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

Abstract

ObjectiveEnd-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 REFVIDunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype.MethodsCommon 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).ResultsStage 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).InterpretationABO 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 2013

Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

“…Previous genome-wide association studies (GWAS) in predominantly European-ancestry groups have identified ten loci robustly associated with stroke 3–12 . In most instances, the associations with stroke were attributed to individual subtypes of ischemic stroke, such as LAS 5,8,9 , CES 3,4 , and SVS 10,12 , or of ICH 6 , although some loci were associated with two or more stroke subtypes 7,9,11,13 or with any stroke 10 . We hypothesized that combining a substantially larger sample size with a transancestral analytic approach would identify additional risk loci and improve fine mapping of causal variants.…”

Genetics of Ischemic Stroke in Young Adults

“…Four of these loci have P values reaching genome-wide significance in the large METASTROKE Consortium, the largest GWAS of IS to date, and all 4 genome-wide significant associations were subtype specific: 4q25 ( PITX2 ) and 16q22 ( ZFHX3 ) with cardioembolic stroke, 43,44 7p21 ( HDAC9 ) and 6p21 with large artery atherosclerotic stroke. 15,45,46 Two additional loci, that is, the 9p21 locus ( CDKN2B-AS1 ) with large artery atherosclerotic stroke 45,47,48 and 9q34 locus ( ABO ) with total IS, large artery atherosclerotic stroke, and cardioembolic stroke 49 did not reach genome-wide significance but were robustly replicated in other studies, albeit with small effect sizes. Notably, 1 locus, NINJ2 (12p13), which was initially identified in population-based cohort studies to be associated with all IS, has not been replicated in well-powered hospital-based case–control studies.…”

“…52,53 Last, the ABO locus, which was initially identified by GWAS associated with the clotting trait (ie, von Willebrand factor), was associated with cardioembolic and large artery atherosclerotic strokes. 49 However, little is known about the biological relevance of HDAC9 and the 6p21 locus to the large artery atherosclerotic stroke. HDAC9 encodes histone deacetylase 9 and may affect transcriptional regulation by altering chromosome structure.…”

D-Dimer in African Americans

“…A LocusZoom plot 21 is displayed in Figure S4. A total of 9 variants at the chr 1 locus were significant at the 1 × 10 −9 level, including two index SNPs previously associated with D-dimer in European GWAS (rs12029080 18 , rs2022309 22 ). However, none of these variants remained significant after conditioning on the lead variant rs2022030 (Figure S5a).…”