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Pathway analysis of a genome-wide gene by air pollution interaction study in asthmatic children

Journal of Exposure Science & Environmental Epidemiology volume 29, pages 539–547 (2019)Cite this article

Abstract

Objectives

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.

Methods

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.

Results

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.

Conclusion

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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References

  1. Searing DA, Rabinovitch N. Environmental pollution and lung effects in children. Curr Opin Pediatr. 2011;23:314–8.

    Article  CAS  Google Scholar 

  2. Schwela D. Air pollution and health in urban areas. Rev Environ Health. 2000;15:13–42.

    Article  CAS  Google Scholar 

  3. World Health Organization. Effects of air pollution on children' s health and developement. A review of the evidence. Bonn. http://www.euro.who.int/__data/assets/pdf_file/0010/74728/E86575.pdf.2005. Date last accessed: April 2013.

  4. Schildcrout JS, Sheppard L, Lumley T, Slaughter JC, Koenig JQ, Shapiro GG. Ambient air pollution and asthma exacerbations in children: an eight-city analysis. Am J Epidemiol. 2006;164:505–17.

    Article  Google Scholar 

  5. Sunyer J, Spix C, Quenel P, Ponce-de-Leon A, Ponka A, Barumandzadeh T, et al. Urban air pollution and emergency admissions for asthma in four European cities: the APHEA project. Thorax. 1997;52:760–5.

    Article  CAS  Google Scholar 

  6. Romieu I, Meneses F, Ruiz S, Sienra JJ, Huerta J, White MC, et al. Effects of air pollution on the respiratory health of asthmatic children living in Mexico city. Am J Respir Crit Care Med. 1996;154:300–7.

    Article  CAS  Google Scholar 

  7. HEI panel on the Health Effects of Traffic-Related Air Pollution. Traffic-related air pollution: a critical review of the literature on emissions, exposure, and health effects. Boston, MA: 2010. Report No.: HEI Special Report 17.

  8. Li S, Williams G, Jalaludin B, Baker P. Panel studies of air pollution on children's lung function and respiratory symptoms: a literature review. J Asthma. 2012;49:895–910.

    Article  Google Scholar 

  9. Gao Y, Chan EY, Li LP, He QQ, Wong TW. Chronic effects of ambient air pollution on lung function among Chinese children. Arch Dis Child. 2013;98:128–35.

    Article  Google Scholar 

  10. Rosenlund M, Forastiere F, Porta D, De Sario M, Badaloni C, Perucci CA. Traffic-related air pollution in relation to respiratory symptoms, allergic sensitisation and lung function in schoolchildren. Thorax. 2009;64:573–80.

    Article  CAS  Google Scholar 

  11. Gauderman WJ, Vora H, McConnell R, Berhane K, Gilliland F, Thomas D, et al. Effect of exposure to traffic on lung development from 10 to 18 years of age: a cohort study. Lancet. 2007;369:571–7.

    Article  Google Scholar 

  12. Schwartz J. Lung function and chronic exposure to air pollution: a cross-sectional analysis of NHANES II. Environ Res. 1989;50:309–21.

    Article  CAS  Google Scholar 

  13. Kelly FJ. Oxidative stress: its role in air pollution and adverse health effects. Occup Environ Med. 2003;60:612–6.

    Article  Google Scholar 

  14. Patel MM, Chillrud SN, Deepti KC, Ross JM, Kinney PL. Traffic-related air pollutants and exhaled markers of airway inflammation and oxidative stress in new york city adolescents. Environ Res. 2013;121:71–8.

    Article  CAS  Google Scholar 

  15. Emmerechts J, Hoylaerts MF. The effect of air pollution on haemostasis. Hamostaseologie. 2012;32:5–13.

    Article  CAS  Google Scholar 

  16. Auerbach A, Hernandez ML. The effect of environmental oxidative stress on airway inflammation. Curr Opin Allergy Clin Immunol. 2012;12:133–9.

    Article  CAS  Google Scholar 

  17. Yang IA, Fong KM, Zimmerman PV, Holgate ST, Holloway JW. Genetic susceptibility to the respiratory effects of air pollution. Postgrad Med J. 2009;85:428–36.

    CAS  PubMed  Google Scholar 

  18. Gref A, Kebede Merid S, Gruzieva O, Ballereau S, Becker A, Bellander T, et al. Genome-wide interaction analysis of air pollution exposure and childhood asthma with functional follow-up. Am J Respir Crit Care Med. 2016;195:1373–83.

    Article  Google Scholar 

  19. Imboden M, Kumar A, Curjuric I, Adam M, Thun GA, Haun M, et al. Modification of the association between PM10 and lung function decline by cadherin 13 polymorphisms in the SAPALDIA cohort: a genome-wide interaction analysis. Environ Health Perspect. 2015;123:72–9.

