Genetics of Intracranial Aneurysms

Zhou, Sirui; Dion, Patrick A.; Rouleau, Guy

doi:10.1161/strokeaha.117.018152

Cited by 69 publications

(62 citation statements)

References 65 publications

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“…In studies conducted by Meng et al 2,24 , involving CFD and histological analysis of canine and rabbit models, a combination of high wall shear stress (WSS) and high WSS gradient at arterial bifurcation was shown to lead to cerebral aneurysm formation by disruption of the internal elastic lamina, loss of smooth muscle cells (SMCs) and a decrease in SMC proliferation rate. Recent evidence suggests than aneurysm formation might be also associated with the influence of multiple genetic factors which determine the strength of the arterial wall, which is further modified by environmental factors, such as smoking and hypertension 25,26 . However, the www.nature.com/scientificreports www.nature.com/scientificreports/ majority of cerebral aneurysms are located solely in a few arterial bifurcations, i.e.…”

Section: Discussionmentioning

confidence: 99%

Morphological and Hemodynamic Risk Factors for Middle Cerebral Artery Aneurysm: a Case-Control Study of 190 Patients

Kaspera

Ćmiel-Smorzyk

Wolański

et al. 2020

Sci Rep

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this study analyzed morphometric and hemodynamic parameters of aneurysmal and non-aneurysmal middle cerebral artery (McA) bifurcations and their relationship with optimal values derived from the principle of minimum work (PMW). The study included 96 patients with MCA aneurysm and 94 controls. Aneurysm patients presented with significantly higher values of the radius and cross-sectional area of the McA trunk, angle between the post-bifurcation branches (α angle) and volume flow rate (VFR) and had significantly lower values of junction exponent and pulsatility index than the controls. The Φ 1 and Φ 2 angles (angles between the MCA trunk axis and the larger and smaller branch, respectively) and α angle in all groups were significantly larger than the optimal PMW-derived angles. The most important independent predictors of MCA aneurysm were junction exponent (odds ratio, OR = 0.42), α angle (oR = 1.07) and VFR (OR = 2.36). Development of cerebral aneurysms might be an independent effect of abnormalities in hemodynamic and morphometric factors. The risk of aneurysm increased proportionally to the deviation of morphometric parameters of the bifurcation from their optimal pMWderived values. The role of bifurcation angle in aneurysm development needs to be explained in future research as the values of this parameter in both aneurysm patients and non-aneurysmal controls in were scattered considerably around the pMW-derived optimum.

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Section: Discussionmentioning

confidence: 99%

Morphological and Hemodynamic Risk Factors for Middle Cerebral Artery Aneurysm: a Case-Control Study of 190 Patients

Kaspera

Ćmiel-Smorzyk

Wolański

et al. 2020

Sci Rep

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“…Dysregulation of this signaling pathway is widely accepted to be central in the pathogenesis of hereditary aortopathies [45]. Numerous familial linkage and GWAS reporting on potential gene loci for IAs have been summarized elsewhere [18,21]. A genome-wide-linkage/ haplotype-association analysis revealed a strong evidence for a linkage of IAs to the chromosomal region 5q14.3 with a p value of 0.001 for marker D5S428; this DNA marker localizes ca.…”

Section: Genetic and Functional Aspects On Edil3 As An Uia/ Asah Riskmentioning

confidence: 99%

“…Selection criteria and constraints of subjects for exome and Sanger sequencing are explained in detail in Supplementary Methods and Table S1. Although genome-wide association studies (GWAS) that focus on the identification of common variants (minor allele frequency, MAF > 5%) revealed a large number of risk loci associated with IA/SAH, the accounted heritability in these loci was low [18]. The prevalence of IA is reported to be approximately 5% in average [2]; for genetic disorders the phenotype prevalence and penetrance should be used to define the allele frequency cutoff [19].…”

