Association of DNA Methylation in Blood Pressure-Related Genes With Ischemic Stroke Risk and Prognosis

Zhang, Huan; Mo, Xing‐Bo; Wang, Aili; Peng, Hao; Guo, Daoxia; Zhong, Chongke; Zhu, Zhengbao; Xu, Tan; Zhang, Yonghong

doi:10.3389/fcvm.2022.796245

Cited by 7 publications

(6 citation statements)

References 53 publications

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“…Low levels of leukocyte DNA methylation of the PRDM6 gene have been previously associated with an increased risk of ischemic stroke and with worse outcomes at 3 months after an ischemic stroke 85 . Moreover, PRDM6 acts as an epigenetic regulator of vascular smooth muscle cell plasticity 86 .…”

Section: Discussionmentioning

confidence: 98%

“…Moreover, our pairwise analysis highlighted a locus at the PRDM6 that explained shared genetic susceptibility of VaD with ischemic stroke (IS) and WMH. Low levels of leukocyte DNA methylation of the PRDM6 gene have been previously associated with an increased risk of ischemic stroke and with worse outcomes at 3 months after an ischemic stroke 85 . Moreover, PRDM6 acts as an epigenetic regulator of vascular smooth muscle cell plasticity 86 .…”

Section: Discussionmentioning

confidence: 98%

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A meta-analysis of genome-wide association studies identifies new genetic loci associated with all-cause and vascular dementia

Fongang

Sargurupremraj²,

Jian³

et al. 2022

Preprint

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Dementia is multifactorial with Alzheimer (AD) and vascular (VaD) pathologies making the largest contributions. Genome-wide association studies (GWAS) have identified over 70 genetic risk loci for AD but the genomic determinants of other dementias, including VaD remain understudied. We hypothesize that common forms of dementia will share genetic risk factors and conducted the largest GWAS to date of "all-cause dementia" (ACD) and examined the genetic overlap with VaD. Our dataset includes 809,299 individuals from European, African, Asian, and Hispanic ancestries with 46,902 and 8,702 cases of ACD and VaD, respectively. We replicated known AD loci at genome-wide significance for both ACD and VaD and conducted bioinformatic analyses in prioritizing genes that are functionally relevant and shared with closely related traits and risk factors. For ACD, novel loci were associated with energy transport throughout the brain (SEMA4D), neuronal excitability (ANO3), amyloid plaques deposition in the brain (RBFOX1), and MRI markers of small vessel disease (HBEGF). Novel VaD loci were associated with hypertension, diabetes, and neuron maintenance (SPRY2, FOXA2, AJAP1, and PSMA3). In addition to the genetic overlap with neurodegenerative processes, genetic risk loci for ACD exhibited overlap with vascular risk factors (Type-II diabetes, blood pressure, lipid levels) and MRI markers of cerebral small vessel disease (cSVD). Our study identified genetic risk loci underlying ACD and VaD that point to the involvement of specific biological pathways and highlights their genetic overlap with vascular risk factors and MRI markers of cSVD. These novel insights could lead to new prevention and treatment strategies.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 98%

A meta-analysis of genome-wide association studies identifies new genetic loci associated with all-cause and vascular dementia

Fongang

Sargurupremraj²,

Jian³

et al. 2022

Preprint

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“…51 SYT7, encoding synaptotagmin 7, has been identified to have significant DNA methylation correlation with IS in a large-scale sequencing study. 52 The roles of FAM109A, MAN2A2, PVRL2, and others in IS require further investigation.…”

Section: Discussion Of Mechanisms Associated Shared Genesmentioning

confidence: 99%

Exploring Genetic Associations of Three Types of Risk Factors with Ischemic Stroke: An Integrated Bioinformatics Study

