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

Friday,2013-10-11 17:01 America/Los_Angeles — eenright
TitleIschemic stroke is associated with the ABO locus: the EuroCLOT study.
Publication TypeJournal Article
Year of Publication2013
AuthorsWilliams, 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, P-G, Ikram, AM, 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, Y-C, 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
Corporate/Institutional AuthorsEuroCLOT Investigators, Wellcome Trust Case Control Consortium 2,, MOnica Risk, Genetics, Archiving and Monograph, MetaStroke, International Stroke Genetics Consortium,
JournalAnn Neurol
Volume73
Issue1
Pagination16-31
Date Published2013 Jan
ISSN1531-8249
KeywordsABO Blood-Group System, Adolescent, Adult, Aged, Aged, 80 and over, Blood Coagulation, Brain Ischemia, Cohort Studies, Europe, Female, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Stroke, Young Adult
Abstract<p><b>OBJECTIVE: </b>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.</p><p><b>METHODS: </b>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).</p><p><b>RESULTS: </b>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).</p><p><b>INTERPRETATION: </b>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.</p>
DOI10.1002/ana.23838
Alternate JournalAnn. Neurol.
PubMed ID23381943
PubMed Central IDPMC3582024
Grant ListHHSN268201100012C / HL / NHLBI NIH HHS / United States
UL1RR025005 / RR / NCRR NIH HHS / United States
N02-HL-6-4278 / HL / NHLBI NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
UL1 RR033176 / RR / NCRR NIH HHS / United States
U01 HG 004446 / HG / NHGRI NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
Z01 AG000015 / AG / NIA NIH HHS / United States
R01 HL075366 / HL / NHLBI NIH HHS / United States
R01 NS45012 / NS / NINDS NIH HHS / United States
R01 NS045012 / NS / NINDS NIH HHS / United States
R01 NS017950 / NS / NINDS NIH HHS / United States
R01 NS042733 / NS / NINDS NIH HHS / United States
U01 HG004446 / HG / NHGRI NIH HHS / United States
Z01 AG000015-50 / AG / NIA NIH HHS / United States
095626 / / Wellcome Trust / United Kingdom
R01 AG016495 / AG / NIA NIH HHS / United States
R01HL59367 / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
R01 AG015928 / AG / NIA NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
HHSN268201100005G / HL / NHLBI NIH HHS / United States
HHSN268201100008I / HL / NHLBI NIH HHS / United States
N01-HC-85081 / HC / NHLBI NIH HHS / United States
HHSN268201100005C / / PHS HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
HL105756 / HL / NHLBI NIH HHS / United States
N01 HC015103 / HC / NHLBI NIH HHS / United States
R01 HL085251 / HL / NHLBI NIH HHS / United States
Z01 AG-000015-50 / AG / NIA NIH HHS / United States
R56 AG020098 / AG / NIA NIH HHS / United States
HHSN268201100009C / / PHS HHS / United States
HHSN268201100011I / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
N01 HC085085 / HC / NHLBI NIH HHS / United States
AG033193 / AG / NIA NIH HHS / United States
/ / Department of Health / United Kingdom
R01 HL087652 / HL / NHLBI NIH HHS / United States
AG-20098 / AG / NIA NIH HHS / United States
HHSN268200625226C / / PHS HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
HL093029 / HL / NHLBI NIH HHS / United States
HL087652 / HL / NHLBI NIH HHS / United States
WT098051 / / Wellcome Trust / United Kingdom
N01HC55222 / HL / NHLBI NIH HHS / United States
N02HL64278 / HL / NHLBI NIH HHS / United States
N01-HC-85086 / HC / NHLBI NIH HHS / United States
R01 HL093029 / HL / NHLBI NIH HHS / United States
