We aimed to investigate the role of genetics in the respiratory response of asthmatic children to air pollution, with a genome-wide level analysis of gene by nitrogen dioxide (NO2) and carbon monoxide (CO) interaction on lung function and to identify biological pathways involved.
We used a two-step method for fast linear mixed model computations for genome-wide association studies, exploring whether variants modify the longitudinal relationship between 4-month average pollution and post-bronchodilator FEV1 in 522 Caucasian and 88 African-American asthmatic children. Top hits were confirmed with classic linear mixed-effect models. We used the improved gene set enrichment analysis for GWAS (i-GSEA4GWAS) to identify plausible pathways.
Two SNPs near the EPHA3 (rs13090972 and rs958144) and one in TXNDC8 (rs7041938) showed significant interactions with NO2 in Caucasians but we did not replicate this locus in African-Americans. SNP–CO interactions did not reach genome-wide significance. The i-GSEA4GWAS showed a pathway linked to the HO-1/CO system to be associated with CO-related FEV1 changes. For NO2-related FEV1 responses, we identified pathways involved in cellular adhesion, oxidative stress, inflammation, and metabolic responses.
The host lung function response to long-term exposure to pollution is linked to genes involved in cellular adhesion, oxidative stress, inflammatory, and metabolic pathways.
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We would like to thank Steve Melly for his contribution on the air pollution database preparation and our colleagues Paul V. Williams, Teal S. Hallstrand, and Anne N. Fuhlbrigge for the Childhood Management Asthma (CAMP) Program Group. We dedicate this manuscript to the memory of our friend and colleague Dr. Gail G. Shapiro who passed away unexpectedly during this study. Dr. Shapiro dedicated her life to understanding the causes of childhood asthma and determining the best treatments for asthma. She is deeply missed by her colleagues, patients, and the asthma community. A special thank you to all participants of the CAMP study and their families.
Each author participated sufficiently in the current work. All authors were involved in the conception, hypotheses delineation, and design of the present article. DI wrote the article and all authors had a substantial involvement in its revision prior to submission. Management of the data and the analysis was performed by DI in consultation with BAC, AZ, DRG, and STW. DRG, PK, and JS provided comprehensive input on air pollution exposure assessment and modeling. STW, DSP, JV, HMB, and GHK supported the genome-wide and pathway analyses. DC C-C provided input on bioinformatic tools. EFMcK, JSS, TL, and STW represent the CAMP research group who designed, conducted, and completed the study.
The Childhood Asthma Management Program trial and CAMP Continuation Study were supported by contracts NO1-HR-16044, 16045, 16046, 16047, 16048, 16049, 16050, 16051, and 16052 with the National Heart, Lung, and Blood Institute and General Clinical Research Center grants M01RR00051, M01RR0099718-24, M01RR02719-14, and RR00036 from the National Center for Research Resources. The CAMP Continuation Study/Phases 2 and 3 were supported by grants U01HL075232, U01HL075407, U01HL075408, U01HL075409, U01HL075415, U01HL075416, U01HL075417, U01HL075419 and U01HL075420 from the National Heart, Lung, and Blood Institute. The National Jewish Health site was also supported in part by Colorado CTSA grant UL1RR025780 from NCRR/NIH and UL1TR000154. In addition, all work on data collected from the CAMP Genetic Ancillary Study was conducted at the Channing Laboratory of the Brigham and Women’s Hospital under appropriate CAMP policies and human subject’s protections. The CAMP Genetics Ancillary Study is supported by U01 HL075419, U01 HL65899, P01 HL083069, R01 HL086601, and RC2 HL101543 from the National Heart, Lung and Blood Institute, National Institutes of Health. This study was also funded by: the National Institutes of Health (NHLBI P01 HL083069, U01 HL075419, U01 HL65899, R01 HL086601; NIEHS P01 ES09825, R21 ES020194, P30 ES000002); the U.S. Environmental Protection Agency (RD 83241601, RD 83479801), and the International Initiative for Environment and Public Health Cyprus Program of HSPH. The contents of this publication are solely the responsibility of the grantee and do not necessarily represent the official views of the US EPA. Further, US EPA does not endorse the purchase of any commercial products or services mentioned in the publication.
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