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

Frances M.K. Williams, Angela M. Carter, Pirro G. Hysi, Gabriela Surdulescu, Dylan Hodgkiss, Nicole Soranzo, Matthew Traylor, Steve Bevan, Martin Dichgans, Peter M.W. Rothwell, Cathie Sudlow, Martin Farrall, Kaisa Silander, Mari Kaunisto, Peter Wagner, Olli Saarela, Kari Kuulasmaa, Jarmo Virtamo, Veikko Salomaa, Philippe AmouyelDominique Arveiler, Jean Ferrieres, Per Gunnar Wiklund, M. Arfan Ikram, Albert Hofman, Giorgio B. Boncoraglio, Eugenio A. Parati, Anna Helgadottir, Solveig Gretarsdottir, Unnur Thorsteinsdottir, Gudmar Thorleifsson, Kari Stefansson, Sudha Seshadri, Anita DeStefano, Andreas Gschwendtner, Bruce Psaty, Will Longstreth, Braxton D. Mitchell, Yu Ching Cheng, Robert Clarke, Marco Ferrario, Joshua C. Bis, Christopher Levi, John Attia, Elizabeth G. Holliday, Rodney J. Scott, Myriam Fornage, Pankaj Sharma, Karen L. Furie, Jonathan Rosand, Mike Nalls, James Meschia, Thomas H. Mosely, Alun Evans, Aarno Palotie, Hugh S. Markus, Peter J. Grant, Tim D. Spector, Investigators EuroCLOT Investigators, Trust Case Control Consortium 2 Wellcome Trust Case Control Consortium 2, Risk, Genetics, Archiving MOnica Risk, Genetics, Archiving, MetaStroke, Stroke Genetics Consortium International Stroke Genetics Consortium

Research output: Contribution to journalArticle

89 Scopus citations

Abstract

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. 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). 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). 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.

Original languageEnglish (US)
Pages (from-to)16-31
Number of pages16
JournalUnknown Journal
Volume73
Issue number1
DOIs
StatePublished - Jan 2013

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Fingerprint Dive into the research topics of 'Ischemic stroke is associated with the ABO locus: the EuroCLOT study.'. Together they form a unique fingerprint.

  • Cite this

    Williams, F. M. K., Carter, A. M., Hysi, P. G., Surdulescu, G., Hodgkiss, D., Soranzo, N., Traylor, M., Bevan, S., Dichgans, M., Rothwell, P. M. W., Sudlow, C., Farrall, M., Silander, K., Kaunisto, M., Wagner, P., Saarela, O., Kuulasmaa, K., Virtamo, J., Salomaa, V., ... International Stroke Genetics Consortium, S. G. C. (2013). Ischemic stroke is associated with the ABO locus: the EuroCLOT study. Unknown Journal, 73(1), 16-31. https://doi.org/10.1002/ana.23838