NS17950 / NS / NINDS NIH HHS / United States
HHSN268201100010C / / PHS HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
U01HG004402 / HG / NHGRI NIH HHS / United States
AG08122 / AG / NIA NIH HHS / United States
AG-027058 / AG / NIA NIH HHS / United States
N01-HC-85082 / HC / NHLBI NIH HHS / United States
R01 NS-42733 / NS / NINDS NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
HHSN268200782096C / HG / NHGRI NIH HHS / United States
HL075366 / HL / NHLBI NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
R01 AG008122 / AG / NIA NIH HHS / United States
N01 HC-55222 / HC / NHLBI NIH HHS / United States
HHSN268201100008C / / PHS HHS / United States
P30 DK072488 / DK / NIDDK NIH HHS / United States
HHSN268201100012C / / PHS HHS / United States
R01 AG033193 / AG / NIA NIH HHS / United States
R01HL087641 / HL / NHLBI NIH HHS / United States
U01 NS069208 / NS / NINDS NIH HHS / United States
R01 NS039987 / NS / NINDS NIH HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
N01-HC-85083 / HC / NHLBI NIH HHS / United States
090532 / / Wellcome Trust / United Kingdom
N01-HC-75150 / HC / NHLBI NIH HHS / United States
N01-HC-85080 / HC / NHLBI NIH HHS / United States
WT084724MA / / Wellcome Trust / United Kingdom
Z01 AG-000954-06 / AG / NIA NIH HHS / United States
098051 / / Wellcome Trust / United Kingdom
R01 HL080295 / HL / NHLBI NIH HHS / United States
085475/B/08/Z / / Wellcome Trust / United Kingdom
AG031287 / AG / NIA NIH HHS / United States
HHSN268201100007C / / PHS HHS / United States
N01 HC085084 / HC / NHLBI NIH HHS / United States
R01 AG020098 / AG / NIA NIH HHS / United States
N01HC85082 / HL / NHLBI NIH HHS / United States
U01 HG004436 / HG / NHGRI NIH HHS / United States
N01HC75150 / HL / NHLBI NIH HHS / United States
WT091310 / / Wellcome Trust / United Kingdom
HHSN268201100009C / HL / NHLBI NIH HHS / United States
HHSN268201100011C / / PHS HHS / United States
OSRP2/1006 / / The Dunhill Medical Trust / United Kingdom
N01HC85083 / HL / NHLBI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
DK063491 / DK / NIDDK NIH HHS / United States
AG16495 / AG / NIA NIH HHS / United States
075491/Z/04 / / Wellcome Trust / United Kingdom
HHSN268201100007I / HL / NHLBI NIH HHS / United States
N01-HC-85079 / HC / NHLBI NIH HHS / United States
U01 NS069208-01 / NS / NINDS NIH HHS / United States
HHSN268200782096C / / PHS HHS / United States
HL080295 / HL / NHLBI NIH HHS / United States
N01-HC-85239 / HC / NHLBI NIH HHS / United States
AG-023629 / AG / NIA NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
HHSN268201100006C / / PHS HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
Z01 AG000954-06 / / Intramural NIH HHS / United States
R01 HL073410 / HL / NHLBI NIH HHS / United States
R01 AG027058 / AG / NIA NIH HHS / United States
N01 HC045133 / HC / NHLBI NIH HHS / United States
U01NS069208 / NS / NINDS NIH HHS / United States
N01HC85080 / HL / NHLBI NIH HHS / United States
P30DK072488 / DK / NIDDK NIH HHS / United States
N01 HC035129 / HC / NHLBI NIH HHS / United States
R56 AG023629 / AG / NIA NIH HHS / United States
UL 1RR033176 / RR / NCRR NIH HHS / United States
085475/Z/08/Z / / Wellcome Trust / United Kingdom
Z01 AG000954 / AG / NIA NIH HHS / United States
R01 NS-39987 / NS / NINDS NIH HHS / United States
N01HC85081 / HL / NHLBI NIH HHS / United States
R01HL086694 / HL / NHLBI NIH HHS / United States
090532/Z09/Z / / Wellcome Trust / United Kingdom
R01 AG031287 / AG / NIA NIH HHS / United States

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