Immune cell-specific smoking-related expression characteristics are revealed by re-analysis of transcriptomes from the CEDAR cohort

INTRODUCTION: Smoking is known to affect whole-blood expression and methylation profiles. Although whole-genome methylation studies indicated that effects observed in blood may be driven by changes within leukocyte subtypes, these phenomena have not been explored using expression profiling. MATERIAL AND METHODS: This study reanalyzed data from the Correlated Expression and Disease Association Research (CEDAR) patient cohort recruited by Momozawa et al. (E-MTAB-6667). Data from gene expression profiling of immunomagnetically sorted CD4(+), CD8(+), CD14(+), CD15(+), and CD19(+) cells were processed. Differential expression analyses were conducted in each immune cell type, followed by gene ontology analysis and supplementary investigations. RESULTS: Ninety-four differentially expressed genes were found (CD8(+) n = 58, CD14(+) n = 20, CD4(+) n = 14, CD19(+) n = 2). Two key smoking-related genes were overexpressed in specific cell types: LRRN3 (CD4(+), CD8(+)) and MMP25 (CD8(+), CD14(+)). In CD4(+) cells smoking was associated with reduced expression of the NK cell receptor KLRB1, suggesting CD4(+) subpopulation shifts and differences in interferon signaling (reduced IRF1 and IL18RAP in smokers). Key results and their integration with an immune protein-protein interaction network revealed that smoking influences integrins in CD8(+) cells (ITGB7, ITGAL, ITGAM, ITGB2). C-type lectin CLEC4A was reduced in CD8(+) cells and CLEC10A was increased in CD14(+) cells from smokers; moreover, CLEC5A (CD8(+)), CLEC7A (CD8(+)) and CLEC9A (CD19(+)) were related to smoking in supplementary analyses. CD14(+) cells from smokers exhibited overexpression of LDLR and the formyl peptide receptor FPR3. CONCLUSIONS: Smoking specifically alters vital immune regulation genes in lymphocyte subtypes, especially CD4(+), CD8(+) and CD14(+) cells.