TY - JOUR T1 - Ischemic stroke is associated with the ABO locus: the EuroCLOT study. JF - Ann Neurol Y1 - 2013 A1 - Williams, Frances M K A1 - Carter, Angela M A1 - Hysi, Pirro G A1 - Surdulescu, Gabriela A1 - Hodgkiss, Dylan A1 - Soranzo, Nicole A1 - Traylor, Matthew A1 - Bevan, Steve A1 - Dichgans, Martin A1 - Rothwell, Peter M W A1 - Sudlow, Cathie A1 - Farrall, Martin A1 - Silander, Kaisa A1 - Kaunisto, Mari A1 - Wagner, Peter A1 - Saarela, Olli A1 - Kuulasmaa, Kari A1 - Virtamo, Jarmo A1 - Salomaa, Veikko A1 - Amouyel, Philippe A1 - Arveiler, Dominique A1 - Ferrieres, Jean A1 - Wiklund, Per-Gunnar A1 - Ikram, M Arfan A1 - Hofman, Albert A1 - Boncoraglio, Giorgio B A1 - Parati, Eugenio A A1 - Helgadottir, Anna A1 - Gretarsdottir, Solveig A1 - Thorsteinsdottir, Unnur A1 - Thorleifsson, Gudmar A1 - Stefansson, Kari A1 - Seshadri, Sudha A1 - DeStefano, Anita A1 - Gschwendtner, Andreas A1 - Psaty, Bruce A1 - Longstreth, Will A1 - Mitchell, Braxton D A1 - Cheng, Yu-Ching A1 - Clarke, Robert A1 - Ferrario, Marco A1 - Bis, Joshua C A1 - Levi, Christopher A1 - Attia, John A1 - Holliday, Elizabeth G A1 - Scott, Rodney J A1 - Fornage, Myriam A1 - Sharma, Pankaj A1 - Furie, Karen L A1 - Rosand, Jonathan A1 - Nalls, Mike A1 - Meschia, James A1 - Mosely, Thomas H A1 - Evans, Alun A1 - Palotie, Aarno A1 - Markus, Hugh S A1 - Grant, Peter J A1 - Spector, Tim D KW - ABO Blood-Group System KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Blood Coagulation KW - Brain Ischemia KW - Cohort Studies KW - Europe KW - Female KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Stroke KW - Young Adult AB -

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 × 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.

VL - 73 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23381943?dopt=Abstract ER -