Y Chromosome Gene Expression in the Blood of Male Patients With Ischemic Stroke Compared With Male Controls

doi:10.1016/j.genm.2012.01.005

Gender Medicine

Volume 9, Issue 2, April 2012, Pages 68-75.e3

https://doi.org/10.1016/j.genm.2012.01.005 Get rights and content

Abstract

Background

Sex is suggested to be an important determinant of ischemic stroke risk factors, etiology, and outcome. However, the basis for this remains unclear. The Y chromosome is unique in males. Genes expressed in males on the Y chromosome that are associated with stroke may be important genetic contributors to the unique features of males with ischemic stroke, which would be helpful for explaining sex differences observed between men and women.

Objective

We compared Y chromosome gene expression in males with ischemic stroke and male controls.

Methods

Blood samples were obtained from 40 male patients ≤3, 5, and 24 hours after ischemic stroke and from 41 male controls (July 2003–April 2007). RNA was isolated from blood and was processed using Affymetrix Human U133 Plus 2.0 expression arrays (Affymetrix Inc., Santa Clara, California). Y chromosome genes differentially expressed between male patients with stroke and male control subjects were identified using an ANCOVA adjusted for age and batch. A P < 0.05 and a fold change >1.2 were considered significant.

Results

Seven genes on the Y chromosome were differentially expressed in males with ischemic stroke compared with controls. Five of these genes (VAMP7, CSF2RA, SPRY3, DHRSX, and PLCXD1) are located on pseudoautosomal regions of the human Y chromosome. The other 2 genes (EIF1AY and DDX3Y) are located on the nonrecombining region of the human Y chromosome. The identified genes were associated with immunology, RNA metabolism, vesicle fusion, and angiogenesis.

Conclusions

Specific genes on the Y chromosome are differentially expressed in blood after ischemic stroke. These genes provide insight into potential molecular contributors to sex differences in ischemic stroke.

Introduction

Ischemic stroke is influenced by a person's sex, with suggested differences in risk factors, outcomes, and etiology between men and women.1, 2, 3, 4, 5 For example, men have increased stroke risk in middle age compared with women,1, 6 whereas women tend to have strokes at a later age and have more cardioembolic stroke.1, 3, 7 These differences have been explained by hormone-dependent and hormone-independent mechanisms.⁸ Peripheral and brain immune and inflammatory responses, cell apoptosis, and cell death may contribute to the sex differences in stroke.9, 10 The Y chromosome is unique in males and is a clear genetic difference that exists between males and females. Previous studies have demonstrated the importance of the Y chromosome in brain function and disease. The sex-determining region Y gene (SRY) on the Y chromosome modulates brain dopamine concentrations and has been linked to increased risk in men of dopamine-related disorders, such as schizophrenia and Parkinson disease.¹¹ Whether there is a similar association between Y chromosome gene expression and ischemic stroke is unknown. Thus, we set out to discover genes expressed in males on the Y chromosome that are associated with stroke, which may identify genetic contributors to the unique features of males with ischemic stroke and may help explain sex differences observed between males and females.

Although the Y chromosome has few genes, it is complex. It can be divided into 2 regions: the pseudoautosomal region (PAR) and the nonrecombining region of the Y chromosome (NRY). The PAR accounts for 5% of the Y chromosome and encodes genes that are identical to those present on the X chromosome. Gene expression levels for these PAR genes can be different in males and females, which may result in a variety of dose-dependent effects.12, 13, 14 The NRY accounts for the remaining 95% of the Y chromosome. Genes in the NRY are considered Y specific since they are not recombined with the X chromosome. Some of these genes are expressed mainly in testes (testis-specific genes), and some have nonidentical homologues on the male X chromosome (Y-linked homologues). It remains unclear whether the functions of these X and Y homologues are interchangeable,¹⁵ but some studies16, 17 have suggested that they have different functions. Thus, genes expressed on the Y chromosome may contribute to sex differences in stroke.

