Stress and Bronchodilator Response in Children with Asthma

Abstract

Rationale: Stress is associated with asthma morbidity in Puerto Ricans (PRs), who have reduced bronchodilator response (BDR).

Objectives: To examine whether stress and/or a gene regulating anxiety (ADCYAP1R1) is associated with BDR in PR and non-PR children with asthma.

Methods: 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.

Measurements and main results: 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 β2-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).

Conclusions: 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.

Keywords: Puerto Ricans; asthma; bronchodilator response; stress.

Figure 1.

Bronchodilator response among children with stress or anxiety. All multivariable models were adjusted for age, sex, household income, current environmental tobacco smoke, and use of inhaled corticosteroids; models for the Rhode Island Puerto Rico Asthma Center (RIPRAC) and the National Health and Nutrition Examination Survey (NHANES) cohorts were also adjusted for race/ethnicity. Plotted are the beta estimates and 95% confidence intervals for each cohort. Puerto Rico shows the estimate of effect for the comparison between children in the upper quartile of the Checklist of Children’s Distress Symptoms (CCDS) scores and those in the lowest three quartiles. RIPRAC shows the estimate of effect for the comparison between children with anxiety and panic scores above a clinical cutoff and those with scores below such cutoff. Additionally shown for RIPRAC is the estimate of effect for the comparison between children with scores above the clinical cutoff for both anxiety and panic, and those with scores below the clinical cutoff for anxiety and panic. NHANES shows the estimate of effect for the comparison between children in the highest quartile of anxiety in the previous month and those in the lowest three quartiles. *P < 0.05; **P < 0.01.

Figure 2.

Boxplots of bronchodilator responsiveness in Puerto Rican children with asthma, by household stress score. The “highest stress” group comprises children with both high personal stress (in the upper quartile of the Checklist of Children’s Distress Symptoms) and high maternal stress (in the upper quartile of the maternal Perceived Stress Score). The “lowest stress” group comprises children with neither high personal stress nor high maternal stress. The middle group is children with either high personal stress or high maternal stress, but not both. PREFEV1 = baseline (prebronchodilator) FEV₁.

Figure 3.

Estimated effect of the minor allele (A) of single-nucleotide polymorphism rs34548976 on bronchodilator response (percent change in FEV₁) in seven cohorts of children with asthma. CAMP = Childhood Asthma Management Program; CARE = Childhood Asthma Research and Education Network; CHOP = Children’s Hospital of Philadelphia; GACRS = Genetics of Asthma in Costa Rica Study; GALA = Genetics of Asthma in Latino Americans; SAGE = The Study of African Americans, Asthma, Genes and Environment. *P < 0.05; **P < 0.01.

Figure 4.

Increased functional connectivity in brain regions (amygdala–insula) previously associated with increased anxiety in at-risk adults with the rs34548976 risk allele. Resting-state functional magnetic resonance imaging was performed, and bilateral amygdala volumes were seeded, examining whole-brain corrected brain regions showing differential functional connectivity with insula (arrows) in rs3458976 AA allele carriers (n = 11) compared with GG/AG allele carriers (n = 31). (A) Group differences are shown in the horizontal (left), sagittal (middle), and coronal (right) planes between AA and G-carrier groups. (B) Whole-brain corrected (P < 0.01) regions associated with amygdala functional activity at resting state in the AA allele carriers. (C) Whole-brain corrected (P < 0.01) regions associated with amygdala functional activity at resting state in the G allele carriers. Similar results were seen with increased amygdala–insula connectivity using an additive model (AA/AG/GG) and when comparing AA with AG groups separately. All signals represent whole-brain corrected voxels at P < 0.01.