title: Ischemic stroke is associated with the ABO locus: the EuroCLOT study.
abstract: 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).
  
  
  CONCLUSIONS
  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.
authors: Department of Twin Research and Genetic Epidemiology, King's College London, United Kingdom. frances.williams@kcl.ac.uk
authors: Frances M K
authors: FM
authors: Williams
authors: Angela M
authors: AM
authors: Carter
authors: Pirro G
authors: PG
authors: Hysi
authors: Gabriela
authors: G
authors: Surdulescu
authors: Dylan
authors: D
authors: Hodgkiss
authors: Nicole
authors: N
authors: Soranzo
authors: Matthew
authors: M
authors: Traylor
authors: Steve
authors: S
authors: Bevan
authors: Martin
authors: M
authors: Dichgans
authors: Peter M W
authors: PM
authors: Rothwell
authors: Cathie
authors: C
authors: Sudlow
authors: Martin
authors: M
authors: Farrall
authors: Kaisa
authors: K
authors: Silander
authors: Mari
authors: M
authors: Kaunisto
authors: Peter
authors: P
authors: Wagner
authors: Olli
authors: O
authors: Saarela
authors: Kari
authors: K
authors: Kuulasmaa
authors: Jarmo
authors: J
authors: Virtamo
authors: Veikko
authors: V
authors: Salomaa
authors: Philippe
authors: P
authors: Amouyel
authors: Dominique
authors: D
authors: Arveiler
authors: Jean
authors: J
authors: Ferrieres
authors: Per-Gunnar
authors: PG
authors: Wiklund
authors: M Arfan
authors: MA
authors: Ikram
authors: Albert
authors: A
authors: Hofman
authors: Giorgio B
authors: GB
authors: Boncoraglio
authors: Eugenio A
authors: EA
authors: Parati
authors: Anna
authors: A
authors: Helgadottir
authors: Solveig
authors: S
authors: Gretarsdottir
authors: Unnur
authors: U
authors: Thorsteinsdottir
authors: Gudmar
authors: G
authors: Thorleifsson
authors: Kari
authors: K
authors: Stefansson
authors: Sudha
authors: S
authors: Seshadri
authors: Anita
authors: A
authors: DeStefano
authors: Andreas
authors: A
authors: Gschwendtner
authors: Bruce
authors: B
authors: Psaty
authors: Will
authors: W
authors: Longstreth
authors: Braxton D
authors: BD
authors: Mitchell
authors: Yu-Ching
authors: YC
authors: Cheng
authors: Robert
authors: R
authors: Clarke
authors: Marco
authors: M
authors: Ferrario
authors: Joshua C
authors: JC
authors: Bis
authors: Christopher
authors: C
authors: Levi
authors: John
authors: J
authors: Attia
authors: Elizabeth G
authors: EG
authors: Holliday
authors: Rodney J
authors: RJ
authors: Scott
authors: Myriam
authors: M
authors: Fornage
authors: Pankaj
authors: P
authors: Sharma
authors: Karen L
authors: KL
authors: Furie
authors: Jonathan
authors: J
authors: Rosand
authors: Mike
authors: M
authors: Nalls
authors: James
authors: J
authors: Meschia
authors: Thomas H
authors: TH
authors: Mosely
authors: Alun
authors: A
authors: Evans
authors: Aarno
authors: A
authors: Palotie
authors: Hugh S
authors: HS
authors: Markus
authors: Peter J
authors: PJ
authors: Grant
authors: Tim D
authors: TD
authors: Spector
mesh_terms: D000017:ABO Blood-Group System / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001777:Blood Coagulation / Q000235:genetics*; D002545:Brain Ischemia / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D015331:Cohort Studies; D005060:Europe / Q000453:epidemiology; D005260:Female; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D020521:Stroke / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D055815:Young Adult
chemical_list: D000017:ABO Blood-Group System
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