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Asthma
Original research
Environmental risks and sphingolipid signatures in adult asthma and its phenotypic clusters: a multicentre study
  1. Chao-Chien Wu1,
  2. Chin-Chou Wang1,2,
  3. Wen-Yu Chung3,
  4. Chau-Chyun Sheu4,
  5. Yi-Hsin Yang5,
  6. Ming-Yen Cheng6,
  7. Ruay-Sheng Lai7,
  8. Sum-Yee Leung1,
  9. Chi-Cheng Lin8,
  10. Yu-Feng Wei9,
  11. Ching-Hsiung Lin10,11,12,
  12. Sheng-Hao Lin10,11,12,
  13. Jeng-Yuan Hsu13,
  14. Wei-Chang Huang14,15,16,17,
  15. Chia-Cheng Tseng1,
  16. Yung-Fa Lai9,
  17. Meng-Hsuan Cheng18,19,
  18. Huang-Chi Chen20,
  19. Chih-Jen Yang18,
  20. Shih-Chang Hsu21,22,
  21. Chian-Heng Su18,
  22. Chien-Jen Wang23,
  23. Huei-Ju Liu23,
  24. Hua-Ling Chen23,
  25. Yuan-Ting Hsu23,
  26. Chih-Hsing Hung24,25,
  27. Chon-Lin Lee26,
  28. Ming-Shyan Huang9,18,
  29. Shau-Ku Huang23,27
  1. 1 Department of Internal Medicine, Chang Gung Memorial Hospital Kaohsiung Branch, Kaohsiung, Taiwan
  2. 2 Department of Public Health, Kaohsiung Medical University, Kaohsiung, Taiwan
  3. 3 Department of Computer Science and Information Engineering, National Kaohsiung University of Science and Technology, Kaohsiung, Taiwan
  4. 4 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
  5. 5 National Institute of Cancer Research, National Health Research Institutes, Maioli, Taiwan
  6. 6 Hong Kong Baptist University, Hong Kong, Hong Kong
  7. 7 Division of Chest Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
  8. 8 Department of Internal Medicine, Antai Medical Care Corp Antai Tian Sheng Memorial Hospital, Pingtung, Taiwan
  9. 9 Department of Internal Medicine, E-Da Hospital, Kaohsiung, Taiwan
  10. 10 Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan
  11. 11 Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, Taiwan
  12. 12 Department of Recreation and Holistic Wellness, MingDao University, Changhua, Taiwan
  13. 13 Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
  14. 14 Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
  15. 15 Department of Medical Technology, Jen-Teh Junior College of Medicine Nursing and Management, Miaoli, Taiwan
  16. 16 School of Medicine, Chung Shan Medical University, Taichung, Taiwan
  17. 17 Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
  18. 18 Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
  19. 19 Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
  20. 20 Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung, Taiwan
  21. 21 Emergency Department, Taipei Municipal Wan-Fang Hospital, Taipei, Taiwan
  22. 22 Department of Emergency, Taipei Medical University School of Medicine, Taipei, Taiwan
  23. 23 National Institute of Environmental Health Sciences, National Health Research Institutes, Maioli, Taiwan
  24. 24 Department of Pediatrics, Kaohsiung Medical University, Kaohsiung, Taiwan
  25. 25 Department of Pediatrics, Kaohsiung Municipal Siaogang Hospital, Kaohsiung, Taiwan
  26. 26 Department of Marine Environment and Engineering, National Sun Yat-sen University, Kaohsiung, Taiwan
  27. 27 Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  1. Correspondence to Professor Shau-Ku Huang, National Institute of Environmental Health Sciences, National Health Research Institutes, Maioli, Taiwan 350; skhuang{at}nhri.edu.tw; Dr Ming-Shyan Huang, Department of Internal Medicine, E-Da Cancer Hospital, Kaohsiung, Taiwan; ed110209{at}edah.org.tw; Dr Chon-Lin Lee, Department of Marine Environment and Engineering, National Sun Yat-Sen University, Kaohsiung, Taiwan; a0780047{at}g-mail.nsysu.edu.tw; Dr Chih-Hsing Hung, Department of Pediatrics, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan; pedhung{at}gmail.com

  • Present affiliation The present affiliation of Chian-Heng Su is: Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan

Abstract

Background Adult asthma is phenotypically heterogeneous with unclear aetiology. We aimed to evaluate the potential contribution of environmental exposure and its ensuing response to asthma and its heterogeneity.

