Ischemic Stroke Is Associated with the ABO Locus: The EuroCLOT Study
Author(s):
F. M. K.
Williams, A. M.
Carter, P. G.
Hysi, G.
Surdulescu, D.
Hodgkiss, N.
Soranzo, M.
Traylor, S.
Bevan, M.
Dichgans, P. M. W.
Rothwell, C.
Sudlow, M.
Farrall, K.
Silander, M.
Kaunisto, P.
Wagner, O.
Saarela, K.
Kuulasmaa, J.
Virtamo, V.
Salomaa, P.
Amouyel, D.
Arveiler, J.
Ferrieres, P. G.
Wiklund, M. A.
Ikram, A.
Hofman, G. B.
Boncoraglio, E. A.
Parati, A.
Helgadottir, S.
Gretarsdottir, U.
Thorsteinsdottir, G.
Thorleifsson, K.
Stefansson, S.
Seshadri, A.
DeStefano, A.
Gschwendtner, B.
Psaty, W.
Longstreth, B. D.
Mitchell, Y. C.
Cheng, R.
Clarke, M.
Ferrario, J. C.
Bis, C.
Levi, J.
Attia, E. G.
Holliday, R. J.
Scott, M.
Fornage, P.
Sharma, K. L.
Furie, J.
Rosand, M.
Nalls, J.
Meschia, T. H.
Mosely, A.
Evans, A.
Palotie, H. S.
Markus, P. J.
Grant, T. D.
Spector,
EuroCLOT Investigators
,
Wellcome Trust Case Control Consor
,
Int Stroke Genetics Consortium
Abstract:
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 volunteers 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 x 10(-8)) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity (p = 2.6 x 10(-186)), rs10665 with FVII (p = 2.4 x 10(-47)), and rs505922 in the ABO gene with both von Willebrand factor (p = 4.7 x 10(-57)) and factor VIII (p = 1.2 x 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 2012;73:16-31
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ISBN:
0364-5134
Publication Year:
2013
Periodical:
Annals of Neurology
Periodical Number:
1
Volume:
73
Pages:
16-31
Author Address:
Williams, FMK
Kings Coll London, Dept Twin Res & Genet Epidemiol, St Thomas Hosp Campus,3rd Floor S Wing,Block 8,We, London SE1 7EH, England
Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England
Univ Leeds, Div Cardiovasc & Diabet Res, Leeds, W Yorkshire, England
Wellcome Trust Sanger Inst, Hinxton, England
Broad Inst Massachusetts Inst Technol & Harvard, Program Med & Populat Genet & Genet Anal Platform, Cambridge, MA USA
Univ Helsinki, Dept Med Genet, Helsinki, Finland
Univ Cent Hosp, Helsinki, Finland
St Georges Univ London, Stroke & Dementia Res Ctr, London, England
Univ Munich, Klinikum Univ Munich, Inst Stroke & Dementia Res, Munich, Germany
Univ Oxford, Dept Clin Neurol, Stroke Prevent Res Unit, Oxford, England
Univ Edinburgh, Div Clin Neurosci, Edinburgh, Midlothian, Scotland
Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England
Univ Oxford, Dept Cardiovasc Med, Oxford, England
Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland
Natl Inst Hlth & Welf, Chron Dis Epidemiol & Prevent Unit, Helsinki, Finland
Pasteur Inst Lille, Dept Epidemiol & Publ Hlth, Lille, France
Univ Strasbourg, Dept Epidemiol & Publ Hlth, Strasbourg, France
Fac Med, Dept Epidemiol, Toulouse, France
Umea Univ, Dept Internal Med, Umea, Sweden
Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands
Res Hosp, Neurol Inst Carlo Besta, Dept Neurol, Milan, Italy
DeCODE Genet, Reykjavik, Iceland
Boston Univ, Sch Med, Boston, MA 02118 USA
Boston Univ, Sch Publ Hlth, Boston, MA USA
Framingham Heart Dis Epidemiol Study, Framingham, MA USA
Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA
Univ Washington, Seattle, WA 98195 USA
Grp Hlth Res Inst, Grp Hlth, Seattle, WA USA
Univ Washington, Dept Neurol, Seattle, WA 98195 USA
Univ Maryland, Dept Med, Baltimore, MD 21201 USA
Univ Oxford, Clin Trial Serv Unit, Oxford, England
Univ Insubria, Varese, Italy
Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA
Univ Newcastle, Callaghan, NSW 2308, Australia
John Hunter Hosp, New Lambton Hts, Australia
Hunter Med Res Inst, New Lambton, Australia
Univ Texas Houston, Hlth Sci Ctr, Ctr Human Genet, Houston, TX USA
Univ Texas Houston, Hlth Sci Ctr, Inst Mol Med, Houston, TX USA
Univ London Imperial Coll Sci Technol & Med, Cerebrovasc Res Unit, London, England
Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA
Harvard Univ, Sch Med, Boston, MA USA
Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA
Univ Mississippi, Med Ctr, Jackson, MS 39216 USA
Queens Univ Belfast, Belfast, Antrim, North Ireland
