DNA Methylation in Stroke. Update of Latest Advances

Krupiński, Jerzy; Carrera, Caty; Muiño, Elena; Torres, Nuria; Al-Baradie, Raid Saleem; Cullell, Nàtalia; Fernández‐Cadenas, Israel

doi:10.1016/j.csbj.2017.12.001

Cited by 28 publications

(16 citation statements)

References 58 publications

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“…Using EWAS, Rask-Andersen et al 25 reported myocardial infarction-specific methylation pattern in 211 CpG-sites of individuals living in northern Sweden. However, no significant stroke-associated methylation pattern was observed in 27 stroke patients 8 . Baccarelli et al 26 showed an association between hypomethylation and stroke occurrence or mortality.…”

Section: Discussionmentioning

confidence: 86%

“…Genetic background accounts for approximately 37.9% of stroke pathogenesis 8 – 10 . However, the frequency of susceptible genetic variants in stroke patients varies between 5 and 10% 9 , which indicates cryptic genetic changes beyond DNA sequences 8 , 11 . One of these cryptic variations involving novel epigenetic pathways is DNA methylation, histone modifications or non-coding RNA 11 .…”

Section: Introductionmentioning

confidence: 99%

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Genome-wide blood DNA methylation analysis in patients with delayed cerebral ischemia after subarachnoid hemorrhage

Kim

Youn

et al. 2020

Sci Rep

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Little is known about the epigenetic changes associated with delayed cerebral ischemia (DCI) pathogenesis after subarachnoid hemorrhage (SAH). Here, we investigated genome-wide DNA methylation profiles specifically associated with DCI, which is a major contributor to poor clinical outcomes. An epigenome-wide association study (EWAS) and quantitative real-time PCR (qRT-PCR) were conducted in 40 SAH patients (DCI, n = 13; non-DCI, n = 27). A replication study using bisulfite modification and methylation-specific PCR was further performed in 36 patients (DCI, n = 12; non-DCI, n = 24). The relative degree of methylation was described as the median and 25th-75th percentile. No significant differences in clinical characteristics between DCI and non-DCI groups were observed. Among the top 10 differentially methylated genes analyzed via EWAS, two aberrantly methylated CpG sites of cg00441765 (INSR gene) and cg11464053 (CDHR5 gene) were associated with decreased mRNA expression (2 −ΔCt). They include INSR [0.00020 (0.00012-0.00030) in DCI vs. 0.00050 (0.00030-0.00068) in non-DCI] and CDHR5 [0.114 (0.053-0.143) in DCI vs. 0.170 (0.110-0.212) in non-DCI]. Compared with non-DCI cases, patients with DCI exhibited an increased degree of methylation in the replication study: INSR, 0.855 (0.779-0.913) in DCI vs. 0.582 (0.565-0.689) in non-DCI; CDHR5, 0.786 (0.708-0.904) in DCI vs. 0.632 (0.610-0.679) in non-DCI. Hypermethylation of two novel genes, INSR and CDHR5 may serve as a biomarker for early detection of DCI following SAH. Delayed cerebral ischemia (DCI) is a major contributor to poor neurologic outcomes in patients diagnosed with subarachnoid hemorrhage (SAH) 1. However, it is also a preventable and treatable complication. Well-known risk factors for DCI include female gender, cigarette smoking, hyperglycemia, high Hunt-Hess (HH) grade and thick hemorrhage at admission 1-3. The majority of genetic studies investigating DCI have focused on gene expression or linkage analyses of candidate genes 4. Candidate genes include those associated with inflammation, endothelial dysfunction, fibrinolysis, and brain metabolism. A previous meta-analysis 5 showed that ApoE ε4 carriers had a higher risk of DCI than non-ε4 carriers. Kim et al. 6 reported that DCI was more frequently observed in patients expressing haptoglobin (Hp) 2-2 than Hp 1-1 phenotype. In particular, SAH patients with Hp 2-1, and non-DCI patients showed higher α1intensities than DCI patients. A genome-wide association study (GWAS) 7 revealed that SNP rs999662 encompassing solute carrier family 12 member 3 (SLC12A3) was significantly associated with high transcranial Doppler (TCD) velocities, such as angiographic vasospasm, which leads to DCI 7. Genetic background accounts for approximately 37.9% of stroke pathogenesis 8-10. However, the frequency of susceptible genetic variants in stroke patients varies between 5 and 10% 9 , which indicates cryptic genetic changes beyond DNA sequences 8,11. One of these cryptic variations involving novel epigenetic pathways is DNA

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Section: Discussionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Genome-wide blood DNA methylation analysis in patients with delayed cerebral ischemia after subarachnoid hemorrhage