Section: Exome Sequencing Variant Calling Filtering Strategies Varmentioning

confidence: 99%

Exome sequencing in 38 patients with intracranial aneurysms and subarachnoid hemorrhage

et al. 2020

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Objective Genetic risk factors for unruptured intracranial aneurysms (UIA) and aneurysmal subarachnoid hemorrhage (aSAH) are poorly understood. We aimed to verify recently reported risk genes and to identify novel sequence variants involved in the etiology of UIA/aSAH. Methods We performed exome sequencing (ES) in 35 unrelated individuals and 3 family members, each with a history of UIA and/or aSAH. We searched for sequence variants with minor allele frequency (MAF) ≤ 5% in the reported risk genes ADAMTS15, ANGPTL6, ARHGEF17, LOXL2, PCNT, RNF213, THSD1 and TMEM132B. To identify novel putative risk genes we looked for unknown (MAF = 0) variants shared by the three relatives. Results We identified 20 variants with MAF ≤ 5% in 18 individuals: 9 variants in PCNT (9 patients), 4 in RNF213 (3 patients), 3 in THSD1 (6 patients), 2 in ANGPTL6 (3 patients), 1 in ADAMTS15 (1 patient) and 1 in TMEM132B (1 patient). In the affected family, prioritization of shared sequence variants yielded five novel putative risk genes. Based on predicted pathogenicity of identified variants, population genetics data and a high functional relevance for vascular biology, EDIL3 was selected as top candidate and screened in additional 37 individuals with UIA and/or aSAH: a further very rare EDIL3 sequence variant in two unrelated sporadic patients was identified. Conclusions Our data support a role of sequence variants in PCNT, RNF213 and THSD1 as susceptibility factors for cerebrovascular disease. The documented function in vascular wall integrity, the crucial localization of affected amino acids and gene/variant association tests suggest EDIL3 as a further valid candidate disease gene for UIA/aSAH.

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“…The contribution of an intrinsic wall deformity to the pathophysiology of a cerebral aneurysm has been supported by genetic, experimental, and clinical studies. Genetic disorders with a variety of phenotypes have been reported to also present with cerebral aneurysms ( Table 2 ) [ 55 , 56 ]. Although the link between the involved gene and the aneurysm phenotype is not fully understood, there are likely some common genetic predispositions to the main clinical features and aneurysm.…”

Section: Risk Factors and Biomarkers Associated With Formation And Rumentioning

confidence: 99%

“…A multifactorial genetic predisposition would more strongly underlie the pathogenesis of a cerebral aneurysm formation than a single genetic disorder. Significant genes associated with intrinsic wall deformities have been determined from whole exome sequencing and genome-wide association studies, but the findings were inconsistent and conflicting [ 56 ]. Disease heterogeneity, different levels of genetic burden per stage, and gene-environment interaction would explain the genetic complexities of the cerebral aneurysm.…”

Section: Risk Factors and Biomarkers Associated With Formation And Rumentioning

confidence: 99%

New Pathophysiological Considerations on Cerebral Aneurysms

Jung

2018

Neurointervention

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Cerebral aneurysm is a common cerebrovascular disease that is sometimes complicated by rupture or an enlarged mass. We are now aggressively evaluating and managing unruptured cerebral aneurysms based on a significant concern for the high morbidity and mortality related to its associated complications. However, the actual rupture rate is very low and the diagnostic and treatment modalities are expensive and invasive, which may lead to unnecessary costs and potential medical complications. This disproportionate situation is related to a poor understanding of the natural course and pathophysiology of cerebral aneurysms. In consideration of the concept that not all cerebral aneurysms must be removed, we need to examine their course and progression more accurately. Cerebral aneurysms may follow a variety of pathophysiological scenarios over their lifetime, from formation to growth and rupture. The disease course and the final outcome can differ depending on the timing and intensity of the pathological signals acting on the cerebral vessel wall. We should delineate a method of predicting the stability and risk of rupture of the lesion based on a comprehensive knowledge of the vessel wall integrity. This review deals with the basic knowledge and advanced concepts underlying the pathophysiology of cerebral aneurysms.

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Genetics of Intracranial Aneurysms

Cited by 69 publications

References 65 publications

Morphological and Hemodynamic Risk Factors for Middle Cerebral Artery Aneurysm: a Case-Control Study of 190 Patients

Morphological and Hemodynamic Risk Factors for Middle Cerebral Artery Aneurysm: a Case-Control Study of 190 Patients

Exome sequencing in 38 patients with intracranial aneurysms and subarachnoid hemorrhage

New Pathophysiological Considerations on Cerebral Aneurysms

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