Role of Apolipoprotein E Genotypes in Aneurysmal Subarachnoid Hemorrhage: Susceptibility, Complications, and Prognosis

Hu, Xiuying; Xie, Zhiyi; Zan, Xin; Ma, Lu; Li, Hao; You, Chao; Jiang, Yan

doi:10.1016/j.wneu.2018.07.019

Cited by 6 publications

(6 citation statements)

References 44 publications

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Section: Discussioncontrasting

confidence: 96%

“…The study showed no significant association between APOE polymorphism and functional outcome after SAH. The results were not consistent with previous meta-analyses [42, 44]. In the meta-analysis published in 2006 [42], the apparent deleterious effect of ε4+ genotypes on outcome after SAH might be a false-positive finding.…”

Section: Discussioncontrasting

confidence: 78%

“…In the meta-analysis published in 2006 [42], the apparent deleterious effect of ε4+ genotypes on outcome after SAH might be a false-positive finding. Hu et al [44] reported that patients with aSAH carrying the ε4 had an increased risk of poor outcome (HR 2.21, 95% CI: 1.21–4.05) compared to non-ε4 carriers, especially in Asian patients (HR 4.99, 95% CI: 1.73–14.40), but not in white patients who were ε4 carriers (HR 1.38, 95% CI: 0.69–2.76). The result in Caucasian was analogous to our meta-analysis.…”

Section: Discussionmentioning

confidence: 99%

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Association between Apolipoprotein E Polymorphism and Clinical Outcome after Ischemic Stroke, Intracerebral Hemorrhage, and Subarachnoid Hemorrhage

et al. 2021

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Backgrounds: Previous studies reported inconsistent results regarding associations between apolipoprotein E (APOE) polymorphism and clinical outcomes after ischemic stroke (IS), intracerebral hemorrhage (ICH), or subarachnoid hemorrhage (SAH). Thus, the study was designed to make a systematic review and meta-analysis regarding the association between APOE polymorphism and clinical outcome after IS, ICH, and SAH. Methods: To identify studies eligible for this meta-analysis, we searched for articles published before August 2021 in the databases (PubMed, Web of Science, and Google Scholar). We used STATA 12.0 software to compute hazard ratios (HRs) and their 95% confidence intervals (CIs) regarding APOE polymorphism and clinical outcome after IS, ICH, and SAH. Results: Meta-analysis showed no significant association between APOE polymorphism and functional outcome after IS with fixed effects models (ε4 carrier vs. non-ε4 carrier: HR, 1.00; 95% CI: 0.83–1.21, I2 = 29.4%, p = 0.183; ε2 carrier vs. non-ε2 carrier: HR, 0.92; 95% CI: 0.72–1.16, I2 = 15.6%, p = 0.307). Meta-analysis showed that ICH patients carrying ε4 allele have increased risk of poor outcome in Caucasian population with fixed effects models (ε4 carrier vs. non-ε4 carrier: HR, 1.75; 95% CI: 1.19–2.57, I2 = 0.0%, p = 0.543). Meta-analysis showed no significant association between APOE polymorphism and functional outcomes after SAH with random effects models (ε4 carrier vs. non-ε4 carrier: HR, 1.51; 95% CI: 0.80–2.84, I2 = 57.1%, p = 0.022). Conclusions: In conclusion, the present study demonstrated APOE ε4 carriers show worse functional outcomes after ICH, but not after IS or SAH. More large-scale studies were critical to explore the association between APOE polymorphism and clinical outcome after IS, ICH, and SAH.

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Section: Discussioncontrasting

confidence: 96%

Section: Discussioncontrasting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

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Association between Apolipoprotein E Polymorphism and Clinical Outcome after Ischemic Stroke, Intracerebral Hemorrhage, and Subarachnoid Hemorrhage

et al. 2021

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“…These studies have yielded mixed findings, with some reporting minor implications and others reporting no statistically significant associations. 21,26,28,40,60…”

Section: Genetic Modifiers Of Aneurysm Rupture and Subsequent Outcomesmentioning

confidence: 99%

Genetic basis of intracranial aneurysm formation and rupture: clinical implications in the postgenomic era

Samuel

Radovanović

2019

Neurosurgical Focus

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OBJECTIVEDespite the prevalence and impact of intracranial aneurysms (IAs), the molecular basis of their pathogenesis remains largely unknown. Moreover, there is a dearth of clinically validated biomarkers to efficiently screen patients with IAs and prognosticate risk for rupture. The aim of this study was to survey the literature to systematically identify the spectrum of genetic aberrations that have been identified in IA formation and risk of rupture.METHODSA literature search was performed using the Medical Subject Headings (MeSH) system of databases including PubMed, EMBASE, and Google Scholar. Relevant studies that reported on genetic analyses of IAs, rupture risk, and long-term outcomes were included in the qualitative analysis.RESULTSA total of 114 studies were reviewed and 65 were included in the qualitative synthesis. There are several well-established mendelian syndromes that confer risk to IAs, with variable frequency. Linkage analyses, genome-wide association studies, candidate gene studies, and exome sequencing identify several recurrent polymorphic variants at candidate loci, and genes associated with the risk of aneurysm formation and rupture, including ANRIL (CDKN2B-AS1, 9p21), ARGHEF17 (11q13), ELN (7q11), SERPINA3 (14q32), and SOX17 (8q11). In addition, polymorphisms in eNOS/NOS3 (7q36) may serve as predictive markers for outcomes following intracranial aneurysm rupture. Genetic aberrations identified to date converge on posited molecular mechanisms involved in vascular remodeling, with strong implications for an associated immune-mediated inflammatory response.CONCLUSIONSComprehensive studies of IA formation and rupture have identified candidate risk variants and loci; however, further genome-wide analyses are needed to identify high-confidence genetic aberrations. The literature supports a role for several risk loci in aneurysm formation and rupture with putative candidate genes. A thorough understanding of the genetic basis governing risk of IA development and the resultant aneurysmal subarachnoid hemorrhage may aid in screening, clinical management, and risk stratification of these patients, and it may also enable identification of putative mechanisms for future drug development.

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“…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.…”

Section: Introductionmentioning

confidence: 95%

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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Role of Apolipoprotein E Genotypes in Aneurysmal Subarachnoid Hemorrhage: Susceptibility, Complications, and Prognosis

Cited by 6 publications

References 44 publications

Association between Apolipoprotein E Polymorphism and Clinical Outcome after Ischemic Stroke, Intracerebral Hemorrhage, and Subarachnoid Hemorrhage

Association between Apolipoprotein E Polymorphism and Clinical Outcome after Ischemic Stroke, Intracerebral Hemorrhage, and Subarachnoid Hemorrhage

Genetic basis of intracranial aneurysm formation and rupture: clinical implications in the postgenomic era

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

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