    Article  CAS  Google Scholar 

  20. Moreno-Macias H, Dockery DW, Schwartz J, Gold DR, Laird NM, Sienra-Monge JJ, et al. Ozone exposure, vitamin C intake, and genetic susceptibility of asthmatic children in Mexico city: a cohort study. Respir Res. 2013;14:14.

    Article  CAS  Google Scholar 

  21. Ierodiakonou D, Zanobetti A, Coull BA, Melly S, Postma DS, Boezen HM, et al. Ambient air pollution, lung function, and airway responsiveness in asthmatic children. J Allergy Clin Immunol. 2016;137:390–9.

    Article  CAS  Google Scholar 

  22. The Childhood Asthma Management Program Research Group. The childhood asthma management program (CAMP): design, rationale, and methods. childhood asthma management program research group. Control Clin Trials. 1999;20:91–120.

    Article  Google Scholar 

  23. American Thoracic Society. Standardization of spirometry, 1994 update. Am J Respir Crit Care Med. 1995;152:1107–36.

    Article  Google Scholar 

  24. Sikorska K, Rivadeneira F, Groenen PJ, Hofman A, Uitterlinden AG, Eilers PH, et al. Fast linear mixed model computations for genome-wide association studies with longitudinal data. Stat Med. 2013;32:165–80.

    Article  Google Scholar 

  25. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–75.

    Article  CAS  Google Scholar 

  26. Zhang K, Cui S, Chang S, Zhang L, Wang J. i-GSEA4GWAS: a web server for identification of pathways/gene sets associated with traits by applying an improved gene set enrichment analysis to genome-wide association study. Nucleic Acids Res. 2010;38:W90–5. (Web Server issue).

    Article  CAS  Google Scholar 

  27. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545–50.

    Article  CAS  Google Scholar 

  28. Romieu I, Moreno-Macias H, London SJ. Gene by environment interaction and ambient air pollution. Proc Am Thorac Soc. 2010;7:116–22.

    Article  CAS  Google Scholar 

  29. Bowatte G, Lodge CJ, Perret JL, Matheson MC, Dharmage SC. Interactions of GST polymorphisms in air pollution exposure and respiratory diseases and allergies. Curr Allergy Asthma Rep. 2016;16:85.

    Article  Google Scholar 

  30. Miao H, Wang B. EphA receptor signaling--complexity and emerging themes. Semin Cell Dev Biol. 2012;23:16–25.

    Article  CAS  Google Scholar 

  31. Arvanitis D, Davy A. Eph/ephrin signaling: networks. Genes Dev. 2008;22:416–29.

    Article  CAS  Google Scholar 

  32. Pasquale EB. Eph-ephrin bidirectional signaling in physiology and disease. Cell. 2008;133:38–52.

    Article  CAS  Google Scholar 

  33. Zhuang G, Song W, Amato K, Hwang Y, Lee K, Boothby M, et al. Effects of cancer-associated EPHA3 mutations on lung cancer. J Natl Cancer Inst. 2012;104:1182–97.

    Article  Google Scholar 

  34. Guntur VP, Reinero CR. The potential use of tyrosine kinase inhibitors in severe asthma. Curr Opin Allergy Clin Immunol. 2012;12:68–75.

    Article  CAS  Google Scholar 

  35. Huang Z, Rose AH, Hoffmann PR. The role of selenium in inflammation and immunity: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal. 2012;16:705–43.

    Article  CAS  Google Scholar 

  36. Xu J, Li T, Wu H, Xu T. Role of thioredoxin in lung disease. Pulm Pharmacol Ther. 2012;25:154–62.

    Article  CAS  Google Scholar 

  37. Imboden M, Bouzigon E, Curjuric I, Ramasamy A, Kumar A, Hancock DB, et al. Genome-wide association study of lung function decline in adults with and without asthma. J Allergy Clin Immunol. 2012;129:1218–28.

    Article  Google Scholar 

  38. Schwanzer-Pfeiffer D, Rossmanith E, Schildberger A, Falkenhagen D. Characterization of SVEP1, KIAA, and SRPX2 in an in vitro cell culture model of endotoxemia. Cell Immunol. 2010;263:65–70.

    Article  CAS  Google Scholar 

  39. Gilges D, Vinit MA, Callebaut I, Coulombel L, Cacheux V, Romeo PH, et al. Polydom: a secreted protein with pentraxin, complement control protein, epidermal growth factor and von willebrand factor A domains. Biochem J. 2000;352:49–59. Pt 1

    Article  CAS  Google Scholar 

  40. Ono JG, Worgall TS, Worgall S. Airway reactivity and sphingolipids-implications for childhood asthma. Mol Cell Pediatr. 2015;2:13.

    Article  Google Scholar 

  41. Zhao CN, Fan Y, Huang JJ, Zhang HX, Gao T, Wang C, et al. The association of GSDMB and ORMDL3 gene polymorphisms with asthma: a meta-analysis. Allergy Asthma Immunol Res. 2015;7:175–85.

