John M Brehm1, Sima K Ramratnam1, Sze Man Tse2, Damien C Croteau-Chonka2, Maria Pino-Yanes3,4,5, Christian Rosas-Salazar1, Augusto A Litonjua2, Benjamin A Raby2, Nadia Boutaoui1, Yueh-Ying Han1, Wei Chen1, Erick Forno1, Anna L Marsland6, Nicole R Nugent7, Celeste Eng3,4, Angel Colón-Semidey8, María Alvarez8, Edna Acosta-Pérez8, Melissa L Spear3,4, Fernando D Martinez9, Lydiana Avila10, Scott T Weiss2, Manuel Soto-Quiros10, Carole Ober11, Dan L Nicolae11, Kathleen C Barnes12, Robert F Lemanske13,14, Robert C Strunk15, Andrew Liu16, Stephanie J London17, Frank Gilliland18, Patrick Sleiman19,20, Michael March19, Hakon Hakonarson19,20, Qing Ling Duan2, Jay K Kolls1, Gregory K Fritz7, Donglei Hu3,4, Negar Fani21, Jennifer S Stevens21, Lynn M Almli21, Esteban G Burchard3,4, Jaemin Shin22, Elizabeth L McQuaid7, Kerry Ressler21, Glorisa Canino8, Juan C Celedón1. 1. 1 Division of Pulmonary Medicine, Allergy and Immunology, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, and. 2. 2 Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. 3. 3 Department of Bioengineering and Therapeutic Sciences and. 4. 4 Department of Medicine, University of California at San Francisco, San Francisco, California. 5. 5 CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. 6. 6 Department of Psychology, University of Pittsburgh, Pittsburgh, Pennsylvania. 7. 7 Department of Psychiatry and Human Behavior, Brown University School of Medicine, Providence, Rhode Island. 8. 8 Behavioral Sciences Research Institute, University of Puerto Rico, Medical Science Campus, San Juan, Puerto Rico. 9. 9 Arizona Respiratory Center and BIO5 Institute, University of Arizona, Tucson, Arizona. 10. 10 Division of Pediatric Pulmonology, Hospital Nacional de Niños, San José, Costa Rica. 11. 11 Department of Human Genetics, University of Chicago, Chicago, Illinois. 12. 12 Department of Medicine, Johns Hopkins University, Baltimore, Maryland. 13. 13 Department of Pediatrics and. 14. 14 Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. 15. 15 Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri. 16. 16 Department of Pediatrics, National Jewish Health, Denver, Colorado. 17. 17 National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina. 18. 18 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California. 19. 19 The Center for Applied Genomics, The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania. 20. 20 Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. 21. 21 Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia; and. 22. 22 Center for Advanced Brain Imaging, Georgia Institute of Technology and Georgia State University, Atlanta, Georgia.
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.
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.
Entities:
Keywords:
Puerto Ricans; asthma; bronchodilator response; stress
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