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Genetic risk factors for intracranial aneurysms: a meta-analysis in more than 116,000 individuals.

ABSTRACT: 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).

SUBMITTER: Alg VS

PROVIDER: S-EPMC3716358 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Genetic risk factors for intracranial aneurysms: a meta-analysis in more than 116,000 individuals.

Alg Varinder S VS Sofat Reecha R Houlden Henry H Werring David J DJ

Neurology 20130601 23

<h4>Objective</h4>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.<h4>Methods</h4>We conducted a comprehensive systematic review and meta-analysis of ...[more]

PMID: 23733552

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Project description:Background and Purpose- Determinants for molecular and structural instability, that is, impending growth or rupture, of intracranial aneurysms (IAs) remain uncertain. To elucidate this, we endeavored to estimate the actual turnover rates of the main molecular constituent in human IA (collagen) on the basis of radiocarbon (14C) birth dating in relation to IA hemodynamics. Methods- Collagen turnover rates in excised human IA samples were calculated using mathematical modeling of 14C birth dating data of collagen in relation to risk factors and histological markers for collagen maturity/turnover in selected IA. Hemodynamics were simulated using image-based computational fluid dynamics. Correlation, logistic regression, and receiver operating characteristic analyses were performed. Results- Collagen turnover rates were estimated in 46 IA (43 patients); computational fluid dynamics could be performed in 20 IA (20 patients). The mean collagen turnover rate (γ) constituted 126% (±1% error) per year. For patients with arterial hypertension, γ was greater than 2600% annually, whereas γ was distinctly lower with 32% (±1% error) per year for patients without risk factors, such as smoking and hypertension. There was a distinct association between histological presence of rather immature collagen in human IA and the presence of modifiable risk factors. Spatial-temporal averaged wall shear stress predicted rapid collagen turnover (odds ratio, 1.6 [95% CI, 1.0-2.7]). Receiver operating characteristic analysis demonstrated a good test accuracy (area under the curve, 0.798 [95% CI, 0.598-0.998]) for average wall shear stress with a threshold ≥4.9 Pa for rapid collagen turnover. Conclusions- Our data indicate that turnover rates and stability of collagen in human IA are strongly associated with the presence of modifiable risk factors and aneurysmal hemodynamics. These findings underline the importance of strict risk factor modification in patients with unruptured IA. Future should include more detailed risk factor data to establish a more causal understanding of hemodynamics and the rupture risk of individual IA.

Project description:ImportanceThe risk of procedural clinical complications and the case-fatality rate (CFR) from preventive treatment of unruptured intracranial aneurysms varies between studies and may depend on treatment modality and risk factors.ObjectiveTo assess current procedural clinical 30-day complications and the CFR from endovascular treatment (EVT) and neurosurgical treatment (NST) of unruptured intracranial aneurysms and risk factors of clinical complications.Data sourcesWe searched PubMed, Excerpta Medica Database, and the Cochrane Database for studies published between January 1, 2011, and January 1, 2017.Study selectionStudies reporting on clinical complications, the CFR, and risk factors, including 50 patients or more undergoing EVT or NST for saccular unruptured intracranial aneurysms after January 1, 2000, were eligible.Data extraction and synthesisPer treatment modality, we analyzed clinical complication risk and the CFR with mixed-effects logistic regression models for dichotomous data. For studies reporting data on complication risk factors, we obtained risk ratios (RRs) or odds ratios (ORs) with 95% CIs and pooled risk estimates with weighted random-effects models.Main outcomes and measuresClinical complications within 30 days and the CFR.ResultsWe included 114 studies (106?433 patients with 108?263 aneurysms). For EVT (74 studies), the pooled clinical complication risk was 4.96% (95% CI, 4.00%-6.12%), and the CFR was 0.30% (95% CI, 0.20%-0.40%). Factors associated with complications from EVT were female sex (pooled OR, 1.06 [95% CI, 1.01-1.11]), diabetes (OR, 1.81 [95% CI, 1.05-3.13]), hyperlipidemia (OR, 1.76 [95% CI, 1.3-2.37]), cardiac comorbidity (OR, 2.27 [95% CI, 1.53-3.37]), wide aneurysm neck (>4 mm or dome-to-neck ratio >1.5; OR, 1.71 [95% CI, 1.38-2.11]), posterior circulation aneurysm (OR, 1.42 [95% CI, 1.15-1.74]), stent-assisted coiling (OR, 1.82 [95% CI, 1.16-2.85]), and stenting (OR, 3.43 [95% CI, 1.45-8.09]). For NST (54 studies), the pooled complication risk was 8.34% (95% CI, 6.25%-11.10%) and the CFR was 0.10% (95% CI, 0.00%-0.20%). Factors associated with complications from NST were age (OR per year increase, 1.02 [95% CI, 1.01-1.02]), female sex (OR, 0.43 [95% CI, 0.32-0.85]), coagulopathy (OR, 2.14 [95% CI, 1.13-4.06]), use of anticoagulation (OR, 6.36 [95% CI, 2.55-15.85]), smoking (OR, 1.95 [95% CI, 1.36-2.79]), hypertension (OR, 1.45 [95% CI, 1.03-2.03]), diabetes (OR, 2.38 [95% CI, 1.54-3.67]), congestive heart failure (OR, 2.71 [95% CI, 1.57-4.69]), posterior aneurysm location (OR, 7.25 [95% CI, 3.70-14.20]), and aneurysm calcification (OR, 2.89 [95% CI, 1.35-6.18]).Conclusions and relevanceThis study identifies risk factors for procedural complications. Large data sets with individual patient data are needed to develop and validate prediction scores for absolute complication risks and CFRs from EVT and NST modalities.

