Journal
ANNALS OF NEUROLOGY
Volume 73, Issue 1, Pages 16-31Publisher
WILEY-BLACKWELL
DOI: 10.1002/ana.23838
Keywords
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Categories
Funding
- Wellcome Trust
- EU FP7
- DFG/DLR
- Fondation Leducq
- Vasc. Dem. Res. Foundation
- Jackstaedt Foundation
- Corona Foundation
- Georg Thieme Verlag
- UpToDate
- W. Kohlhammer Verlag. P.A.
- Medtronic
- Zoll LifeCor
- US Department of Veterans Affairs
- Wellcome Trust funding of TwinsUK
- EU [QLRT-2001-01254]
- National Institute of Health Research (NIHR) Biomedical Resource Centre
- St Thomas' National Health Service (NHS) Foundation Trust
- King's College London
- Wellcome Trust, as part of the WTCCC2 project [085475/B/08/Z, 085475/Z/08/Z, WT084724MA]
- Vascular Dementia Research Foundation
- Medical Research Council
- Stroke Association
- Dunhill Medical Trust
- NIHR
- NIHR Biomedical Research Centre, Oxford
- Binks Trust
- Scottish Funding Council
- Chief Scientist Office
- European Community's Seventh Framework Programme
- ENGAGE project [HEALTH-F4-2007-201413]
- Academy of Finland Center of Excellence in Complex Disease Genetics
- Academy of Finland [251704]
- Academy of Finland, Center of Excellence in Complex Disease Genetics [213506, 129680]
- European Community's Seventh Framework Program
- ENGAGE Consortium [HEALTH-F4-2007-201413]
- EU/SYNSYS-Synaptic Systems [242167]
- Sigrid Juselius Foundation, Finland
- NIH National Heart, Lung, and Blood Institute (NHLBI) [R01 HL085251, R01 HL073410]
- NHLBI [HHSN268201100005C, HHSN2682011000 06C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHS N268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694, N01-HC-25195, N02-HL-6-4278, HL093029]
- National Human Genome Research Institute [U01HG004402]
- NINDS [NS17950]
- NIA [AG08122, AG16495, AG033193, AG031287]
- DIVISION OF EPIDEMIOLOGY AND CLINICAL APPLICATIONS [N01HC085085, N01HC055222, N01HC085084, N01HC075150, N01HC035129, N01HC015103, N01HC025195, N01HC085082, N01HC045133, N01HC085080, N01HC085083, N01HC085081, N01HC085079, N01HC085086] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [UL1RR025005, UL1RR033176] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL087652, R01HL093029, R01HL064278, R01HL080295, R01HL085083, R01HL059367, U01HL080295, R01HL105756, R01HL086694, R01HL075366, R01HL073410, R01HL087641, R01HL085251] Funding Source: NIH RePORTER
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [U01HG004402, U01HG004446, U01HG004436] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK072488, P30DK063491] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [U01NS069208, R01NS017950, R01NS042733, R01NS039987, R01NS045012] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG016495, R01AG020098, ZIAAG000015, R01AG023629, R01AG015928, R01AG033193, Z01AG000015, Z01AG000954, R56AG020098, R01AG027058, R01AG031287, R56AG023629, R01AG008122] Funding Source: NIH RePORTER
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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. ANN NEUROL 2012;73:16-31
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