TY - JOUR
T1 - Genetic Factors Influencing Coagulation Factor XIII B-Subunit Contribute to Risk of Ischemic Stroke
AU - METASTROKE Consortium
AU - Wellcome Trust Case Control Consortium 2
AU - Hanscombe, Ken B.
AU - Traylor, Matthew
AU - Hysi, Pirro G.
AU - Bevan, Stephen
AU - Dichgans, Martin
AU - Rothwell, Peter M.
AU - Worrall, Bradford B.
AU - Seshadri, Sudha
AU - Sudlow, Cathie
AU - Williams, Frances M.K.
AU - Markus, Hugh S.
AU - Lewis, Cathryn M.
N1 - Publisher Copyright:
© 2015 The Authors.
PY - 2015/8/1
Y1 - 2015/8/1
N2 - BACKGROUND AND PURPOSE: Abnormal coagulation has been implicated in the pathogenesis of ischemic stroke, but how this association is mediated and whether it differs between ischemic stroke subtypes is unknown. We determined the shared genetic risk between 14 coagulation factors and ischemic stroke and its subtypes.METHODS: Using genome-wide association study results for 14 coagulation factors from the population-based TwinsUK sample (N≈2000 for each factor), meta-analysis results from the METASTROKE consortium ischemic stroke genome-wide association study (12 389 cases, 62 004 controls), and genotype data for 9520 individuals from the WTCCC2 ischemic stroke study (3548 cases, 5972 controls-the largest METASTROKE subsample), we explored shared genetic risk for coagulation and stroke. We performed three analyses: (1) a test for excess concordance (or discordance) in single nucleotide polymorphism effect direction across coagulation and stroke, (2) an estimation of the joint effect of multiple coagulation-associated single nucleotide polymorphisms in stroke, and (3) an evaluation of common genetic risk between coagulation and stroke.RESULTS: One coagulation factor, factor XIII subunit B (FXIIIB), showed consistent effects in the concordance analysis, the estimation of polygenic risk, and the validation with genotype data, with associations specific to the cardioembolic stroke subtype. Effect directions for FXIIIB-associated single nucleotide polymorphisms were significantly discordant with cardioembolic disease (smallest P=5.7×10(-04)); the joint effect of FXIIIB-associated single nucleotide polymorphisms was significantly predictive of ischemic stroke (smallest P=1.8×10(-04)) and the cardioembolic subtype (smallest P=1.7×10(-04)). We found substantial negative genetic covariation between FXIIIB and ischemic stroke (rG=-0.71, P=0.01) and the cardioembolic subtype (rG=-0.80, P=0.03).CONCLUSIONS: Genetic markers associated with low FXIIIB levels increase risk of ischemic stroke cardioembolic subtype.
AB - BACKGROUND AND PURPOSE: Abnormal coagulation has been implicated in the pathogenesis of ischemic stroke, but how this association is mediated and whether it differs between ischemic stroke subtypes is unknown. We determined the shared genetic risk between 14 coagulation factors and ischemic stroke and its subtypes.METHODS: Using genome-wide association study results for 14 coagulation factors from the population-based TwinsUK sample (N≈2000 for each factor), meta-analysis results from the METASTROKE consortium ischemic stroke genome-wide association study (12 389 cases, 62 004 controls), and genotype data for 9520 individuals from the WTCCC2 ischemic stroke study (3548 cases, 5972 controls-the largest METASTROKE subsample), we explored shared genetic risk for coagulation and stroke. We performed three analyses: (1) a test for excess concordance (or discordance) in single nucleotide polymorphism effect direction across coagulation and stroke, (2) an estimation of the joint effect of multiple coagulation-associated single nucleotide polymorphisms in stroke, and (3) an evaluation of common genetic risk between coagulation and stroke.RESULTS: One coagulation factor, factor XIII subunit B (FXIIIB), showed consistent effects in the concordance analysis, the estimation of polygenic risk, and the validation with genotype data, with associations specific to the cardioembolic stroke subtype. Effect directions for FXIIIB-associated single nucleotide polymorphisms were significantly discordant with cardioembolic disease (smallest P=5.7×10(-04)); the joint effect of FXIIIB-associated single nucleotide polymorphisms was significantly predictive of ischemic stroke (smallest P=1.8×10(-04)) and the cardioembolic subtype (smallest P=1.7×10(-04)). We found substantial negative genetic covariation between FXIIIB and ischemic stroke (rG=-0.71, P=0.01) and the cardioembolic subtype (rG=-0.80, P=0.03).CONCLUSIONS: Genetic markers associated with low FXIIIB levels increase risk of ischemic stroke cardioembolic subtype.
KW - coagulation
KW - genome-wide association study
KW - stroke
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U2 - 10.1161/STROKEAHA.115.009387
DO - 10.1161/STROKEAHA.115.009387
M3 - Article
C2 - 26159793
AN - SCOPUS:84964697159
SN - 0039-2499
VL - 46
SP - 2069
EP - 2074
JO - Stroke; a journal of cerebral circulation
JF - Stroke; a journal of cerebral circulation
IS - 8
ER -