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Ischemic stroke is associated with the ABO locus: The EuroCLOT study
Author(s) -
Williams Frances M. K.,
Carter Angela M.,
Hysi Pirro G.,
Surdulescu Gabriela,
Hodgkiss Dylan,
Soranzo Nicole,
Traylor Matthew,
Bevan Steve,
Dichgans Martin,
Rothwell Peter M. W.,
Sudlow Cathie,
Farrall Martin,
Silander Kaisa,
Kaunisto Mari,
Wagner Peter,
Saarela Olli,
Kuulasmaa Kari,
Virtamo Jarmo,
Salomaa Veikko,
Amouyel Philippe,
Arveiler Dominique,
Ferrieres Jean,
Wiklund PerGunnar,
Arfan Ikram M.,
Hofman Albert,
Boncoraglio Giorgio B.,
Parati Eugenio A.,
Helgadottir Anna,
Gretarsdottir Solveig,
Thorsteinsdottir Unnur,
Thorleifsson Gudmar,
Stefansson Kari,
Seshadri Sudha,
DeStefano Anita,
Gschwendtner Andreas,
Psaty Bruce,
Longstreth Will,
Mitchell Braxton D.,
Cheng YuChing,
Clarke Robert,
Ferrario Marco,
Bis Joshua C.,
Levi Christopher,
Attia John,
Holliday Elizabeth G.,
Scott Rodney J.,
Fornage Myriam,
Sharma Pankaj,
Furie Karen L.,
Rosand Jonathan,
Nalls Mike,
Meschia James,
Mosely Thomas H.,
Evans Alun,
Palotie Aarno,
Markus Hugh S.,
Grant Peter J.,
Spector Tim D.
Publication year - 2013
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.23838
Subject(s) - single nucleotide polymorphism , odds ratio , stroke (engine) , abo blood group system , genome wide association study , linkage disequilibrium , medicine , snp , genetic association , genetic predisposition , risk factor , tag snp , case control study , oncology , bioinformatics , genetics , biology , genotype , disease , gene , mechanical engineering , engineering
Objective : End‐stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischemic stroke. We explored whether genetic variants associated with end‐stage coagulation in healthy REFVIDunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype. Methods : Common genetic variants identified through genome‐wide association studies of coagulation factors and fibrin structure/function in healthy twins (n = 2,100, Stage 1) were examined in ischemic stroke (n = 4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases, 55,000 controls) was used for replication (Stage 3). Results : Stage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association ( p < 5 × 10 –8 ) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity ( p = 2.6 × 10 –186 ), rs10665 with FVII ( p = 2.4 × 10 –47 ), and rs505922 in the ABO gene with both von Willebrand factor ( p = 4.7 × 10 –57 ) and factor VIII ( p = 1.2 × 10 –36 ). In Stage 2, the 23 independent SNPs were examined in stroke cases/noncases using MOnica Risk, Genetics, Archiving and Monograph (MORGAM) and Wellcome Trust Case Control Consortium 2 collections. SNP rs505922 was nominally associated with ischemic stroke (odds ratio = 0.94, 95% confidence interval = 0.88–0.99, p = 0.023). Independent replication in Meta‐Stroke confirmed the rs505922 association with stroke, beta (standard error, SE) = 0.066 (0.02), p = 0.001, a finding specific to large‐vessel and cardioembolic stroke ( p = 0.001 and p = < 0.001, respectively) but not seen with small‐vessel stroke ( p = 0.811). Interpretation : ABO gene variants are associated with large‐vessel and cardioembolic stroke but not small‐vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype. Ann Neurol 2013