Stress and Bronchodilator Response in Children with Asthma.
BACKGROUND
Stress is associated with asthma morbidity in Puerto Ricans (PRs), who have reduced bronchodilator response (BDR).


OBJECTIVE
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.


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.
1 Division of Pulmonary Medicine, Allergy and Immunology, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, and.
John M
JM
Brehm
1 Division of Pulmonary Medicine, Allergy and Immunology, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, and.
Sima K
SK
Ramratnam
2 Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Sze Man
SM
Tse
2 Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Damien C
DC
Croteau-Chonka
3 Department of Bioengineering and Therapeutic Sciences and.|4 Department of Medicine, University of California at San Francisco, San Francisco, California.|5 CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.
Maria
M
Pino-Yanes
1 Division of Pulmonary Medicine, Allergy and Immunology, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, and.
Christian
C
Rosas-Salazar
2 Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Augusto A
AA
Litonjua
2 Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Benjamin A
BA
Raby
1 Division of Pulmonary Medicine, Allergy and Immunology, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, and.
Nadia
N
Boutaoui
1 Division of Pulmonary Medicine, Allergy and Immunology, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, and.
Yueh-Ying
YY
Han
1 Division of Pulmonary Medicine, Allergy and Immunology, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, and.
Wei
W
Chen
1 Division of Pulmonary Medicine, Allergy and Immunology, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, and.
Erick
E
Forno
6 Department of Psychology, University of Pittsburgh, Pittsburgh, Pennsylvania.
Anna L
AL
Marsland
7 Department of Psychiatry and Human Behavior, Brown University School of Medicine, Providence, Rhode Island.
Nicole R
NR
Nugent
3 Department of Bioengineering and Therapeutic Sciences and.|4 Department of Medicine, University of California at San Francisco, San Francisco, California.
Celeste
C
Eng
8 Behavioral Sciences Research Institute, University of Puerto Rico, Medical Science Campus, San Juan, Puerto Rico.
Angel
A
Colón-Semidey
8 Behavioral Sciences Research Institute, University of Puerto Rico, Medical Science Campus, San Juan, Puerto Rico.
María
M
Alvarez
8 Behavioral Sciences Research Institute, University of Puerto Rico, Medical Science Campus, San Juan, Puerto Rico.
Edna
E
Acosta-Pérez
3 Department of Bioengineering and Therapeutic Sciences and.|4 Department of Medicine, University of California at San Francisco, San Francisco, California.
Melissa L
ML
Spear
9 Arizona Respiratory Center and BIO5 Institute, University of Arizona, Tucson, Arizona.
Fernando D
FD
Martinez
10 Division of Pediatric Pulmonology, Hospital Nacional de Niños, San José, Costa Rica.
Lydiana
L
Avila
2 Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Scott T
ST
Weiss
10 Division of Pediatric Pulmonology, Hospital Nacional de Niños, San José, Costa Rica.
Manuel
M
Soto-Quiros
11 Department of Human Genetics, University of Chicago, Chicago, Illinois.
Carole
C
Ober
11 Department of Human Genetics, University of Chicago, Chicago, Illinois.
Dan L
DL
Nicolae
12 Department of Medicine, Johns Hopkins University, Baltimore, Maryland.
Kathleen C
KC
Barnes
13 Department of Pediatrics and.|14 Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
Robert F
RF
Lemanske
15 Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.
Robert C
RC
Strunk
16 Department of Pediatrics, National Jewish Health, Denver, Colorado.
Andrew
A
Liu
17 National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina.
Stephanie J
SJ
London
18 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
Frank
F
Gilliland
19 The Center for Applied Genomics, The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania.|20 Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Patrick
P
Sleiman
19 The Center for Applied Genomics, The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania.
Michael
M
March
19 The Center for Applied Genomics, The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania.|20 Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Hakon
H
Hakonarson
2 Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Qing Ling
QL
Duan
1 Division of Pulmonary Medicine, Allergy and Immunology, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, and.
Jay K
JK
Kolls
7 Department of Psychiatry and Human Behavior, Brown University School of Medicine, Providence, Rhode Island.
Gregory K
GK
Fritz
3 Department of Bioengineering and Therapeutic Sciences and.|4 Department of Medicine, University of California at San Francisco, San Francisco, California.
Donglei
D
Hu
21 Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia; and.
Negar
N
Fani
21 Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia; and.
Jennifer S
JS
Stevens
21 Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia; and.
Lynn M
LM
Almli
3 Department of Bioengineering and Therapeutic Sciences and.|4 Department of Medicine, University of California at San Francisco, San Francisco, California.
Esteban G
EG
Burchard
22 Center for Advanced Brain Imaging, Georgia Institute of Technology and Georgia State University, Atlanta, Georgia.
Jaemin
J
Shin
7 Department of Psychiatry and Human Behavior, Brown University School of Medicine, Providence, Rhode Island.
Elizabeth L
EL
McQuaid
21 Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia; and.
Kerry
K
Ressler
8 Behavioral Sciences Research Institute, University of Puerto Rico, Medical Science Campus, San Juan, Puerto Rico.
Glorisa
G
Canino
1 Division of Pulmonary Medicine, Allergy and Immunology, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, and.
Juan C
JC
Celedón
D000293:Adolescent; D001007:Anxiety / Q000150:complications* / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics; D001249:Asthma / Q000150:complications / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics; D001993:Bronchodilator Agents / Q000627:therapeutic use*; D016022:Case-Control Studies; D002648:Child; D003430:Cross-Sectional Studies; D015536:Down-Regulation; D005260:Female; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D016014:Linear Models; D008297:Male; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide; D011647:Puerto Rico; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / Q000235:genetics*; D012237:Rhode Island; D012307:Risk Factors; D013315:Stress, Psychological / Q000150:complications* / Q000175:diagnosis / Q000208:ethnology; D016896:Treatment Outcome
C495503:ADCYAP1R1 protein, human; C553443:ADRB2 protein, human; D001993:Bronchodilator Agents; D005819:Genetic Markers; D018343:Receptors, Adrenergic, beta-2; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
Puerto Ricans; asthma; bronchodilator response; stress