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Genetic factors involves in intracranial aneurysms--actualities.

ABSTRACT: Intracranial aneurysm (IA) is a common vascular disorder, which frequently leads to fatal vascular rupture leading to subarachnoid hemorrhage (SAH). Although various acquired risk factors associated with IAs have been identified, heritable conditions are associated with IAs formation but these syndromes account for less than 1% of all IAs in the population. Cerebral aneurysm disease is related to hemodynamic and genetic factors, associated with structural weakness in the arterial wall, which was acquired by a specific, often unknown, event. Possibly, the trigger moment of aneurysm formation may depend on the dynamic arterial growth, which is closely related to aging/ atherosclerosis. Genetic factors are known to have an important role in IA pathogenesis. Literature data provide complementary evidence that the variants on chromosomes 8q and 9p are associated with IA and that the risk of IA in patients with these variants is greatly increased with cigarette smoking. Intracranial aneurysms are acquired lesions (5-10% of the population). In comparison with sporadic aneurysms, familial aneurysms tend to be larger, more often located in the middle cerebral artery, and more likely to be multiple.DNA = deoxyribonucleic acid, FIA = familial Intracranial Aneurysm, GWAS = genome-wide association studies, IL-6 = interleukin-6, ISUIA = International Study of Unruptured Intracranial Aneurysms, IA = Intracranial aneurysm, mRNA = Messager ribonucleic acid, SNPs = single-nucleotide polymorphisms, SMCs = smooth muscle cells, sIAs = sporadic IAs, SAH = subarachnoid hemorrhage, TNF-? = tumor necrosis factor-alpha, COL4A1 = type IV collagen alpha-1.

SUBMITTER: Mohan D

PROVIDER: S-EPMC4556916 | biostudies-literature | 2015 Jul-Sep

REPOSITORIES: biostudies-literature

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Genetic factors involves in intracranial aneurysms--actualities.

Mohan D D Munteanu V V Coman T T Ciurea A V AV

Journal of medicine and life 20150701 3

<h4>Unlabelled</h4>Intracranial aneurysm (IA) is a common vascular disorder, which frequently leads to fatal vascular rupture leading to subarachnoid hemorrhage (SAH). Although various acquired risk factors associated with IAs have been identified, heritable conditions are associated with IAs formation but these syndromes account for less than 1% of all IAs in the population. Cerebral aneurysm disease is related to hemodynamic and genetic factors, associated with structural weakness in the arter ...[more]

PMID: 26351537

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Project description:There is an urgent need to identify risk factors for sporadic intracranial aneurysm (IA) development and rupture. A genetic component has long been recognized, but firm conclusions have been elusive given the generally small sample sizes and lack of replication. Genome-wide association studies have overcome some limitations, but the number of robust genetic risk factors for IA remains uncertain.We conducted a comprehensive systematic review and meta-analysis of all genetic association studies (including genome-wide association studies) of sporadic IA, conducted according to Strengthening the Reporting of Genetic Association Studies and Human Genome Epidemiology Network guidelines. We tested the robustness of associations using random-effects and sensitivity analyses.Sixty-one studies including 32,887 IA cases and 83,683 controls were included. We identified 19 single nucleotide polymorphisms associated with IA. The strongest associations, robust to sensitivity analyses for statistical heterogeneity and ethnicity, were found for the following single nucleotide polymorphisms: on chromosome 9 within the cyclin-dependent kinase inhibitor 2B antisense inhibitor gene (rs10757278: odds ratio [OR] 1.29; 95% confidence interval [CI] 1.21-1.38; and rs1333040: OR 1.24; 95% CI 1.20-1.29), on chromosome 8 near the SOX17 transcription regulator gene (rs9298506: OR 1.21; 95% CI 1.15-1.27; and rs10958409: OR 1.19; 95% CI 1.13-1.26), and on chromosome 4 near the endothelin receptor A gene (rs6841581: OR 1.22; 95% CI 1.14-1.31).Our comprehensive meta-analysis confirms a substantial genetic contribution to sporadic IA, implicating multiple pathophysiologic pathways, mainly relating to vascular endothelial maintenance. However, the limited data for IA compared with other complex diseases necessitates large-scale replication studies in a full spectrum of populations, with investigation of how genetic variants relate to phenotype (e.g., IA size, location, and rupture status).

