The X-Chromosome Has a Different Pattern of Gene Expression in Women Compared With Men With Ischemic Stroke

Clinical and epidemiological evidence suggests that ischemic stroke (IS) risk, etiology, response to treatment, and outcome are different between men and women. Females tend to have more cardioembolic stroke and men more arterial and lacunar stroke. Differences in response to thrombolysis and functional outcome may also exist between the sexes.

The sex differences in IS have frequently been attributed to hormonal differences, including estrogen, progesterone, and testosterone. However, some X-linked diseases can affect the brain, clotting, and the immune response independent of hormonal effects such as Fragile X, hemophilia, and Fabry disease. Thus, we sought to determine whether there is sex- specific expression of genes on the X-chromosome after IS. 

The human X-chromosome has many features that are unique in the human genome. Females inherit 1 X-chromosome from each parent, whereas males inherit a single, maternal X-chromosome. Gene expression on 1 of the female X-chromosomes is silenced during development by X-chromosome inactivation. However, for X-chromosome inactivation “escapees” (15%–25% of the X-chromosome genes), differential expression as well as developmental reactivation of the inactive copy have been reported. In males, the short tips of the X-chromosome can recombine with the equivalent segments on the Y-chromosome (pseudoautosomal regions). Genes outside these regions of the X-chromosome are strictly X-linked and most do not have homologs on the Y-chromosome. There are homologous genes on the X-chromosome, outside of the pseudoautosomal regions, but their functional similarity to the Y-chromosome paralogs is unclear. X/Y paralogs have a sex-specific pattern of expression, which suggests these paralogs may not have equivalent functions. Biological sex affected X-chromosome gene expression in blood after IS. Although some of the X-chromosome gene expression changes were identical in both sexes, some were unique to males or females. These findings suggest that the X-chromosome contributes to differences that exist between men and women with IS. Although a number of the biological processes presented subsequently have been implicated in playing a key role in the response to stroke, most of the individual genes have not been associ- ated with vascular risk factors or stroke nor have their sexually dimorphic patterns of expression been suggested in human studies. Genes expressed within the first 3-hour time window are among the most interesting because they are unaffected by treatment and are being induced during the time when acute stroke therapy is likely to be beneficial. Genes that change expression in the 3- to 5-hour time period might be those most likely to be affected by treatment because treatment was initiated after the first blood sample but before 3 hours after stroke. Genes expressed at 24 hours likely represent the full complement of the immune cell changes associated with cell death, cellular phagocytosis as well as in the beginnings of repair.