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

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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 statusAccepted/In press - 2022

Keywords

  • Asthma

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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