonka Damien C DC Pino-Yanes Maria M Rosas-Salazar Christian C Litonjua Augusto A AA Raby Benjamin A BA Boutaoui Nadia N Han Yueh-Ying YY Chen Wei W Forno Erick E Marsland Anna L AL Nugent Nicole R NR Eng Celeste C Colón-Semidey Angel A Alvarez María M Acosta-Pérez Edna E Spear Melissa L ML Martinez Fernando D FD Avila Lydiana L Weiss Scott T ST Soto-Quiros Manuel M Ober Carole C Nicolae Dan L DL Barnes Kathleen C KC Lemanske Robert F RF Strunk Robert C RC Liu Andrew A London Stephanie J SJ Gilliland Frank F Sleiman Patrick P March Michael M Hakonarson Hakon H Duan Qing Ling QL Kolls Jay K JK Fritz Gregory K GK Hu Donglei D Fani Negar N Stevens Jennifer S JS Almli Lynn M LM Burchard Esteban G EG Shin Jaemin J McQuaid Elizabeth L EL Ressler Kerry K Canino Glorisa G Celedón Juan C JC

American journal of respiratory and critical care medicine 20150701 1

<h4>Rationale</h4>Stress is associated with asthma morbidity in Puerto Ricans (PRs), who have reduced bronchodilator response (BDR).<h4>Objectives</h4>To examine whether stress and/or a gene regulating anxiety (ADCYAP1R1) is associated with BDR in PR and non-PR children with asthma.<h4>Methods</h4>This was a cross-sectional study of stress and BDR (percent change in FEV1 after BD) in 234 PRs ages 9-14 years with asthma. We assessed child stress using the Checklist of Children's Distress Symptoms ...[more]

PMID: 25918834

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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

Stress and Bronchodilator Response in Children with Asthma.

Publications

Stress and Bronchodilator Response in Children with Asthma.

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