Smoking-induced expression of the GPR15 gene indicates its potential role in chronic inflammatory pathologies

Significance Statement

Tobacco smoking is considered the leading preventable cause of morbidity and mortality. Smoking affects more than 1 billion individuals worldwide and accounts for an estimated 3 million deaths per year. However, the exact molecular mechanisms how smoking influences the organism, is still not understood. Smoking-induced molecular alterations have been analysed in previous studies and peripheral gene-expression profiling has allowed for the detection of early molecular signatures relevant to the toxic effects of smoking. In addition to the toxic effects, smoking also induces prominent immunological changes in the lungs. The aim of our study was to find systemic changes that are caused by smoking. We performed whole transcriptome analysis of the peripheral blood in smokers and non-smokers. As a results we found significant up-regulation of GPR15, that is chemoattractant and regulates the homing of immune cells. The activation of GPR15 expression was coincided with the hypomethylation of GPR15 locus. Our study indicates that smoking causes systemic molecular changes that regulate innate immunity and chronic inflammation. Our results support the understanding that the smoking health effects are mediated by inflammatory response.

Journal Reference

Am J Pathol. 2015;185(11):2898-906.

Kõks G¹, Uudelepp ML², Limbach M¹, Peterson P¹, Reimann E³, Kõks S⁴.

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Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia; Department of Genetics, Tartu University Hospital, Tartu, Estonia.
Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia; Department of Reproductive Biology, Estonian University of Life Sciences, Tartu, Estonia.
Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia; Department of Reproductive Biology, Estonian University of Life Sciences, Tartu, Estonia. Electronic address: [email protected].

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Abstract

Despite the described clear epigenetic effects of smoking, the effect of smoking on genome-wide gene expression in the blood is obscure. We therefore studied the smoking-induced changes in the gene-expression profile of the peripheral blood. RNA was extracted from the whole blood of 48 individuals with a detailed smoking history (24 never-smokers, 16 smokers, and 8 ex-smokers). Gene-expression profiles were evaluated with RNA sequencing, and results were analyzed separately in 24 men and 24 women. In the male smokers, 13 genes were statistically significantly (false-discovery rate <0.1) differentially expressed; in female smokers, 5 genes. Although most of the differentially expressed genes were different between the male and female smokers, the G-protein-coupled receptor 15 gene (GPR15) was differentially expressed in both male and female smokers compared with never-smokers. Analysis of GPR15 methylation identified significantly greater hypomethylation in smokers compared with that in never-smokers. GPR15 is the chemoattractant receptor that regulates T-cell migration and immunity. Up-regulation of GPR15 could explain to some extent the health hazards of smoking with regard to chronic inflammatory diseases.

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