Abstract
BackgroundCigarette smoking is the leading modifiable risk factor for disease and death worldwide. Previous studies quantifying gene-level expression have documented the effect of smoking on mRNA levels. Using RNA sequencing, it is possible to analyze the impact of smoking on complex regulatory phenomena (e.g. alternative splicing, differential isoform usage) leading to a more detailed understanding of the biology underlying smoking-related disease.MethodsWe used whole-blood RNA sequencing to describe gene and exon-level expression differences between 229 current and 286 former smokers in the COPDGene study. We performed differential gene expression and differential exon usage analyses using the voom/limma and DEXseq R packages. Samples from current and former smokers were compared while controlling for age, gender, race, lifetime smoke exposure, cell counts, and technical covariates.ResultsAt an adjusted p-value <0.05, 171 genes were differentially expressed between current and former smokers. Differentially expressed genes included 7 long non-coding RNAs that have not been previously associated with smoking: LINC00599, LINC01362, LINC00824, LINC01624, RP11-563D10.1, RP11-98G13.1, AC004791.2. Secondary analysis of acute smoking (having smoked within 2-h) revealed 5 of the 171 smoking genes demonstrated an acute response above the baseline effect of chronic smoking. Exon-level analyses identified 9 exons from 8 genes with significant differential usage by smoking status, suggesting smoking-induced changes in isoform expression.ConclusionsTranscriptomic changes at the gene and exon levels from whole blood can refine our understanding of the molecular mechanisms underlying the response to smoking.
Highlights
Cigarette smoking is the leading modifiable risk factor for disease and death worldwide
Alternative splicing and differential isoform usage play a critical role in human biology, but little is known about alternative splicing with respect to cigarette smoking
We used RNA sequencing (RNA-seq) in a large study of current and former smokers to identify transcripts that are altered by smoking
Summary
Cigarette smoking is the leading modifiable risk factor for disease and death worldwide. Cigarette smoking increases risk of many diseases including cancer, chronic obstructive pulmonary disease, coronary heart disease, To identify the molecular mechanisms underlying response to smoke exposure, previous studies have characterized gene expression changes in a number of human tissues including, peripheral whole blood [6,7,8,9], lymphocytes [10], monocytes [11], bronchial epithelial cells [12, 13], alveolar macrophages [14], and lung tissue [15,16,17] This includes a recently published meta-analysis of 1421 current, 3955. Alternative splicing and differential isoform usage play a critical role in human biology, but little is known about alternative splicing with respect to cigarette smoking
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