Project description:BACKGROUND:Rupture of an intracranial aneurysm (IA) causes a systemic response that involves an immune/inflammatory reaction. Our previous study revealed a downregulation of genes related to T lymphocytes and an upregulation of genes related to monocytes and neutrophils after IA rupture. It remains unknown whether that resulted from alterations in transcription or cell count. We sought to characterize the systemic response to IA rupture through analysis of transcript expression profiles in peripheral blood cells. We also investigated effects of IA rupture on the composition of mononuclear cells in peripheral blood. METHODS:We included 19 patients in the acute phase of IA rupture (RAA, first 72 h), 20 patients in the chronic phase (RAC, 3-15 months), and 20 controls. Using deep transcriptome sequencing, we analyzed the expression of protein-coding and noncoding RNAs. Expression levels, transcript biotypes, alternative splicing and other features of the regulated transcripts were studied. A functional analysis was performed to determine overrepresented ontological groups among gene expression profiles. Flow cytometry was used to analyze alterations in the level of mononuclear leukocyte subpopulations. RESULTS:Comparing RAA and controls, we identified 491 differentially expressed transcripts (303 were downregulated, and 188 were upregulated in RAA). The results indicate that the molecular changes in response to IA rupture occur at the level of individual transcripts. Functional analysis revealed that the most impacted biological processes are related to regulation of lymphocyte activation and toll-like receptor signaling pathway. Differences between RAC and controls were less prominent. Analysis of leukocyte subsets revealed a significantly decreased number of CD4+ lymphocytes and increase of classical and intermediate monocytes in RAA patients compared to controls. CONCLUSIONS:IA rupture in the acute phase strongly influences the transcription profiles of peripheral blood cells as well as the composition of mononuclear cells. A specific pattern of gene expression alteration was found, suggesting a depression of lymphocyte response and enhancement of monocyte activity.

Project description:Background and purposeIntracranial aneurysm formation and rupture risk are, in part, determined by genetic factors and sex. To examine their role, we compared 3 mouse strains commonly used in cerebrovascular studies in a model of intracranial aneurysm formation and rupture.MethodsIntracranial aneurysms were induced in male CD1 (Crl:CD1[ICR]), male and female C57 (C57BL/6NCrl), and male 129Sv (129S2/SvPasCrl or 129S1/SvImJ) mice by stereotaxic injection of elastase at the skull base, combined with systemic deoxycorticosterone acetate-salt hypertension. Neurological deficits and mortality were recorded. Aneurysms and subarachnoid hemorrhage grades were quantified postmortem, either after spontaneous mortality or at 7 to 21 days if the animals survived. In separate cohorts, we examined proinflammatory mediators by quantitative reverse transcriptase-polymerase chain reaction, arterial blood pressure via the femoral artery, and the circle of Willis by intravascular latex casting.ResultsWe found striking differences in aneurysm formation, rupture, and postrupture survival rates among the groups. 129Sv mice showed the highest rates of aneurysm rupture (80%), followed by C57 female (36%), C57 male (27%), and CD1 (21%). The risk of aneurysm rupture and the presence of unruptured aneurysms significantly differed among all 3 strains, as well as between male and female C57. The same hierarchy was observed upon Kaplan-Meier analysis of both overall survival and deficit-free survival. Subarachnoid hemorrhage grades were also more severe in 129Sv. CD1 mice showed the highest resistance to aneurysm rupture and the mildest outcomes. Higher mean blood pressures and the major phenotypic difference in the circle of Willis anatomy in 129Sv provided an explanation for the higher incidence of and more severe aneurysm ruptures. TNFα (tumor necrosis factor-alpha), IL-1β (interleukin-1-beta), and CCL2 (chemokine C-C motif ligand 2) expressions did not differ among the groups.ConclusionsThe outcome of elastase-induced intracranial aneurysm formation and rupture in mice depends on genetic background and shows sexual dimorphism.

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Genetic factors involves in intracranial aneurysms--actualities.

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Genetic factors involves in intracranial aneurysms--actualities.

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