Ischemic stroke is associated with the ABO locus

the EuroCLOT study.

Frances M.K. Williams, Angela M. Carter, Pirro G. Hysi, Gabriela Surdulescu, Dylan Hodgkiss, Nicole Soranzo, Matthew Traylor, Steve Bevan, Martin Dichgans, Peter M.W. Rothwell, Cathie Sudlow, Martin Farrall, Kaisa Silander, Mari Kaunisto, Peter Wagner, Olli Saarela, Kari Kuulasmaa, Jarmo Virtamo, Veikko Salomaa, Philippe Amouyel & 43 others Dominique Arveiler, Jean Ferrieres, Per Gunnar Wiklund, M. Arfan Ikram, Albert Hofman, Giorgio B. Boncoraglio, Eugenio A. Parati, Anna Helgadottir, Solveig Gretarsdottir, Unnur Thorsteinsdottir, Gudmar Thorleifsson, Kari Stefansson, Sudha Seshadri, Anita DeStefano, Andreas Gschwendtner, Bruce Psaty, Will Longstreth, Braxton D. Mitchell, Yu Ching Cheng, Robert Clarke, Marco Ferrario, Joshua C. Bis, Christopher Levi, John Attia, Elizabeth G. Holliday, Rodney J. Scott, Myriam Fornage, Pankaj Sharma, Karen L. Furie, Jonathan Rosand, Mike Nalls, James Meschia, Thomas H. Mosely, Alun Evans, Aarno Palotie, Hugh S. Markus, Peter J. Grant, Tim D. Spector, Investigators EuroCLOT Investigators, Trust Case Control Consortium 2 Wellcome Trust Case Control Consortium 2, Risk, Genetics, Archiving MOnica Risk, Genetics, Archiving, MetaStroke, Stroke Genetics Consortium International Stroke Genetics Consortium

Research output: Contribution to journalArticle

77 Citations (Scopus)

Abstract

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. 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). 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). 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.

Original languageEnglish (US)
Pages (from-to)16-31
Number of pages16
JournalAnnals of Neurology
Volume73
Issue number1
DOIs
StatePublished - Jan 1 2013
Externally publishedYes

Fingerprint

Stroke
Single Nucleotide Polymorphism
Fibrin
Factor XIII
Blood Coagulation Factors
Genome-Wide Association Study
Linkage Disequilibrium
Factor VIII
von Willebrand Factor
Genetic Predisposition to Disease
Genes
Healthy Volunteers
Odds Ratio
Confidence Intervals
Phenotype

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Williams, F. M. K., Carter, A. M., Hysi, P. G., Surdulescu, G., Hodgkiss, D., Soranzo, N., ... International Stroke Genetics Consortium, S. G. C. (2013). Ischemic stroke is associated with the ABO locus: the EuroCLOT study. Annals of Neurology, 73(1), 16-31. https://doi.org/10.1002/ana.23838

Ischemic stroke is associated with the ABO locus : the EuroCLOT study. / Williams, Frances M.K.; Carter, Angela M.; Hysi, Pirro G.; Surdulescu, Gabriela; Hodgkiss, Dylan; Soranzo, Nicole; Traylor, Matthew; Bevan, Steve; Dichgans, Martin; Rothwell, Peter M.W.; Sudlow, Cathie; Farrall, Martin; Silander, Kaisa; Kaunisto, Mari; Wagner, Peter; Saarela, Olli; Kuulasmaa, Kari; Virtamo, Jarmo; Salomaa, Veikko; Amouyel, Philippe; Arveiler, Dominique; Ferrieres, Jean; Wiklund, Per Gunnar; Ikram, M. Arfan; Hofman, Albert; Boncoraglio, Giorgio B.; Parati, Eugenio A.; Helgadottir, Anna; Gretarsdottir, Solveig; Thorsteinsdottir, Unnur; Thorleifsson, Gudmar; Stefansson, Kari; Seshadri, Sudha; DeStefano, Anita; Gschwendtner, Andreas; Psaty, Bruce; Longstreth, Will; Mitchell, Braxton D.; Cheng, Yu Ching; Clarke, Robert; Ferrario, Marco; Bis, Joshua C.; Levi, Christopher; Attia, John; Holliday, Elizabeth G.; Scott, Rodney J.; Fornage, Myriam; Sharma, Pankaj; Furie, Karen L.; Rosand, Jonathan; Nalls, Mike; Meschia, James; Mosely, Thomas H.; Evans, Alun; Palotie, Aarno; Markus, Hugh S.; Grant, Peter J.; Spector, Tim D.; EuroCLOT Investigators, Investigators; Wellcome Trust Case Control Consortium 2, Trust Case Control Consortium 2; MOnica Risk, Genetics, Archiving, Risk, Genetics, Archiving; MetaStroke; International Stroke Genetics Consortium, Stroke Genetics Consortium.

In: Annals of Neurology, Vol. 73, No. 1, 01.01.2013, p. 16-31.

