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Cerebral vasospasm after sub-arachnoid hemorrhage as a clinical predictor and phenotype for genetic association study.

ABSTRACT: A typology of cerebral vasospasm has been proposed based on distinct clinical manifestations: delayed cerebral ischemia, symptomatic 'vasospasm', angiographic vasospasm, and transcranial Doppler vasospasm. We examined each distinct clinical manifestation in a nonparametric genetic association study.The purpose of this study was to examine and compare each four distinct acute clinical manifestations and test its perspectives in genetic association studies.Two hundred forty-five Caucasian patients with sub-arachnoid hemorrhage were evaluated for these four distinct clinical manifestations along with 906?600 single-nucleotide polymorphisms across the human genome.The four clinical manifestations were significantly associated with each other as P-values ranged from 3·31?×?10(-4) to 8·10?×?10(-15) . Transcranial Doppler vasospasm showed significant genetic association with single nucleotide polymorphism (SNP) (rs999662, P?=?3·39?×?10(-8) ). Statistical P-value of rs999662 in association with delayed cerebral ischemia, symptomatic 'vasospasm', and angiographic vasospasm was 0·0017, 0·0017, and 0·19, respectively.Despite different criteria for each of the four clinical manifestations, they are significantly associated with each other. Our results suggest transcranial Doppler vasospasm may be an appropriate intermediate but still clinically relevant phenotype for genetic association studies. Association with SNP rs999662 indicates a potential role for the region containing the solute carrier family 12 member 3 (SLC12A3) gene in transcranial Doppler vasospasm following sub-arachnoid hemorrhage.

SUBMITTER: Kim H

PROVIDER: S-EPMC3475757 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Cerebral vasospasm after sub-arachnoid hemorrhage as a clinical predictor and phenotype for genetic association study.

Kim Hyungsuk H Crago Elizabeth E Kim Mirim M Sherwood Paula P Conley Yvette Y Poloyac Samuel S Kerr Mary M

International journal of stroke : official journal of the International Stroke Society 20120509 8

<h4>Background</h4>A typology of cerebral vasospasm has been proposed based on distinct clinical manifestations: delayed cerebral ischemia, symptomatic 'vasospasm', angiographic vasospasm, and transcranial Doppler vasospasm. We examined each distinct clinical manifestation in a nonparametric genetic association study.<h4>Aims</h4>The purpose of this study was to examine and compare each four distinct acute clinical manifestations and test its perspectives in genetic association studies.<h4>Metho ...[more]

PMID: 22568564

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Project description:The diagnosis of cerebral vasospasm after Subarachnoid-Hemorrhage is currently very difficult, additional tools such as blood biomarkers are necessary. We tested the ability of gene expression profiles of blood cells to predict vasospasm. 32 patients suffering subarachnoid-hemorrhage were included in this prospective monocentre study. They were grouped according to have a complicated cerebral vasospasm (Vasospasm) or not (Control) and Paired according to age (+/- 10 years), sex, Fisher grade (+/- 1), location, smoking (at least 3 first parameters). Gene expression profiles of blood cells were determined using 25,000~gene microarray. Blood sample: 2.5 mL harvested in PAXgene® Blood RNA tubes (PreAnalytix) RNA extraction: PAXgene® Blood RNA kit (Qiagen). We used a Universel Reference RNA (Stratagene). RNA amplification and labelling: kit Amino Allyl MessageAmp II (Ambion). We hybridized 4 microarrays per patient using pangenomic microarrays from the "Réseau National des Génopôles" (Illkirch, France). 2 slides were hybridized with reference RNA labelled Cy3 and patient RNA labelled Cy5, and 2 slides were hybridized with reference RNA labelled Cy5 and patient RNA labelled Cy3. Hybridation : Agilent protocol with few modifications : 750 ng of each labelled RNA were hubriddized at 60°C during 17 hours in an Aglient hybridization oven. After washings, Slides were scanned with a GenePix 4000B scanner (Molecular Devices). Image intensity data were extracted with GenePix Pro 6.0 analysis software. Quantification of Cy3 and Cy5 and selection of good spots were performed using the MAIA software (Novikov E and Barillot E. Software package for automatic microarray image analysis (MAIA). The ACUITY software was then used to normalize log ratios Cy3/Cy5 with Lowess non linear normalization, to filter out genes not present in at least 3 slides out of 4, to evaluate the reproducibility of the 4 microarrays of each patient (hierarchical clustering, Self Organizing Maps). Statistical analyses to insure reproducibility was performed using Excel (correlation coefficients, ANOVA). Only slides that passed all reprocubility tests were validated.

Project description:IntroductionCerebral vasospasm (CVS) is the most common neurological complication after aneurysmal subarachnoid hemorrhage (aSAH) and associated with poor functional outcome and mortality. Reports on incidence and predictors of CVS in Chinese patients with aSAH were scarce. We aimed to estimate the incidence and predictors of angiographic vasospasm (AV), symptomatic vasospasm (SV), and cerebral infarction in Chinese patients with aSAH.MethodsWe retrospectively reviewed the medical records of 542 consecutive aSAH patients admitted to neurosurgery department of the First Affiliated Hospital of Xinjiang Medical University in Urumqi city of China between January 1, 2011 and December 31, 2015. AV, SV and cerebral infarction were defined based on clinical data and neuroimaging findings. Univariate and multivariate analyses were performed to identify predictors of AV, SV or cerebral infarction.Results343 (63.3%) patients fulfilled the inclusion and exclusion criteria. Of them, 182(53.1%) developed AV, 99 (28.9%) developed SV, and 87 (25.4%) developed cerebral infarction. A history of hypertension, poor modified Fisher grade (3-4) and poor Hunt-Hess grade (4-5) on admission were common risk factors for AV, SV and cerebral infarction. Patients from Uyghur ethnic group or other minorities were less likely to develop AV, SV or cerebral infarction, compared to those from Han ethic group after adjustment of other potential confounders. Additionally, age ?53 years, leukocyte count ?11× 109/L on admission and being current or former smokers were independent risk factors of cerebral infarction. Leukocyte count ?11× 109/L on admission and aneurysm size ? 10 mm were independent risk factors of SV. Serum glucose level ?7.0 mmol/L on admission was an independent risk factor of AV.ConclusionRisk factors of different definitions of CVS were diverse in Chinese patients with aSAH; however, risk factors of SV and cerebral infarction seem to be similar. We recommend early and aggressive therapy in these patients at-risk of CVS.

Dataset Information

Cerebral vasospasm after sub-arachnoid hemorrhage as a clinical predictor and phenotype for genetic association study.

Publications

Cerebral vasospasm after sub-arachnoid hemorrhage as a clinical predictor and phenotype for genetic association study.

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