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

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

Annals of neurology (2013-02-06)

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 Amouyel, Dominique 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

PMID23381943

摘要

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.