Identification of the key genes and immune infiltrating cells determined by sex differences in ischaemic stroke through co‐expression network module

Abstract Background There are considerable sex differences in patients with myocardial infarction (MI). However, the recent temporal trends in characteristics and outcomes in women vs. men, particularly in an Asian population, remain poorly understood. Purpose We aim to evaluate the sex differences in characteristics and outcomes, and how have these differences evolved over the past 2 decades in patients with MI. Methods From a well-validated territory-wide database in Hong Kong, we included patients with incident acute MI from 1999/01/01 to 2018/12/31. Outcomes of interest include, at 30 days, all-cause death, new-onset heart failure (HF), and ischaemic stroke. Trends in sex differences in baseline characteristics were evaluated using linear and Poisson regression, while differences in outcomes were evaluated using Cox proportional hazard model, adjusted with demographics, comorbidities, and baseline medications. A Fine-Gray model was used to evaluate HF and ischaemic stroke to account for competing risk, with all-cause death defined as competing event. Results A total of 130,218 patients (age 73.6±13.9 years, 40.0% female) were included. Women were older (79.5±11.7 vs. 69.6±13.8 years, P<0.001) and had a more pronounced increasing trend in age over time (interaction P<0.001). Women were also more comorbid overall (Charlson Comorbidity Index [CCI] 1.25 vs 0.85, age-adjusted P<0.001), but the rising trend in CCI over time was less pronounced than in men (interaction P<0.001) (Figure 1). Women had more baseline hypertension, diabetes, and severe renal disease than men (age-adjusted P<0.001), while the increasing trends in these comorbidities were all more pronounced in men than in women (all interaction P<0.001). Women were more likely to have ST-elevation overall (P<0.001). Although the crude 30-day mortality rate was higher in women (32.6% vs 23.9%), after adjustment for confounders, they had a lower risk of death (hazard ratio [HR] 0.97, 95% CI [0.96 to 0.99], P=0.003). There was no significant difference in the decreasing trend in 30-day mortality between both sexes (interaction P=0.787) (Figure 1). Women had a higher risk of developing HF (HR 1.04 [1.01 to 1.08], P=0.012) and ischemic stroke (HR 1.36 [1.24 to 1.48], P<0.001) in 30 days. Among patients aged ≤55 (N=15,324), women (N=2,161, 14.1%) had higher risks of all-cause death (HR 1.61 [1.40 to 1.85], P<0.001), HF (HR 1.64 [1.17 to 2.32], P=0.004), and ischemic stroke (HR 1.69 [1.14 to 2.51], P=0.010) in 30 days, even after adjustment for covariates. The excess mortality in women declined over time (interaction P=0.002). Conclusions Women MI patients were older and more comorbid compared to men, which contributed to the higher risk of death, HF, and ischemic stroke among women. Among young MI patients, the increased risk for adverse outcomes among women was particularly pronounced, though the sex differences in mortality reduced over time. FUNDunding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): The Shenzhen Key Medical DisciplineThe Sanming Project of HKU-SZH Cardiology

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Sex differences in the evaluation and treatment of acute ischaemic stroke

The Lancet Neurology ◽

10.1016/s1474-4422(18)30201-1 ◽

2018 ◽

Vol 17 (7) ◽

pp. 641-650 ◽

Cited By ~ 27

Author(s):

Cheryl Bushnell ◽

Virginia J Howard ◽

Lynda Lisabeth ◽

Valeria Caso ◽

Seana Gall ◽

...

Keyword(s):

Sex Differences ◽

Ischaemic Stroke ◽

Acute Ischaemic Stroke

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Sex differences in acute ischaemic stroke patients: clinical presentation, causes and outcomes

European Journal of Neurology ◽

10.1111/ene.14299 ◽

2020 ◽

Vol 27 (8) ◽

pp. 1680-1688

Author(s):

F. Medlin ◽

M. Amiguet ◽

A. Eskandari ◽

P. Michel

Keyword(s):

Sex Differences ◽

Ischaemic Stroke ◽

Acute Ischaemic Stroke ◽

Clinical Presentation ◽

Stroke Patients

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Sex differences in ischaemic stroke: potential cellular mechanisms

