Environmental risks and sphingolipid signatures in adult asthma and its phenotypic clusters: A multicentre study

Chao-Chien Wu, Chin Chou Wang, Wen-Yu Chung, Chau-Chyun Sheu, Yi-Hsin Yang, Ming-Yen Cheng, Ruay-Sheng Lai, Sum-Yee Leung, Chi-Cheng Lin, Yu-Feng Wei, Ching-Hsiung Lin, Sheng-Hao Lin, Jeng-Yuan Hsu, Wei-Chang Huang, Chia-Cheng Tseng, Yung-Fa Lai, Meng-Hsuan Cheng, Huang-Chi Chen, Chih-Jen Yang, Shih-Chang HsuChian-Heng Su, Chien-Jen Wang, Huei-Ju Liu, Hua-Ling Chen, Yuan-Ting Hsu, Chih-Hsing Hung*, Chon-Lin Lee*, Ming-Shyan Huang*, Shau-Ku Huang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number218396
JournalThorax
DOIs
Publication statusE-pub ahead of print - 16 Jun 2022

Scopus Subject Areas

  • Pulmonary and Respiratory Medicine

User-Defined Keywords

  • Asthma

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