Ischemic stroke is associated with the ABO locus: the EuroCLOT study.
Williams FM., Carter AM., Hysi PG., Surdulescu G., Hodgkiss D., Soranzo N., Traylor M., Bevan S., Dichgans M., Rothwell PM., Sudlow C., Farrall M., Silander K., Kaunisto M., Wagner P., Saarela O., Kuulasmaa K., Virtamo J., Salomaa V., Amouyel P., Arveiler D., Ferrieres J., Wiklund PG., Ikram MA., Hofman A., Boncoraglio GB., Parati EA., Helgadottir A., Gretarsdottir S., Thorsteinsdottir U., Thorleifsson G., Stefansson K., Seshadri S., DeStefano A., Gschwendtner A., Psaty B., Longstreth W., Mitchell BD., Cheng YC., Clarke R., Ferrario M., Bis JC., Levi C., Attia J., Holliday EG., Scott RJ., Fornage M., Sharma P., Furie KL., Rosand J., Nalls M., Meschia J., Mosely TH., Evans A., Palotie A., Markus HS., Grant PJ., Spector TD., EuroCLOT Investigators None., Wellcome Trust Case Control Consortium 2 None., MOnica Risk, Genetics, Archiving and Monograph None., MetaStroke None., International Stroke Genetics Consortium None.
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.