Clinical Science ◽

10.1042/cs20160841 ◽

2017 ◽

Vol 131 (7) ◽

pp. 533-552 ◽

Cited By ~ 33

Author(s):

Anjali Chauhan ◽

Hope Moser ◽

Louise D. McCullough

Keyword(s):

Sex Differences ◽

Ischaemic Stroke ◽

Recurrent Stroke ◽

Young Male ◽

Nursing Home Care ◽

Cellular Mechanisms ◽

Ischaemic Injury ◽

Stroke Incidence ◽

Incidence And Mortality ◽

Tissue Plasminogen

Stroke remains a leading cause of mortality and disability worldwide. More women than men have strokes each year, in part because women live longer. Women have poorer functional outcomes, are more likely to need nursing home care and have higher rates of recurrent stroke compared with men. Despite continued advancements in primary prevention, innovative acute therapies and ongoing developments in neurorehabilitation, stroke incidence and mortality continue to increase due to the aging of the U.S. population. Sex chromosomes (XX compared with XY), sex hormones (oestrogen and androgen), epigenetic regulation and environmental factors all contribute to sex differences. Ischaemic sensitivity varies over the lifespan, with females having an “ischaemia resistant” phenotype that wanes after menopause, which has recently been modelled in the laboratory. Pharmacological therapies for acute ischaemic stroke are limited. The only pharmacological treatment for stroke approved by the Food and Drug Administration (FDA) is tissue plasminogen activator (tPA), which must be used within hours of stroke onset and has a number of contraindications. Pre-clinical studies have identified a number of potentially efficacious neuroprotective agents; however, nothing has been effectively translated into therapy in clinical practice. This may be due, in part, to the overwhelming use of young male rodents in pre-clinical research, as well as lack of sex-specific design and analysis in clinical trials. The review will summarize the current clinical evidence for sex differences in ischaemic stroke, and will discuss sex differences in the cellular mechanisms of acute ischaemic injury, highlighting cell death and immune/inflammatory pathways that may contribute to these clinical differences.

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Bioinformatics Analysis of Gene Expression Profiles of Sex Differences in Ischemic Stroke

BioMed Research International ◽

10.1155/2019/2478453 ◽

2019 ◽

Vol 2019 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Wenhao Zhu ◽

Yinan Nan ◽

Shaoqing Wang ◽

Wei Liu

Keyword(s):

Gene Expression ◽

Immune Response ◽

Sex Differences ◽

Ischemic Stroke ◽

Functional Enrichment ◽

Biological Processes ◽

Receptor Signaling ◽

Ppi Network ◽

Apoptotic Process ◽

Key Genes

Ischemic stroke (IS) is a complex disease with sex differences in epidemiology, presentations, and outcomes. However, the sex-specific mechanism underlying IS remains unclear. The purpose of this study was to identify key genes contributing to biological differences between sexes. First, we downloaded the gene expression data of GSE22255 from Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) were identified using R software and related packages. Second, DEGs were separately analyzed by Gene Ontology enrichment and pathways analyses. Third, protein-protein interaction (PPI) network was constructed to further investigate the interactions of DEGs. A total of 123 DEGs were identified between sexes, including 8 upregulated and 115 downregulated genes. In the PPI network, ten key genes were identified, including IL1α, IL1β, IL6, IL8, CXCL1, CXCL2, CXCL20, CCL4, ICAM1, and PTGS2. Functional enrichment analysis revealed that these genes were mainly enriched in biological processes of immune response and apoptotic process, also in pathways of TNF and NOD-like receptor signaling. In conclusion, the above ten genes may have a protective effect on IS females through their direct or indirect involvement in biological processes of immune response and apoptotic process, as well as in TNF and NOD-like receptor signaling pathways. The results of this study may help to gain new insights into the sex-specific mechanisms underlying IS females and may suggest potential therapeutic targets for disease treatment.

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Effect of sex differences on prognosis of intravenous thrombolysis: data from the Thrombolysis Implementation and Monitor of Acute Ischemic Stroke in China (TIMS-China)

Stroke and Vascular Neurology ◽

10.1136/svn-2020-000351 ◽

2020 ◽

pp. svn-2020-000351 ◽

Cited By ~ 1

Author(s):

Hongyu Zhou ◽

Weiqi Chen ◽

Yuesong Pan ◽

Yue Suo ◽

Xia Meng ◽

...