    Article  Google Scholar 

  42. Heijink IH, Nawijn MC, Hackett TL. Airway epithelial barrier function regulates the pathogenesis of allergic asthma. Clin Exp Allergy. 2014;44:620–30.

    Article  CAS  Google Scholar 

  43. Faura Tellez G, Willemse BW, Brouwer U, Nijboer-Brinksma S, Vandepoele K, Noordhoek JA, et al. Protocadherin-1 localization and cell-adhesion function in airway epithelial cells in asthma. PLoS ONE. 2016;11:e0163967.

    Article  Google Scholar 

  44. Ierodiakonou D, Postma DS, Koppelman GH, Boezen HM, Gerritsen J, Ten Hacken N, et al. E-cadherin gene polymorphisms in asthma patients using inhaled corticosteroids. Eur Respir J. 2011;38:1044–52.

    Article  CAS  Google Scholar 

  45. Jiang LH, Yang W, Zou J, Beech DJ. TRPM2 channel properties, functions and therapeutic potentials. Expert Opin Ther Targets. 2010;14:973–88.

    Article  CAS  Google Scholar 

  46. Xu R, Li Q, Zhou XD, Perelman JM, Kolosov VP. Oxidative stress mediates the disruption of airway epithelial tight junctions through a TRPM2-PLCgamma1-PKCalpha signaling pathway. Int J Mol Sci. 2013;14:9475–86.

    Article  Google Scholar 

  47. Xu YD, Cui JM, Wang Y, Yin LM, Gao CK, Liu YY, et al. The early asthmatic response is associated with glycolysis, calcium binding and mitochondria activity as revealed by proteomic analysis in rats. Respir Res. 2010;11:9921–11–107.

    Google Scholar 

  48. Kinhult J, Andersson JA, Uddman R, Stjarne P, Cardell LO. Pituitary adenylate cyclase-activating peptide 38 a potent endogenously produced dilator of human airways. Eur Respir J. 2000;15:243–7.

    Article  CAS  Google Scholar 

  49. Kinhult J, Uddman R, Cardell LO. The induction of carbon monoxide-mediated airway relaxation by PACAP 38 in isolated guinea pig airways. Lung. 2001;179:1–8.

    Article  CAS  Google Scholar 

  50. Linden A, Cardell LO, Yoshihara S, Nadel JA. Bronchodilation by pituitary adenylate cyclase-activating peptide and related peptides. Eur Respir J. 1999;14:443–51.

    Article  CAS  Google Scholar 

  51. Douiri S, Bahdoudi S, Hamdi Y, Cubi R, Basille M, Fournier A, et al. Involvement of endogenous antioxidant systems in the protective activity of pituitary adenylate cyclase-activating polypeptide against hydrogen peroxide-induced oxidative damages in cultured rat astrocytes. J Neurochem. 2016;137:913–30.

    Article  CAS  Google Scholar 

  52. Thomas D. Gene--environment-wide association studies: emerging approaches. Nat Rev Genet. 2010;11:259–72.

    Article  CAS  Google Scholar 

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Acknowledgements

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.

Author contributions

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.

Funding

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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Authors and Affiliations

  1. Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    Despo Ierodiakonou, H. Marike Boezen & Judith M. Vonk

  2. Groningen Research Institute for Asthma and COPD, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    Despo Ierodiakonou, Dirkje S. Postma, H. Marike Boezen, Judith M. Vonk & Gerard H. Koppelman

  3. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, United States

    Brent A. Coull

  4. Environmental Epidemiology and Risk Program, Harvard T.H. Chan School of Public Health, Boston, MA, United States

    Antonella Zanobetti, Petros Koutrakis, Joel Schwartz & Diane R. Gold

  5. Department of Pulmonology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    Dirkje S. Postma

  6. Department of Respiratory Medicine, St. Vincent University Hospital, Dublin, Ireland

    Edward F. McKone

  7. Department of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Seattle, WA, United States

    Jonathan S. Schildcrout

  8. Department of Pediatric Pulmonology and Pediatric Allergology-Beatrix Children Hospital, University of Groningen, University Medical Center, Groningen, The Netherlands

    Gerard H. Koppelman

  9. Channing Division of Network Medicine, Brigham and Women’s Hospital, Department of Medicine, Harvard Medical School, Boston, MA, United States

    Damien C. Croteau-Chonka, Diane R. Gold & Scott T. Weiss

  10. Department of Biostatistics, University of Auckland, Auckland, New Zealand

    Thomas Lumley

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Ierodiakonou, D., Coull, B.A., Zanobetti, A. et al. Pathway analysis of a genome-wide gene by air pollution interaction study in asthmatic children. J Expo Sci Environ Epidemiol 29, 539–547 (2019). https://doi.org/10.1038/s41370-019-0136-3

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