Objective:
Ischemic stroke (IS) is sexually dimorphic for risk factors, age, heritability, causes, treatment, and outcome. We identified transcriptional correlates with 90-day outcome that differed between male and female IS subjects.
Methods:
RNA from 72 samples from 2 peripheral blood draws (at ≤3 and 24h post IS onset) was analyzed on Affymetrix U133 Plus 2 microarrays. These represented samples from 36 CLEAR trial IS patients treated with tPA with or without eptifibatide after the first blood sample within 3 hours of stroke onset. Changes in gene expression levels (deltaGE) between 3h and 24h were calculated and the association with percent NIH Stroke Scale (NIHSS) improvement from 3h to 90 days (% Improvement) examined. We used mixed-effects linear regression, including Treatment, Age, Sex, Vascular Risk Factors, 3h NIHSS, % Improvement, and a Sex * % Improvement interaction. Sex differences in association of gene expression with % Improvement were determined by examining the Sex * % Improvement interaction term, p<0.005 was considered statistically significant.
Results:
577 genes correlated differently with % Improvement in IS males and females. These included matrix metalloproteinases (MMPs), which play a major role in BBB dysfunction and outcomes post IS.
MMP11
,
MMP14
and
MM17
correlated with % Improvement in opposite direction in males and females. Inflammatory genes like
IL-27
, implicated in infarct volume and stroke outcome, and ABC transporters (
ABCC9
) also had opposite correlation with % Improvement in males and females. Calmodulin 1 (
CAML1
) was also sexually dimorphic, and a SNP in
CALM1
has been implicated in IS risk and blood coagulation in female IS patients. EIF2 signaling, a major protein synthesis pathway was activated in males (adj. p = 1e-8), while suppressed in females (adj. p value = 1e-9). Protein synthesis and associated unfolded protein response cascade have previously been implicated in stroke outcome.
Conclusions:
The identified sexually dimorphic gene expression associated with 90-day improvement might relate to sex differences in blood immune and clotting pathways. The findings expand our understanding of the genomic underpinnings associated with stroke outcome and may serve as potential sex-specific treatment targets.
Sexually dimorphic gene expression and transcriptome evolution provide mixed evidence for a fast-Z effect in Heliconius
