Ischemic stroke is associated with the ABO locus: the EuroCLOT study
2013 (English)In: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 73, no 1, 16-31 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
Wiley-Blackwell, 2013. Vol. 73, no 1, 16-31 p.
IdentifiersURN: urn:nbn:se:umu:diva-67055DOI: 10.1002/ana.23838ISI: 000314660800007OAI: oai:DiVA.org:umu-67055DiVA: diva2:612723
Errata Annals of Neurology, 2014: 75 (1), 166-167. doi:10.1002/ana.241052013-03-242013-03-122014-04-11Bibliographically approved