Methods Environmental risk was evaluated by assessing the records of National Health Insurance Research Database (NHIRD) and residence-based air pollution (particulate matter with diameter less than 2.5 micrometers (PM2.5) and PM2.5-bound polycyclic aromatic hydrocarbons (PAHs)), integrating biomonitoring analysis of environmental pollutants, inflammatory markers and sphingolipid metabolites in case–control populations with mass spectrometry and ELISA. Phenotypic clustering was evaluated by t-distributed stochastic neighbor embedding (t-SNE) integrating 18 clinical and demographic variables.

Findings In the NHIRD dataset, modest increase in the relative risk with time-lag effect for emergency (N=209 837) and outpatient visits (N=638 538) was observed with increasing levels of PM2.5 and PAHs. Biomonitoring analysis revealed a panel of metals and organic pollutants, particularly metal Ni and PAH, posing a significant risk for current asthma (ORs=1.28–3.48) and its severity, correlating with the level of oxidative stress markers, notably Nε-(hexanoyl)-lysine (r=0.108–0.311, p<0.05), but not with the accumulated levels of PM2.5 exposure. Further, levels of circulating sphingosine-1-phosphate and ceramide-1-phosphate were found to discriminate asthma (p<0.001 and p<0.05, respectively), correlating with the levels of PAH (r=0.196, p<0.01) and metal exposure (r=0.202–0.323, p<0.05), respectively, and both correlating with circulating inflammatory markers (r=0.186–0.427, p<0.01). Analysis of six phenotypic clusters and those cases with comorbid type 2 diabetes mellitus (T2DM) revealed cluster-selective environmental risks and biosignatures.

Interpretation These results suggest the potential contribution of environmental factors from multiple sources, their ensuing oxidative stress and sphingolipid remodeling to adult asthma and its phenotypic heterogeneity.

  • Asthma

Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information.

https://doi.org/10.1136/thoraxjnl-2021-218396

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as online supplemental information.

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    Footnotes

    • C-CWu and C-CWa contributed equally.

    • Contributors C-CWu: conceptualisation, methodology, investigation, resources. C-CWa: conceptualisation, methodology, investigation, resources. W-YC: methodology, investigation, writing-original draft, writing-review and editing. C-CS: conceptualisation, resources. Y-HY: software, formal analysis, investigation, resources, supervision, writing-review and editing. M-YC: software, formal analysis, investigation. R-SL: methodology, investigation, resources. S-YL: methodology, investigation, resources. C-CL: methodology, investigation, resources. Y-FW: methodology, investigation, resources. C-HL: methodology, investigation, resources. S-HL: methodology, investigation, resources. J-YH: methodology, investigation, resources. W-CH: methodology, investigation, resources. C-CT: methodology, investigation, resources. Y-FL: methodology, investigation, resources. M-HC: methodology, investigation, resources. H-CC: methodology, investigation, resources. C-JY: methodology, investigation, resources. S-CH: methodology, investigation, resources. C-HS: software, formal analysis, investigation, writing-review and editing. C-JW: methodology, investigation, resources. H-JL: methodology, investigation, resources. H-LC: investigation, writing-review and editing. Y-TH: investigation, writing-review and editing. C-HH: conceptualisation, methodology, resources, writing-review and editing, project administration. CLL: conceptualisation, methodology, validation, resources, writing-review and editing, supervision. M-SH: conceptualisation, methodology, validation, resources, writing-review and editing, supervision. S-KH: conceptualisation, methodology, validation, formal analysis, investigation, resources, writing-original draft, writing-review and editing, supervision, project administration, funding acquisition, guarantor.

    • Funding This work was supported, in part, by grants from National Health Research Institutes, Taiwan (EOPP10-014, EOSP07-014 and NHRI-102A1-PDCO-03010201) and Ministry of Health and Welfare, Taiwan (EODOH01), National Science Council (NSC 102-2314-B-037-052), Ministry of Science and Technology (MOST 103-2320-B-110–001) and Academia Sinica (BM-102021170), Taiwan.

    • Disclaimer These funding agencies had no role in study design, the collection and analysis of data, the decision to publish or the preparation of the manuscript.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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