In the present study, we compared Y chromosome gene expression in males with ischemic stroke and male controls. A variety of Y chromosome genes were differentially expressed after stroke, suggesting that Y chromosome gene expression may contribute to sex differences in stroke.

Section snippets

Participants

Male patients with acute ischemic stroke were recruited through the CLEAR (Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke) trial, a multicenter, randomized, double-blind safety study of recombinant tissue-type plasminogen activator and eptifibatide (ClinicalTrials.gov identifier: NCT00250991) (July 2003–April 2007).¹⁸ This trial is part of the National Institute of Neurological Disorders and Stroke–funded Specialized Programs of Translational Research in

Demographic Characteristics and Probe Sets

There were 40 male patients with stroke and 41 male controls in this study (Table). There was no significant difference in race between the groups (P = 0.74) (Table). There was a significant difference in the mean (SEM) ages of controls (50.2 [2.7] years) and patients with ischemic stroke (66.9 [2.0] years) (P < 0.05). There was a significant difference in hypertension (P < 0.05) but not in hyperlipidemia (P = 0.61) or diabetes (P = 0.35) between groups (Table).

Of the 123 Y chromosome probe

Discussion

This is the first study, to our knowledge, to demonstrate changes in Y chromosome gene expression in whole blood after ischemic stroke in males. Some of the changes in gene expression after stroke occurred for Y chromosome–specific genes located in the NRY. This finding suggests that the Y chromosome might contribute to sex differences in ischemic stroke.

Conclusions

We compared Y chromosome gene expression in males with ischemic stroke to male controls. Specific genes on the Y chromosome are differentially expressed in blood following ischemic stroke. This suggests that the Y chromosome might contribute to some sex differences in ischemic stroke.

Conflicts of Interest

The authors have indicated that they have no conflicts of interest regarding the content of this article.

Acknowledgments

This study was supported by grants NS056302 (Dr. Sharp) and PO21040N635110 (Dr. Broderick) from the NIH/National Institute of Neurological Disorders and Stroke and the American Heart Association Bugher Foundation (Dr. Sharp). Dr. Jickling is a fellow of the Canadian Institutes of Health Research. Drs. Tian, Xu, and Ander were Bugher Fellows. Dr. Turner is supported by a National Health and Medical Research Council Post-Doctoral Training Fellowship (Australia, #519365). This publication was also

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Original researchY Chromosome Gene Expression in the Blood of Male Patients With Ischemic Stroke Compared With Male Controls

Abstract

Background

Objective

Methods

Results

Conclusions

Introduction

Section snippets

Participants

Demographic Characteristics and Probe Sets

Discussion

Conclusions

Conflicts of Interest

Acknowledgments

Curr Biol

Genomics

Blood

Gender differences in acute ischemic stroke: etiology, stroke patterns and response to thrombolysis

Stroke

Gender differences in stroke examined in a 10-year cohort of patients admitted to a Canadian teaching hospital

Stroke

Gender differences in patients with acute ischemic stroke

Womens Health (Lond Engl)

Risk factors for ischaemic stroke

Int J Stroke

Gender differences in outcomes after ischemic stroke: role of ischemic lesion volume and intracranial large-artery occlusion

Cerebrovasc Dis

The lifetime risk of stroke: estimates from the Framingham Study

Stroke

The gender effect in stroke thrombolysis: of CASES, controls, and treatment-effect modification

Neurology

Mechanisms of gender-linked ischemic brain injury

Restor Neurol Neurosci

The X chromosome in immune functions: when a chromosome makes the difference

Nat Rev Immunol

Sex differences in cerebral ischemia: possible molecular mechanisms

J Neurosci Res

X-inactivation profile reveals extensive variability in X-linked gene expression in females

Nature

A synaptobrevin-like gene in the Xq28 pseudoautosomal region undergoes X inactivation

Nat Genet

Original research
Y Chromosome Gene Expression in the Blood of Male Patients With Ischemic Stroke Compared With Male Controls