Methylation of cysteinyl leukotriene receptor 1 genes associates with lung function in asthmatics exposed to traffic-related air pollution

ABSTRACT

Air pollution is associated with early declines in lung function and increased levels of asthma-related cysteinyl leukotrienes (CysLT) but a biological pathway linking this rapid response has not been delineated. In this randomized controlled diesel exhaust (DE) challenge study of 16 adult asthmatics, increased exposure-attributable urinary leukotriene E4 (uLTE4, a biomarker of cysteinyl leukotriene production) was correlated (p = 0.04) with declines in forced expiratory volume in 1-second (FEV₁) within 6 hours of exposure. Exposure-attributable uLTE4 increases were correlated (p = 0.02) with increased CysLT receptor 1 (CysLTR1) methylation in peripheral blood mononuclear cells which, in turn, was marginally correlated (p = 0.06) with decreased CysLTR1 expression. Decreased CysLTR1 expression was, in turn, correlated (p = 0.0007) with FEV₁ declines. During the same time period, increased methylation of GPR17 (a negative regulator of CysLTR1) was observed after DE exposure (p = 0.02); this methylation increase was correlated (p = 0.001) with decreased CysLTR1 methylation which, in turn, was marginally correlated (p = 0.06) with increased CysLTR1 expression; increased CysLTR1 expression was correlated (p = 0.0007) with FEV₁ increases. Collectively, these data delineate a potential mechanistic pathway linking increased DE exposure-attributable CysLT levels to lung function declines through changes in CysLTR1-related methylation and gene expression.

KEYWORDS:

• Asthma
• cysteinyl leukotriene
• diesel exhaust
• epigenetics
• GPR17
• methylation

Acknowledgments

The authors would like to thank Dusty Christian and Agnes Yuen for their administrative help, including formatting the manuscript.

Authors contributions

All authors generated data and gave constructive criticism of the study manuscript. CC and NR constructed the study design and interpreted the data. MJ, AF, MS, NG and AS performed the statistical analysis. JM, AM, DL, and PR implemented the genetic assays with oversight by MJ and MK. NR and CC wrote the manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Ethics approval and consent to participate

Written consent was obtained from all study participants prior to participation in the study. The study was approved by the University of British Columbia’s institutional review board.

Availability of data and materials

The data set analyzed during the current study are available from the corresponding authors on reasonable request.

Additional information

Funding

This work was supported by Canadian Institutes of Health Research CIHR; AllerGen Network Centre of Excellence. Funding agencies had no participation in the design of the study, nor were they a part of the collection, analysis, interpretation of the data, or preparation of the manuscript.