Ischemic stroke is associated with the ABO locus: The EuroCLOT study

Annals of Neurology - Tập 73 Số 1 - Trang 16-31 - 2013
Frances Williams1, Angela M. Carter2, Pirro G. Hysi1, Gabriela Surdulescu1, Dylan Hodgkiss1, Nicole Soranzo3,4,5, Matthew Brooks6, Steve Bevan6, Martin Dichgans7, Peter M. Rothwell8, Cathie Sudlow9, Martin Farrall10, Kaisa Silander11, Mari Kaunisto11, Peter J. Wagner11, Olli Saarela12, Kari Kuulasmaa12, Jarmo Virtamo12, Veikko Salomaa12, Philippe Amouyel13, Dominique Arveiler14, Jean Ferrières15, Peder Wiklund16, M. Arfan Ikram17, Albert Hofman17, Giorgio B. Boncoraglio18, Eugenio Parati18, Anna Helgadóttir19,10, Sólveig Grétarsdóttir19, Frank J.A. van Rooij19, Guðmar Þorleifsson19, Kāri Stefánsson19, Sudha Seshadri20,21,22, Anita L. DeStefano20,21,22, Andreas Gschwendtner7, Bruce M. Psaty23,24,25,26, W.T. Longstreth27,24,26, Braxton D. Mitchell28, Yu‐Ching Cheng28, Robert Plomin29, M Ferrario30, Joshua C. Bis31, Christopher Levi32,33,34, John Attia32,33,34, Elizabeth Holliday32,33,34, Rodney J. Scott32,33,34, Myriam Fornage35, Pankaj Sharma36, Karen L. Furie37, Jonathan Rosand37, Mike A. Nalls38, James F. Meschia38, T. Mosely39, Alun Evans40,41,42,43,44, Aarno Palotie3,11,4,5, Hugh S. Markus6, Peter J. Grant2, Tim D. Spector1
1Department of Twin Research and Genetic Epidemiology, King’s College London, London, United Kingdom
2Division of Cardiovascular and Diabetes Research, University of Leeds, Leeds, United Kingdom
3Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland
4Program in Medical and Population Genetics and Genetic Analysis Platform, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
5Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom
6Stroke and Dementia Research Centre, St George's University of London, London, United Kingdom
7Institute for Stroke and Dementia Research, Klinikum der Universität Munich, Ludwig-Maximilians-University, Munich, Germany
8Stroke Prevention Research Unit, University Department of Clinical Neurology, Oxford University, Oxford, United Kingdom
9Division of Clinical Neurosciences, University of Edinburgh, Edinburgh, United Kingdom
10Wellcome Trust Centre for Human Genetics and Department of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom
11Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
12Chronic Disease Epidemiology and Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland
13Department of Epidemiology and Public Health, Pasteur Institute of Lille, Lille, France
14Department of Epidemiology and Public Health, University of Strasbourg, Strasbourg, France
15Department of Epidemiology, Faculty of Medicine, Toulouse-Purpan, Toulouse, France
16Department of Internal Medicine, University of Umeo̊, Umeo̊, Sweden
17Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
18Department of Neurology, Research Hospital of the Neurological Institute "Carlo Besta,"Milan, Italy
19deCODE Genetics, Reykjavik, Iceland
20Boston University Schools of Medicine and Public Health, Boston, MA
21Departments of Health Services, University of Washington, Seattlem WA
22Framingham Heart Study, Framingham, MA
23Department of Neurology, University of Washington, WA
24Epidemiology, Health Services, University of Washington, Seattle, WA
25Group Health Research Institute, Group Health, Seattle, WA
26Medicine, and Health Services, University of Washington, Seattle, WA
27Department of Medicine, University of Maryland, Baltimore, MD
28Clinical Trial Service Unit, University of Oxford, Oxford, United Kingdom
29University of Insubria, Varese, Italy
30Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA
31University of Newcastle, Callaghan, Australia
32Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Sciences Center, Houston, TX
33Hunter Medical Research Institute, New Lambton, Australia
34John Hunter Hospital, New Lambton Heights, Australia
35Imperial College Cerebrovascular Research Unit, Imperial College London, London, United Kingdom
36Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA
37Department of Neurology, Mayo Clinic, Jacksonville, FL, USA
38University of Mississippi Medical Center, Jackson, MS
39Queen's University of Belfast, Belfast, United Kingdom
40 Departments of Health Services, University of Washington, Seattle, WA;
41Department of Twin Research and Genetic Epidemiology, King's College London,
42EuroCLOT Investigators, the Wellcome Trust Case Control Consortium 2, MOnica Risk, Genetics, Archiving and Monograph, MetaStroke, and the
43International Stroke Genetics Consortium
44St Thomas' Hospital Campus, 3rd Floor South Wing Block 8, Westminster Bridge Road, London, SE1 7EH.

Tóm tắt

AbstractObjective: 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

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