Liu

Wang

Cui

et al. 2023

Preprint

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Background: Ischemic stroke (IS) is a primary cause of disability and mortality globally. More and more reports suggest a strong association between blood pressure, blood glucose, and blood lipids and their metabolic products with IS. Methods: We extracted the genetic tools of blood pressure, blood glucose, and blood lipids and their metabolites as instrumental variables, which were then paired with GWAS data on IS and a Mendelian randomization (MR) analysis was performed to assess the effect of these exposures on the disease. Following the positive results, colocalization analysis was performed to identify shared genes associated with exposures and IS. We then performed differential expression analysis using the GEO dataset to identify the differentially expressed associated genes (DEAGs) from associated shared genes. Additional analyzes were performed on these DEAGs to obtain their importance scores using four machine learning models. A nomogram was created using genes with high importance scores to predict the level of risk assessment between DEAGs and IS. Results: There is a positive correlation between blood pressure, blood glucose and the risk of IS onset, while blood lipids and their metabolic products are positively or negatively correlated with the risk. There are 64 shared genes of blood pressure, blood lipids and their metabolic products with IS. Thirteen DEAGs were obtained, and among which FURIN, MAN2A2, HDDC3, ALDH2, and TOMM40 were identified as feature genes for creating the nomogram which can quantitatively predict the risk of IS onset with the expression of these feature genes. By cluster analysis, we found that DEAGs expression underlying immune inflammation, angiogenesis and development, lipid metabolism, etc. Conclusion: This study suggests a significant association between blood pressure, blood glucose, and blood lipids and their metabolic products with IS, and predicts that these exposures mainly regulate the occurrence, development, and prognosis of IS through mechanisms such as DNA repair, DNA methylation, mitochondrial repair, apoptosis, autophagy, etc.

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“…Syt7 interacts with BRCA1 to suppress the ubiquitination of HMGB3, which contributes to the role of Syt7 in thyroid cancer [16]. Recent advance reveals that Syt7 is involved in vascular systems, overexpression of Syt7 elevates blood pressure, and the methylation level of Syt7 promoter is significantly altered in ischemic stroke patients [14,18,19]. Calcium widely regulates physiological and pathological processes in multiple cells, and cardiomyocytes are of no exception.…”

Section: Discussionmentioning

confidence: 99%

“…The DNA methylation levels of Syt7 promoter are significantly associated with blood pressure of hypertensive patients. Syt7 knock-in mice showed significantly elevated blood pressure [14,18,19]. However, little is known about whether Syt7 is expressed in the myocardium and involved in the pathogenesis of heart diseases.…”

Section: Introductionmentioning

confidence: 99%

Synaptotagmin‐7 mediates cardiac hypertrophy by targeting autophagy

Sun,

Han,

et al. 2023

The FEBS Journal

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Sustained cardiac hypertrophy damages the heart and weakens cardiac function, often leading to heart failure and even death. Pathological cardiac hypertrophy has become a central therapeutic target for many heart diseases including heart failure. However, the underlying mechanisms of cardiac hypertrophy, especially the involvement of autophagy program, are still ill‐understood. Synaptotagmin‐7 (Syt7), a multifunctional and high‐affinity calcium sensor, plays a pivotal role in asynchronous neurotransmitter release, synaptic facilitation and vesicle pool regulation during synaptic transmission. However, little is known about whether Syt7 is expressed in the myocardium and involved in the pathogenesis of heart diseases. Here we showed that Syt7 was significantly upregulated in Ang II‐treated hearts and cardiomyocytes. Homozygous syt7 knockout (syt7‐/‐) mice exhibited significantly attenuated cardiac hypertrophy and fibrosis and improved cardiac function. We further found that Syt7 exerted a pro‐hypertrophic effect by suppressing the autophagy process. In exploring the upstream mechanisms, microRNA (miR)‐93 was identified to participate in the regulation of Syt7 expression. MiR‐93 protected hearts against Ang II‐induced hypertrophy through targeting Syt7‐autophagy pathway. In summary, our data reveal a new cardiac hypertrophy regulator and a novel hypertrophy regulating model composed of miR‐93, Syt7 and autophagy program. These molecules may serve as potential therapeutic targets in the treatment of cardiac hypertrophy and heart failure.

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Association of DNA Methylation in Blood Pressure-Related Genes With Ischemic Stroke Risk and Prognosis

Cited by 7 publications

References 53 publications

A meta-analysis of genome-wide association studies identifies new genetic loci associated with all-cause and vascular dementia

A meta-analysis of genome-wide association studies identifies new genetic loci associated with all-cause and vascular dementia

Exploring Genetic Associations of Three Types of Risk Factors with Ischemic Stroke: An Integrated Bioinformatics Study

Synaptotagmin‐7 mediates cardiac hypertrophy by targeting autophagy

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