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.

Ischemic stroke is associated with the ABO locus: the EuroCLOT study.

FERRARIO, MARCO MARIO ANGELO;
2013-01-01

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.
2013
http://dx.doi.org/10.1002/ana.23838
ABO Blood-Group System; genetics, Adolescent, Adult, Aged, Aged; 80 and over, Blood Coagulation; genetics, Brain Ischemia; diagnosis/epidemiology/genetics, Cohort Studies, Europe; epidemiology, Female, Genetic Loci; genetics, Genetic Predisposition to Disease; epidemiology/genetics, Genetic Variation; genetics, Genome-Wide Association Study; methods, Humans, Male, Middle Aged, Polymorphism; Single Nucleotide; genetics, Stroke; diagnosis/epidemiology/genetics, Young Adult
Williams, F. M.; Carter, A. M.; Hysi, P. G.; Surdulescu, G.; Hodgkiss, D.; Soranzo, N.; Traylor, M.; Bevan, S.; Dichgans, M.; Rothwell, P. M.; 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, P. G.; Ikram, M. A.; Hofman, A.; Boncoraglio, G. B.; Parati, E. A.; Helgadottir, A.; Gretarsdottir, S.; Thorsteinsdottir, U.; Thorleifsson, G.; Stefansson, K.; Seshadri, S.; Destefano, A.; Gschwendtner, A.; Psaty, B.; Longstreth, W.; Mitchell, B. D.; Cheng, Y. C.; Clarke, R.; Ferrario, MARCO MARIO ANGELO; Bis, J. C.; Levi, C.; Attia, J.; Holliday, E. G.; Scott, R. J.; Fornage, M.; Sharma, P.; Furie, K. L.; Rosand, J.; Nalls, M.; Meschia, J.; Mosely, T. H.; Evans, A.; Palotie, A.; Markus, H. S.; Grant, P. J.; Spector, T. D.; Euroclot, Investigators; Wellcome Trust Case Control Consortium, 2; Monica, Risk; Genetics, Archiving; Monograph, Metastroke; International Stroke Genetics, Consortium
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