Kim

Youn

et al. 2020

Sci Rep

View full text Add to dashboard Cite

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“…The symptoms of ischemic stroke are mainly characterized by impaired brain function, but the primary process of the disease itself is not generally associated with brain tissue. On the contrary, it is a disease related to vasculature, where complex interactions of lipids and endothelium occurred at the vascular and blood levels, with substantial involvement of immune cells and inflammatory factors, and ultimately leading to the formation of plaque and interrupt of blood supply to the brain [4, 32, 33]. Baccarelli et al indicated that subjects with stroke had lower LINE-1 methylation level in blood [34], and Braun et al found in live human individuals that the correlation coefficient of the average methylation level for each CpG across subjects was 0.86 for blood and brain, and the blood had 20.8% of CpGs that correlated to the brain, which is the highest proportion as compared to that in buccal and saliva tissues.…”

Section: Discussionmentioning

confidence: 99%

Overall and sex-specific associations between methylation of the ABCG1 and APOE genes and ischemic stroke or other atherosclerosis-related traits in a sibling study of Chinese population

Qin

Jin

et al. 2019

Clin Epigenet

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Background: Identifying subjects with a high risk of ischemic stroke is fundamental for prevention of the disease. Both genetic and environmental risk factors contribute to ischemic stroke, but the underlying epigenetic mechanisms which mediate genetic and environmental risk effects are not fully understood. The aim of this study was to explore whether DNA methylation loci located in the ATP-binding cassette G1 (ABCG1) and apolipoprotein E (APOE) genes, both involved in the metabolism of lipids in the body, are related to ischemic stroke, using the Fangshan/Family-based Ischemic Stroke Study in China. We also tested if these CpG sites were associated with early signs of cardiovascular atherosclerosis (carotid intima-media thickness (cIMT), ankle-brachial index (ABI), and brachial-ankle pulse wave velocity (baPWV)). Results: DNA methylation at the cg02494239 locus in ABCG1 was correlated with ischemic stroke after adjusting for gender, previous history of diabetes and hypertension, smoking, drinking, body mass index, and blood lipid levels (above vs below mean, OR = 2.416, 95% CI 1.024-5.700, P = 0.044; 75-100% percentile vs 0-25% percentile, OR = 4.461, 95% CI 1.226-16.225, P = 0.023). No statistically significant associations were observed for the cg06500161 site in ABCG1 and the cg14123992 site in APOE with ischemic stroke. The study detected that hypermethylation of the ABCG1 gene was significantly associated with cIMT, hypermethylation of the APOE gene was significantly related to ABI, and methylation of the APOE gene was statistically negatively correlated with baPWV. The above relationships demonstrated gender differences. Conclusions: These findings suggest that epigenetic modification of ABCG1 and APOE may play a role in the pathway from disturbed blood lipid levels to the development of cardiovascular diseases. Future prospective validation of these findings is warranted.

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“…Naderi et al (2019) showed that SG13S114 polymorphism of ALOX5AP gene was associated with acute cerebral infarction. Previous genetic studies have found that some ischemic stroke susceptibility genes on chromosome 14, such as GCH1 gene (Wei et al, 2018), MEG3 gene (Han et al, 2018), MMP-14 gene (Elgebaly et al, 2019), PRKCH gene (Krupinski et al, 2018), are associated with the risk of ischemic stroke.…”

Section: Introductionmentioning

confidence: 99%

Integrating Multi-Omics Data to Identify Novel Disease Genes and Single-Neucleotide Polymorphisms

et al. 2020

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Stroke ranks the second leading cause of death among people over the age of 60 in the world. Stroke is widely regarded as a complex disease that is affected by genetic and environmental factors. Evidence from twin and family studies suggests that genetic factors may play an important role in its pathogenesis. Therefore, research on the genetic association of susceptibility genes can help understand the mechanism of stroke. Genome-wide association study (GWAS) has found a large number of stroke-related loci, but their mechanism is unknown. In order to explore the function of single-nucleotide polymorphisms (SNPs) at the molecular level, in this paper, we integrated 8 GWAS datasets with brain expression quantitative trait loci (eQTL) dataset to identify SNPs and genes which are related to four types of stroke (ischemic stroke, large artery stroke, cardioembolic stroke, small vessel stroke). Thirty-eight SNPs which can affect 14 genes expression are found to be associated with stroke. Among these 14 genes, 10 genes expression are associated with ischemic stroke, one gene for large artery stroke, six genes for cardioembolic stroke and eight genes for small vessel stroke. To explore the effects of environmental factors on stroke, we identified methylation susceptibility loci associated with stroke using methylation quantitative trait loci (MQTL). Thirty-one of these 38 SNPs are at greater risk of methylation and can significantly change gene expression level. Overall, the genetic pathogenesis of stroke is explored from locus to gene, gene to gene expression and gene expression to phenotype.

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DNA Methylation in Stroke. Update of Latest Advances

Cited by 28 publications

References 58 publications

Genome-wide blood DNA methylation analysis in patients with delayed cerebral ischemia after subarachnoid hemorrhage

Genome-wide blood DNA methylation analysis in patients with delayed cerebral ischemia after subarachnoid hemorrhage

Overall and sex-specific associations between methylation of the ABCG1 and APOE genes and ischemic stroke or other atherosclerosis-related traits in a sibling study of Chinese population

Integrating Multi-Omics Data to Identify Novel Disease Genes and Single-Neucleotide Polymorphisms

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