• John M Brehm, Sima K Ramratnam, Sze Man Tse, Damien C Croteau-Chonka, Maria Pino-Yanes, Christian Rosas-Salazar, Augusto A Litonjua, Benjamin A Raby, Nadia Boutaoui, Yueh-Ying Han, Wei Chen, Erick Forno, Anna L Marsland, Nicole R Nugent, Celeste Eng, Angel Colón-Semidey, María Alvarez, Edna Acosta-Pérez, Melissa L Spear, Fernando D Martinez, Lydiana Avila, Scott T Weiss, Manuel Soto-Quiros, Carole Ober, Dan L Nicolae, Kathleen C Barnes, Robert F Lemanske, Robert C Strunk, Andrew Liu, Stephanie J London, Frank Gilliland, Patrick Sleiman, Michael March, Hakon Hakonarson, Qing Ling Duan, Jay K Kolls, Gregory K Fritz, Donglei Hu, Negar Fani, Jennifer S Stevens, Lynn M Almli, Esteban G Burchard, Jaemin Shin, Elizabeth L McQuaid, Kerry Ressler, Glorisa Canino, and Juan C Celedón.
• 1 Division of Pulmonary Medicine, Allergy and Immunology, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, and.
• Am. J. Respir. Crit. Care Med. 2015 Jul 1;192(1):47-56.

RationaleStress is associated with asthma morbidity in Puerto Ricans (PRs), who have reduced bronchodilator response (BDR).ObjectivesTo examine whether stress and/or a gene regulating anxiety (ADCYAP1R1) is associated with BDR in PR and non-PR children with asthma.MethodsThis 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 ResultsHigh 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).ConclusionsHigh 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.

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