Intracranial Aneurysm–Associated Single-Nucleotide Polymorphisms Alter Regulatory DNA in the Human Circle of Willis

Laarman, Melanie D; Vermunt, Marit W.; Kleinloog, Rachel; Boer-Bergsma, Jelkje J. de; Bank, Netherlands Brain; Rinkel, Gabriël J.E.; Creyghton, Menno P.; Mokrý, Michal; Bakkers, Jeroen; Ruigrok, Ynte M.

doi:10.1161/strokeaha.117.018557

Cited by 16 publications

(15 citation statements)

References 22 publications

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“…Although direct experimental investigation of epigenetic landscapes in IA has been sparse, in a recent study, Laarman et al [86] performed ChIP-seq on DNA from postmortem human Circle of Willis tissue to identify histone H3K4me1 and H3K27ac modifications in regulatory regions (distal enhancers and active promoters). They then queried if these regions overlapped with 19 known IA-associated SNP regions (from [22, 23]) and found that 7 of them overlapped with active regulatory regions.…”

Section: Discussionmentioning

confidence: 99%

“…Three of the SNPs they queried were also investigated in the current study, namely, rs1132274 (on chr20), rs6841581 (on chr4), and rs658595 (on chr12). Interestingly, rs6841581 was found by Laarman et al [86] to likely affect TF binding while rs1132274 and rs653859 had minimal and no predicted TF activity, respectively. In a follow-up study, Laarman et al [87] elegantly used chromatin conformation capture technology to identify enhancer targets of 4 known risk loci and confirmed intrinsic enhancer activity via an in vivo reporter assay.…”

Section: Discussionmentioning

confidence: 99%

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Epigenetic landscapes suggest that genetic risk for intracranial aneurysm operates on the endothelium

et al. 2019

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BackgroundGenetics play an important role in intracranial aneurysm (IA) pathophysiology. Genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) that are linked to IA but how they affect disease pathobiology remains poorly understood. We used Encyclopedia of DNA Elements (ENCODE) data to investigate the epigenetic landscapes surrounding genetic risk loci to determine if IA-associated SNPs affect functional elements that regulate gene expression and if those SNPs are most likely to impact a specific type of cells.MethodsWe mapped 16 highly significant IA-associated SNPs to linkage disequilibrium (LD) blocks within the human genome. Within these regions, we examined the presence of H3K4me1 and H3K27ac histone marks and CCCTC-binding factor (CTCF) and transcription-factor binding sites using chromatin immunoprecipitation-sequencing (ChIP-Seq) data. This analysis was conducted in several cell types relevant to endothelial (human umbilical vein endothelial cells [HUVECs]) and inflammatory (monocytes, neutrophils, and peripheral blood mononuclear cells [PBMCs]) biology. Gene ontology analysis was performed on genes within extended IA-risk regions to understand which biological processes could be affected by IA-risk SNPs. We also evaluated recently published data that showed differential methylation and differential ribonucleic acid (RNA) expression in IA to investigate the correlation between differentially regulated elements and the IA-risk LD blocks.ResultsThe IA-associated LD blocks were statistically significantly enriched for H3K4me1 and/or H3K27ac marks (markers of enhancer function) in endothelial cells but not in immune cells. The IA-associated LD blocks also contained more binding sites for CTCF in endothelial cells than monocytes, although not statistically significant. Differentially methylated regions of DNA identified in IA tissue were also present in several IA-risk LD blocks, suggesting SNPs could affect this epigenetic machinery. Gene ontology analysis supports that genes affected by IA-risk SNPs are associated with extracellular matrix reorganization and endopeptidase activity.ConclusionThese findings suggest that known genetic alterations linked to IA risk act on endothelial cell function. These alterations do not correlate with IA-associated gene expression signatures of circulating blood cells, which suggests that such signatures are a secondary response reflecting the presence of IA rather than indicating risk for IA.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Epigenetic landscapes suggest that genetic risk for intracranial aneurysm operates on the endothelium

et al. 2019

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“…71,75 In addition, although this study was oriented toward identifying putative genes in risk loci, it is possible that modifier alleles in intergenic regions may harbor regulatory elements that are of functional significance. 39 Finally, our study specifically did not encompass analyses of gene expression. The extent to which variability in gene expression contributes to aneurysm risk is still unclear, but may provide some clues regarding underlying genetic dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…However, there are implications for modifier alleles playing a role in intergenic regions that harbor regulatory elements. 39…”

Section: Polymorphic Variants and Respective Susceptibility Locimentioning

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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“…Hemodynamic factors, such as irregular shear stress and oscillatory shear index, may contribute to the development and rupture of IA [7, 8]. Single-nucleotide polymorphisms (SNPs) related to IA overlap with the regulatory region of genes expressed in the circle of Willis, which is the location with the highest incidence of aneurysms [9]. The circle of Willis shows anomalies more often among patients with ruptured IA than among those with unruptured IA [10].…”

Section: Introductionmentioning

confidence: 99%

Genetic polymorphisms and transcription profiles associated with intracranial aneurysm: a key role for NOTCH3

Dong

Chen

et al. 2019

Aging

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Intracranial aneurysm (IA) incidence is about 1~2%. However, the specific mechanisms of IA onset and development need further study. Our objective was to discover novel IA-related genes to determine possible etiologies further. We performed next-generation sequencing on nineteen Chinese patients with familial IA and one patient with sporadic IA. We obtained mRNA expression data of 129 samples from Gene Expression Omnibus (GEO) and made statistical computing to discover differentially expressed genes (DEGs). The screened IA-related gene NOTCH3 was determined by bioinformatic data mining. We verified the IA-related indicators of NOTCH3. Association was found between IA and the NOTCH3 SNPs rs779314594, rs200504060 and rs2285981. Levels of NOTCH3 mRNA were lower in IA tissue than in control tissue, but higher in peripheral blood neutrophils from IA patients than in neutrophils from controls. Levels of NOTCH3 protein were lower in IA tissue than in cerebral artery tissue. NOTCH3 also decreased the expression of angiogenesis factors in human umbilical vein endothelial cells. Variation in NOTCH3 and alteration of its expression in cerebral artery or neutrophils may contribute to IA. Our findings also describe a bioinformatic-experimental approach that may prove useful for probing the pathophysiology of other complex diseases.

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Intracranial Aneurysm–Associated Single-Nucleotide Polymorphisms Alter Regulatory DNA in the Human Circle of Willis

Abstract: CoW regulatory regions link IA-associated SNPs to genes with a potential role in the development of IAs. Our data refine previous predictions on SNPs associated with IA and provide a substantial resource from which candidates for follow-up studies can be prioritized.

Cited by 16 publications

References 22 publications

Epigenetic landscapes suggest that genetic risk for intracranial aneurysm operates on the endothelium

Epigenetic landscapes suggest that genetic risk for intracranial aneurysm operates on the endothelium

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

Genetic polymorphisms and transcription profiles associated with intracranial aneurysm: a key role for NOTCH3

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