Research output: Contribution to journalArticle

Williams, FMK, Carter, AM, Hysi, PG, Surdulescu, G, Hodgkiss, D, Soranzo, N, Traylor, M, Bevan, S, Dichgans, M, Rothwell, PMW, 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, I, Wellcome Trust Case Control Consortium 2, TCCC, MOnica Risk, Genetics, Archiving, RGA, MetaStroke & International Stroke Genetics Consortium, SGC 2013, 'Ischemic stroke is associated with the ABO locus: the EuroCLOT study.', Annals of Neurology, vol. 73, no. 1, pp. 16-31. https://doi.org/10.1002/ana.23838
Williams FMK, Carter AM, Hysi PG, Surdulescu G, Hodgkiss D, Soranzo N et al. Ischemic stroke is associated with the ABO locus: the EuroCLOT study. Annals of Neurology. 2013 Jan 1;73(1):16-31. https://doi.org/10.1002/ana.23838
Williams, Frances M.K. ; Carter, Angela M. ; Hysi, Pirro G. ; Surdulescu, Gabriela ; Hodgkiss, Dylan ; Soranzo, Nicole ; Traylor, Matthew ; Bevan, Steve ; Dichgans, Martin ; Rothwell, Peter M.W. ; Sudlow, Cathie ; Farrall, Martin ; Silander, Kaisa ; Kaunisto, Mari ; Wagner, Peter ; Saarela, Olli ; Kuulasmaa, Kari ; Virtamo, Jarmo ; Salomaa, Veikko ; Amouyel, Philippe ; Arveiler, Dominique ; Ferrieres, Jean ; Wiklund, Per Gunnar ; Ikram, M. Arfan ; Hofman, Albert ; Boncoraglio, Giorgio B. ; Parati, Eugenio A. ; Helgadottir, Anna ; Gretarsdottir, Solveig ; Thorsteinsdottir, Unnur ; Thorleifsson, Gudmar ; Stefansson, Kari ; Seshadri, Sudha ; DeStefano, Anita ; Gschwendtner, Andreas ; Psaty, Bruce ; Longstreth, Will ; Mitchell, Braxton D. ; Cheng, Yu Ching ; Clarke, Robert ; Ferrario, Marco ; Bis, Joshua C. ; Levi, Christopher ; Attia, John ; Holliday, Elizabeth G. ; Scott, Rodney J. ; Fornage, Myriam ; Sharma, Pankaj ; Furie, Karen L. ; Rosand, Jonathan ; Nalls, Mike ; Meschia, James ; Mosely, Thomas H. ; Evans, Alun ; Palotie, Aarno ; Markus, Hugh S. ; Grant, Peter J. ; Spector, Tim D. ; EuroCLOT Investigators, Investigators ; Wellcome Trust Case Control Consortium 2, Trust Case Control Consortium 2 ; MOnica Risk, Genetics, Archiving, Risk, Genetics, Archiving ; MetaStroke ; International Stroke Genetics Consortium, Stroke Genetics Consortium. / Ischemic stroke is associated with the ABO locus : the EuroCLOT study. In: Annals of Neurology. 2013 ; Vol. 73, No. 1. pp. 16-31.
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abstract = "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. 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). 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). 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.",
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T1 - Ischemic stroke is associated with the ABO locus

T2 - the EuroCLOT study.

AU - Williams, Frances M.K.

AU - Carter, Angela M.

AU - Hysi, Pirro G.

AU - Surdulescu, Gabriela

AU - Hodgkiss, Dylan

AU - Soranzo, Nicole

AU - Traylor, Matthew

AU - Bevan, Steve

AU - Dichgans, Martin

AU - Rothwell, Peter M.W.

AU - Sudlow, Cathie

AU - Farrall, Martin

AU - Silander, Kaisa

AU - Kaunisto, Mari

AU - Wagner, Peter

AU - Saarela, Olli

AU - Kuulasmaa, Kari

AU - Virtamo, Jarmo

AU - Salomaa, Veikko

AU - Amouyel, Philippe

AU - Arveiler, Dominique

AU - Ferrieres, Jean

AU - Wiklund, Per Gunnar

AU - Ikram, M. Arfan

AU - Hofman, Albert

AU - Boncoraglio, Giorgio B.

AU - Parati, Eugenio A.

AU - Helgadottir, Anna

AU - Gretarsdottir, Solveig

AU - Thorsteinsdottir, Unnur

AU - Thorleifsson, Gudmar

AU - Stefansson, Kari

AU - Seshadri, Sudha

AU - DeStefano, Anita

AU - Gschwendtner, Andreas

AU - Psaty, Bruce

AU - Longstreth, Will

AU - Mitchell, Braxton D.

AU - Cheng, Yu Ching

AU - Clarke, Robert

AU - Ferrario, Marco

AU - Bis, Joshua C.

AU - Levi, Christopher

AU - Attia, John

AU - Holliday, Elizabeth G.

AU - Scott, Rodney J.

AU - Fornage, Myriam

AU - Sharma, Pankaj

AU - Furie, Karen L.

AU - Rosand, Jonathan

AU - Nalls, Mike

AU - Meschia, James

AU - Mosely, Thomas H.

AU - Evans, Alun

AU - Palotie, Aarno

AU - Markus, Hugh S.

AU - Grant, Peter J.

AU - Spector, Tim D.

AU - EuroCLOT Investigators, Investigators

AU - Wellcome Trust Case Control Consortium 2, Trust Case Control Consortium 2

AU - MOnica Risk, Genetics, Archiving, Risk, Genetics, Archiving

AU - MetaStroke,

AU - International Stroke Genetics Consortium, Stroke Genetics Consortium

PY - 2013/1/1

Y1 - 2013/1/1

N2 - 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. 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). 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). 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.

AB - 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. 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). 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). 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.

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