Gene Expression in Peripheral Immune Cells following Cardioembolic Stroke Is Sexually Dimorphic

Abstract

AimsEpidemiological studies suggest that sex has a role in the pathogenesis of cardioembolic stroke. Since stroke is a vascular disease, identifying sexually dimorphic gene expression changes in blood leukocytes can inform on sex-specific risk factors, response and outcome biology. We aimed to examine the sexually dimorphic immune response following cardioembolic stroke by studying the differential gene expression in peripheral white blood cells.Methods and ResultsBlood samples from patients with cardioembolic stroke were obtained at ≤3 hours (prior to treatment), 5 hours and 24 hours (after treatment) after stroke onset (n = 23; 69 samples) and compared with vascular risk factor controls without symptomatic vascular diseases (n = 23, 23 samples) (ANCOVA, false discovery rate p≤0.05, |fold change| ≥1.2). mRNA levels were measured on whole-genome Affymetrix microarrays. There were more up-regulated than down-regulated genes in both sexes, and females had more differentially expressed genes than males following cardioembolic stroke. Female gene expression was associated with cell death and survival, cell-cell signaling and inflammation. Male gene expression was associated with cellular assembly, organization and compromise. Immune response pathways were over represented at ≤3, 5 and 24 h after stroke in female subjects but only at 24 h in males. Neutrophil-specific genes were differentially expressed at 3, 5 and 24 h in females but only at 5 h and 24 h in males.ConclusionsThere are sexually dimorphic immune cell expression profiles following cardioembolic stroke. Future studies are needed to confirm the findings using qRT-PCR in an independent cohort, to determine how they relate to risk and outcome, and to compare to other causes of ischemic stroke.

Altered Expression of Long Noncoding RNAs in Blood After Ischemic Stroke and Proximity to Putative Stroke Risk Loci

“…One study reported differences in DNA methylation in blood of healthy male and female donors 45 , suggesting sexual dimorphism in lncRNA expression. Similarly, the current study found that leukocyte lncRNA expression differed between male and female samples supporting previous evidence of sexual dimorphism in post-stroke mRNA expression 4, 9, 28 .…”

“…For control samples, this time point was recorded as zero. Blood draw timing was included as a covariate in the statistical analyses 4, 5, 9, 28-30 . Blood was frozen and stored at −80°C.…”

“…Previous studies show that coding messenger RNA (mRNA) expression changes in peripheral human blood following stroke and that this expression is sexually dimorphic and temporally dependent 1-9 . Noncoding RNAs (ncRNAs) comprise a majority of the genome and play important developmental and physiological roles, as well as roles in disease mainly by regulating gene expression 10, 11 .…”

“…This regulation by ncRNAs can be on proximal genes or distant genes via many mechanisms, including modifying chromatin, controlling transcription, degrading mRNA, and splicing 12 . Although both long and short ncRNAs have regulatory roles, small noncoding microRNAs have been most studied in ischemic stroke (IS) 9, 13-15 .…”

Blood transcriptome changes after stroke in an African American population

“…obs. Robert Meller RM), which agrees with reports of gene expression differences following stroke between males and females 28, 29. These preliminary data show the clear need for further studies to better understand both racial and sex‐associated differences in response to stroke.…”