Project description:BACKGROUND:Y-stent-assisted coiling for wide-neck intracranial aneurysms required further investigation. PURPOSE:Our aim was to analyze outcomes after Y-stent placement in wide-neck aneurysms. DATA SOURCES:We performed a systematic search of 3 data bases for studies published from 2000 to 2018. STUDY SELECTION:According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we included studies reporting Y-stent-assisted coiling of wide-neck aneurysms. DATA ANALYSIS:Random-effects meta-analysis was used to pool the following: aneurysm occlusion rate, complications, and factors influencing the studied outcomes. DATA SYNTHESIS:We included 27 studies and 750 aneurysms treated with Y-stent placement. The immediate complete/near-complete occlusion rate was 82.2% (352/468; 95% CI, 71.4%-93%; I2 = 92%), whereas the long-term complete/near-complete occlusion rate was 95.4% (564/598; 95% CI, 93.7%-97%; I2 = 0%) (mean radiologic follow-up of 14 months). The aneurysm recanalization rate was 3% (20/496; 95% CI, 1.5%-4.5%; I2 = 0%), and half of the recanalized aneurysms required retreatment. The treatment-related complication rate was 8.9% (63/614; 95% CI, 5.8%-12.1%; I2 = 44%). Morbidity and mortality after treatment were 2.4% (18/540; 95% CI, 1.2%-3.7%; I2 = 0%) and 1.1% (5/668; 95% CI, 0.3%-1.9%; I2 = 0%), respectively. Crossing Y-stent placement was associated with a slightly lower complication rate compared with the kissing configuration (56/572 = 8.4%; 95% CI, 5%-11%; I2 = 46% versus 4/30 = 12.7%; 95% CI, 3%-24%; I2 = 0%). Occlusion rates were quite comparable among Enterprise, Neuroform, and LVIS stents, whereas the Enterprise stent was associated with lower rates of complications (8/89 = 6.5%; 95% CI, 1.6%-11%; I2 = 0%) compared with the others (20/131 = 14%; 95% CI, 5%-26%; I2 = 69% and 9/64 = 11%; 95% CI, 3%-20%; I2 = 18%). LIMITATIONS:This was a small, retrospective series. CONCLUSIONS:Y-stent-assisted coiling yields high rates of long-term angiographic occlusion, with a relatively low rate of treatment-related complications. Y-stent placement with a crossing configuration appears to be associated with better outcomes. Although Y-configuration can be obtained using many types of stents with comparable occlusion rates, the Enterprise stent is associated with lower complication rates.

Dataset Information

Genetic risk factors for intracranial aneurysms: a meta-analysis in more than 116,000 individuals.

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Genetic risk factors for intracranial aneurysms: a meta-analysis in more than 116,000 individuals.

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