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Common variants at 6p21.1 are associated with large artery atherosclerotic stroke.

ABSTRACT: Genome-wide association studies (GWAS) have not consistently detected replicable genetic risk factors for ischemic stroke, potentially due to etiological heterogeneity of this trait. We performed GWAS of ischemic stroke and a major ischemic stroke subtype (large artery atherosclerosis, LAA) using 1,162 ischemic stroke cases (including 421 LAA cases) and 1,244 population controls from Australia. Evidence for a genetic influence on ischemic stroke risk was detected, but this influence was higher and more significant for the LAA subtype. We identified a new LAA susceptibility locus on chromosome 6p21.1 (rs556621: odds ratio (OR)=1.62, P=3.9×10(-8)) and replicated this association in 1,715 LAA cases and 52,695 population controls from 10 independent population cohorts (meta-analysis replication OR=1.15, P=3.9×10(-4); discovery and replication combined OR=1.21, P=4.7×10(-8)). This study identifies a genetic risk locus for LAA and shows how analyzing etiological subtypes may better identify genetic risk alleles for ischemic stroke.

SUBMITTER: Holliday EG

PROVIDER: S-EPMC3651583 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Common variants at 6p21.1 are associated with large artery atherosclerotic stroke.

Holliday Elizabeth G EG Maguire Jane M JM Evans Tiffany-Jane TJ Koblar Simon A SA Jannes Jim J Sturm Jonathan W JW Hankey Graeme J GJ Baker Ross R Golledge Jonathan J Parsons Mark W MW Malik Rainer R McEvoy Mark M Biros Erik E Lewis Martin D MD Lincz Lisa F LF Peel Roseanne R Oldmeadow Christopher C Smith Wayne W Moscato Pablo P Barlera Simona S Bevan Steve S Bis Joshua C JC Boerwinkle Eric E Boncoraglio Giorgio B GB Brott Thomas G TG Brown Robert D RD Cheng Yu-Ching YC Cole John W JW Cotlarciuc Ioana I Devan William J WJ Fornage Myriam M Furie Karen L KL Grétarsdóttir Sólveig S Gschwendtner Andreas A Ikram M Arfan MA Longstreth W T WT Meschia James F JF Mitchell Braxton D BD Mosley Thomas H TH Nalls Michael A MA Parati Eugenio A EA Psaty Bruce M BM Sharma Pankaj P Stefansson Kari K Thorleifsson Gudmar G Thorsteinsdottir Unnur U Traylor Matthew M Verhaaren Benjamin F J BF Wiggins Kerri L KL Worrall Bradford B BB Sudlow Cathie C Rothwell Peter M PM Farrall Martin M Dichgans Martin M Rosand Jonathan J Markus Hugh S HS Scott Rodney J RJ Levi Christopher C Attia John J

Nature genetics 20120902 10

Genome-wide association studies (GWAS) have not consistently detected replicable genetic risk factors for ischemic stroke, potentially due to etiological heterogeneity of this trait. We performed GWAS of ischemic stroke and a major ischemic stroke subtype (large artery atherosclerosis, LAA) using 1,162 ischemic stroke cases (including 421 LAA cases) and 1,244 population controls from Australia. Evidence for a genetic influence on ischemic stroke risk was detected, but this influence was higher a ...[more]

PMID: 22941190

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Project description:ObjectiveTo investigate the association of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors, osteoprotegerin (OPG) and death receptor 5 (DR5) with large-artery atherosclerosis (LAA) stroke and its prognosis.MethodsWe included patients with LAA stroke (n = 132) according to the TOAST classification system and controls (n = 60). To evaluate the extent and severity of cerebral atherosclerosis, the LAA stroke group was subdivided into 3 subgroups by number of cerebral arteries with atherosclerotic stenosis (≥50%): single, double and multiple (≥3). Plasma levels of TRAIL, OPG and DR5 were measured by ELISA. Ordinal logistic regression was used to analyze the association between the plasma levels of TRAIL, OPG, DR5 and the severity of cerebral atherosclerosis. Prognosis was determined by the Modified Rankin Scale at 3 months after stroke. Receiver operating characteristic (ROC) curve was used to evaluated TRAIL as a predictor of prognosis.ResultsPlasma TRAIL level was significantly lower for LAA patients than controls (P<0.001), while plasma OPG and DR5 levels were higher (both P<0.001). Logistic regression analysis revealed that risk of severe cerebral atherosclerosis was reduced significantly with increased plasma level of TRAIL (OR 0.438; 95% CI 0.282-0.681; P<0.001), whereas increased with high plasma levels of OPG and DR5 (OR 2.707; 95% CI 1.702-4.302, P <0.001; OR 3.593; 95% CI 1.878-6.869, P <0.001). Plasma TRAIL level was negatively correlated with the prognosis (r = - 0.372, P <0.001). The optimal cut-off value of TRAIL for prognosis was 848.63 pg/mL. The sensitivity and specificity at this cut-off value were 63.1% and 86.2%, respectively. After adding the plasma TRAIL level into the multivariate model of ROC, the area under the ROC curve was increased from 0.639 to 0.785, but the change was not statistical significant (P = 0.146).ConclusionsTRAIL and its receptors OPG and DR5 may be involved in LAA stroke and the plasma level of TRAIL may be a biomarker predicting the severity of cerebral atherosclerosis and the prognosis of LAA stroke.

Dataset Information

Common variants at 6p21.1 are associated with large artery atherosclerotic stroke.

Publications

Common variants at 6p21.1 are associated with large artery atherosclerotic stroke.

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