Familial Intracranial Aneurysms

Mackey, Jason; Brown, Robert D.; Moomaw, Charles J.; Hornung, Richard; Sauerbeck, Laura; Woo, Daniel; Foroud, Tatiana; Gandhi, Dheeraj; Kleindorfer, Dawn; Flaherty, Matthew L.; Meissner, Irene; Anderson, Craig S.; Rouleau, Guy; Connolly, E. Sander; Deka, Ranjan; Koller, Daniel L.; Abruzzo, Todd; Huston, John; Broderick, Joseph P.

doi:10.1161/strokeaha.112.667261

Cited by 22 publications

(16 citation statements)

References 17 publications

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“…We used a conditional logistic events/trials model used in a previous analysis that examined the locations of intracranial aneurysms among affected individuals within the same family [ 6 ]. Within each family unit, we calculated the proportion of FDRs who had the same circle of Willis variation as the designated proband of the family unit (“total” concordance proportion).…”

Section: Methodsmentioning

confidence: 99%

“…Individuals with first-degree relatives (FDRs) who have had an aSAH have an increased risk of aSAH and of developing unruptured intracranial aneurysms [ 4 , 5 ]. Aneurysms are more likely to occur in the same arterial territory in the circle of Willis within affected members of the same family than in affected individuals from unrelated families [ 6 ]. Aneurysm location may be influenced by variation in the configuration of the circle of Willis.…”

Section: Introductionmentioning

confidence: 99%

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Heritability of circle of Willis variations in families with intracranial aneurysms

et al. 2018

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BackgroundIntracranial aneurysms more often occur in the same arterial territory within families. Several aneurysm locations are associated with specific circle of Willis variations. We investigated whether the same circle of Willis variations are more likely to occur in first-degree relatives than in unrelated individuals.MethodsWe assessed four circle of Willis variations (classical, A1-asymmetry, incomplete posterior communicating artery and fetal circulation) in two independent groups of families with familial aneurysms and ≥2 first-degree relatives with circle of Willis imaging on MRA/CTA. In each (index) family we determined the proportion of first-degree relatives with the same circle of Willis variation as the proband and compared it to the proportion of first-degree relatives of a randomly selected unrelated (comparison) family who had the same circle of Willis variation as the index family’s proband. Concordance in index families and comparison families was compared with a conditional logistic events/trials model. The analysis was simulated 1001 times; we report the median concordances, odds ratios (ORs), and 95% confidence intervals (95%CI). The groups were analysed separately and together by meta-analysis.ResultsWe found a higher overall concordance in circle of Willis configuration in index families than in comparison families (meta-analysis, 244 families: OR 2.2, 95%CI 1.6–3.0) mostly attributable to a higher concordance in incomplete posterior communicating artery (meta-analysis: OR 2.8, 95%CI 1.8–4.3). No association was found for the other three circle of Willis variations.ConclusionsIn two independent groups of families with familial aneurysms, the incomplete PcomA variation occurred more often within than between families suggesting heritability of this circle of Willis variation. Further studies should investigate genetic variants associated with circle of Willis formation.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Heritability of circle of Willis variations in families with intracranial aneurysms

et al. 2018

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“…This circle of Willis variation is most often associated with aneurysms in the anterior cerebral artery (ACA) territory [7][8][9]. A previous study also showed low and similar concordance proportions between index and comparison families for location of aneurysms in the ACA territory (both 27%) [6]. The two studies confirm that the A1 asymmetry/ACA aneurysm association is unlikely to have a heritable component.…”

Section: Discussionmentioning

confidence: 86%

Heritability of Circle of Willis Variations in Families With Intracranial Aneurysms

Kammen

Moomaw

Schaaf

et al. 2017

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Background Intracranial aneurysms more often occur in the same arterial territory within families. Several aneurysm locations are associated with specific circle of Willis variations. We investigated whether the same circle of Willis variations are more likely to occur in first-degree relatives than in unrelated individuals. Methods We assessed four circle of Willis variations (classical, A1-asymmetry, incomplete posterior communicating artery and fetal circulation) in two independent groups of families with familial aneurysms and !2 first-degree relatives with circle of Willis imaging on MRA/ CTA. In each (index) family we determined the proportion of first-degree relatives with the same circle of Willis variation as the proband and compared it to the proportion of firstdegree relatives of a randomly selected unrelated (comparison) family who had the same circle of Willis variation as the index family's proband. Concordance in index families and comparison families was compared with a conditional logistic events/trials model. The analysis was simulated 1001 times; we report the median concordances, odds ratios (ORs), and 95% confidence intervals (95%CI). The groups were analysed separately and together by meta-analysis. Results We found a higher overall concordance in circle of Willis configuration in index families than in comparison families (meta-analysis, 244 families: OR 2.2, 95%CI 1.6-3.0) mostly attributable to a higher concordance in incomplete posterior communicating artery (meta-analysis: OR 2.8, 95%CI 1.8-4.3). No association was found for the other three circle of Willis variations.

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“…Increased familial incidence of aneurysm suggests a genetic component to aneurysmal formation, though a clear genetic/mechanistic pathway has not been determined [103,104]. The formation and growth of intracranial aneurysms is currently considered to be a complex and multifactorial process that stems from a variety of environmental and genetic factors.…”

Section: Intracranial Aneurysms and Rho Signalingmentioning

confidence: 99%

Rho Kinase as a Target for Cerebral Vascular Disorders

2015

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The development of novel pharmaceutical treatments for disorders of the cerebral vasculature is a serious unmet medical need. These vascular disorders are typified by a disruption in the delicate Rho signaling equilibrium within the blood vessel wall. In particular, Rho kinase overactivation in the smooth muscle and endothelial layers of the vessel wall results in cytoskeletal modifications that lead to reduced vascular integrity and abnormal vascular growth. Rho kinase is thus a promising target for the treatment of cerebral vascular disorders. Indeed, preclinical studies indicate that Rho kinase inhibition may reduce the formation/growth/rupture of both intracranial aneurysms and cerebral cavernous malformations.

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Familial Intracranial Aneurysms

Cited by 22 publications

References 17 publications

Heritability of circle of Willis variations in families with intracranial aneurysms

Heritability of circle of Willis variations in families with intracranial aneurysms

Heritability of Circle of Willis Variations in Families With Intracranial Aneurysms

Rho Kinase as a Target for Cerebral Vascular Disorders

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