- Title
- Ischemic stroke is associated with the ABO locus: the EuroCLOT Study
- Creator
- Williams, Frances M. K.; Carter, Angela M.; Sudlow, Cathie; Farrall, Martin; Silander, Kaisa; Kaunisto, Mari; Wagner, Peter; Saarela, Olli; Kuulasmaa, Kari; Virtamo, Jarmo; Salomaa, Veikko; Amouyel, Philippe; Hysi, Pirro G.; Bis, Joshua C.; Levi, Christopher; Attia, John; Holliday, Elizabeth G.; Scott, Rodney J.; Surdulescu, Gabriela; Hodgkiss, Dylan; Soranzo, Nicole; Traylor, Matthew; Bevan, Steve; Dichgans, Martin; Rothwell, Peter M. W.
- Relation
- Annals of Neurology Vol. 73, Issue 1, p. 16-31
- Publisher Link
- http://dx.doi.org/10.1002/ana.23838
- Publisher
- John Wiley & Sons
- Resource Type
- journal article
- Date
- 2013
- Description
- 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 REFVIDunteers 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. Ann Neurol 2013
- Subject
- ischemic stroke; stroke; EuroCLOT Study; fibrin
- Identifier
- http://hdl.handle.net/1959.13/1339863
- Identifier
- uon:28358
- Identifier
- ISSN:0364-5134
- Language
- eng
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