Keyword(s):

Sex Differences ◽

Ischemic Stroke ◽

Ischaemic Stroke ◽

Acute Ischemic Stroke ◽

Functional Outcome ◽

Statistical Significance ◽

Intravenous Thrombolysis ◽

Chinese Patients ◽

Nihss Score ◽

Significant Difference

Background and purposePrevious studies have reported conflicting results as to whether women have poorer functional outcome than men after thrombolytic therapy. This study aims to investigate the relationship between sex differences and the prognosis of intravenous thrombolysis in Chinese patients with acute ischaemic stroke.MethodsThe patients enrolled in this study were from the Chinese Acute Ischemic Stroke Thrombolysis Monitoring and Registration study. The primary outcome was poor functional outcome, defined as a 3-month modified Rankin score of 3–6. The safe outcome was symptomatic intracranial haemorrhage (SICH) and mortality within 7 days and 90 days. Multiple Cox regression model was used to correct the potential covariates to evaluate the association between sex disparities and prognosis. Furthermore, the interaction of preonset Rankin scores, baseline National Institute of Health Stroke Scale (NIHSS) scores and Trial of Org 10172 in Acute Stroke Treatment (TOAST) types was statistically analysed.ResultsA total of 1440 patients were recruited, including 541 women and 899 men. The baseline information indicated that women were older at the time of onset (66.2±11.2 years vs 61.0±11.3 years, p<0.001), and more likely to have a history of atrial fibrillation (25.3% vs 11.2%, p<0.001), and had a higher NIHSS score on admission (12.3±6.8 vs 11.6±6.7, p=0.04). According to the prognosis analysis of unsatisfactory functional recovery, there was no significant difference between women and men (45.9% vs 37.1%; adjusted OR 1.01, 95% CI 0.75 to 1.37). As for the safe outcome, the proportion of SICH and mortality in women is relatively high but did not reach statistical significance. There was no significant interaction with sex, age, preonset Rankin score, NIHSS score, TOAST classification and the prognosis of intravenous thrombolysis.ConclusionsFor Chinese patients with ischaemic stroke, although women are older and more severe at the time of onset, the prognosis after intravenous thrombolysis is not significantly different from men.

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Identification of Key Genes and Pathways Associated with Sex Differences in Osteoarthritis Based on Bioinformatics Analysis

BioMed Research International ◽

10.1155/2019/3482751 ◽

2019 ◽

Vol 2019 ◽

pp. 1-8

Author(s):

Shiying Wang ◽

Huanmei Wang ◽

Wei Liu ◽

Biaofang Wei

Keyword(s):

Gene Expression ◽

Sex Differences ◽

Focal Adhesion ◽

Osteoclast Differentiation ◽

Enrichment Analysis ◽

Functional Enrichment Analysis ◽

Gene Expression Omnibus ◽

Functional Enrichment ◽

Ppi Network ◽

Key Genes

Sex differences have been suggested to play critical roles in the pathophysiology of osteoarthritis (OA), resulting in sex-specific prevalence and incidence. However, their roles in the development of OA remain largely unknown. The aim of this study was to screen out key genes and pathways mediating biological differences between OA females after menopause and OA males. First, the gene expression data of GSE36700 and GSE55457 were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) between sexes were identified using R software, respectively. The overlapping DEGs were obtained. Then, protein-protein interactive (PPI) network was constructed to further analyze interactions between the overlapping DEGs. Finally, enrichment analyses were separately performed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes tools. In our results, a total of 278 overlapping DEGs were identified between OA females after menopause and OA males, including 219 upregulated and 59 downregulated genes. In the PPI network, seven hub genes were identified, including EGF, ERBB2, CDC42, PIK3R2, LCK, CBL, and STAT1. Functional enrichment analysis revealed that these genes were mainly enriched in PI3K-Akt signaling pathway, osteoclast differentiation, and focal adhesion. In conclusion, the results in the current study suggest that pathways of PI3K-Akt, osteoclast differentiation, and focal adhesion may play important roles in the development of OA females after menopause. EGFR, ERBB2, CDC42, and STAT1 may be key genes related to OA progression in postmenopausal women and may be promising therapeutic targets for OA.

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