Smoking affects gene expression in blood of patients with ischemic stroke

Abstract

Objective Though cigarette smoking (CS) is a well‐known risk factor for ischemic stroke (IS), there is no data on how CS affects the blood transcriptome in IS patients. Methods We recruited IS‐current smokers (IS‐SM), IS‐never smokers (IS‐NSM), control‐smokers (C‐SM), and control‐never smokers (C‐NSM). mRNA expression was assessed on HTA‐2.0 microarrays and unique as well as commonly expressed genes identified for IS‐SM versus IS‐NSM and C‐SM versus C‐NSM. Results One hundred and fifty‐eight genes were differentially expressed in IS‐SM versus IS‐NSM; 100 genes were differentially expressed in C‐SM versus C‐NSM; and 10 genes were common to both IS‐SM and C‐SM (P < 0.01; |fold change| ≥ 1.2). Functional pathway analysis showed the 158 IS‐SM‐regulated genes were associated with T‐cell receptor, cytokine–cytokine receptor, chemokine, adipocytokine, tight junction, Jak‐STAT, ubiquitin‐mediated proteolysis, and adherens junction signaling. IS‐SM showed more altered genes and functional networks than C‐SM. Interpretation We propose some of the 10 genes that are elevated in both IS‐SM and C‐SM (GRP15, LRRN3, CLDND1, ICOS, GCNT4, VPS13A, DAP3, SNORA54, HIST1H1D, and SCARNA6) might contribute to increased risk of stroke in current smokers, and some genes expressed by blood leukocytes and platelets after stroke in smokers might contribute to worse stroke outcomes that occur in smokers.

Gene expression in blood reflects smoking exposure among cancer-free women in the Norwegian Women and Cancer (NOWAC) postgenome cohort

“…Around 40% of the genes were over-expressed in CS as compared to both NS and FS (i.e., 60% were underexpressed). Although higher proportions of up-regulated genes have been observed more frequently in other studies 7,[9][10][11] , higher proportions of down-regulated genes have also been observed 14,16 . Interestingly, there could be sex differences in the directionality of observed DEGs, as one study comparing smokers and non-smokers observed that 29% of DEGs in men were down-regulated, compared to 62% in women 7 .…”

“…The study participants had similar proportions of CS, FS, and NS. They had comparable mean age and BMI at the time of blood collection as that of the full cohort, and to that of participants in other studies targeting the relation between smoking exposure and gene expression [9][10][11] . Among the 7713 genes assessed, 911 and 1082 genes were differentially expressed in CS-vs-NS and CS-vs-FS comparisons, respectively.…”

“…Among the women we included in our study, 51%, 24%, and 25% had information available at four, three, and two time points, respectively. Still, this study was based on self-reported smoking information from questionnaires, as in most other studies 9 , 10 , 13 – 16 . Many studies have measured concentrations of the metabolite of nicotine, cotinine, in blood, urine or saliva in addition to self-reported smoking status 9 , 14 – 16 .…”

“…samples') is easy and minimally invasive, and these samples can reveal features that are relevant for studies of human health effects 8 . Current exposure to tobacco smoke has been linked with modulated expression of many genes in blood, for example LRRN3, CLDND1, GPR15, ATF4, SOD2, and CDKN1C [9][10][11][12][13][14][15][16] . Altered gene expression in blood has also been linked to diseases for which smoking is a risk factor 17 .…”

A cell-type deconvolution meta-analysis of whole blood EWAS reveals lineage-specific smoking-associated DNA methylation changes

“…Our analysis further suggests that smoking-associated DNAm changes at LRRN3 are specific to lymphocytes, which is an entirely novel insight. Of note, another recent study has shown that both GPR15 and LRRN3 exhibit elevated expression in the blood of smokers that have had an ischemic stroke, for which smoking is a risk factor 79 . Among the other lymphoid-specific DMCTs, cg02657160 (CPOX) has previously been reported to be specifically hypomethylated in peripheral blood mononuclear cells (PBMCs) of smokers, but not in whole blood 47 .…”