The Association of the 4q25 Susceptibility Variant for Atrial Fibrillation With Stroke Is Limited to Stroke of Cardioembolic Etiology

Abstract

Background and Purpose-Genome-wide association studies recently identified 2 variants on chromosome 4q25 as susceptibility factors for atrial fibrillation. Interestingly, these variants were subsequently also shown to be associated with stroke. However, it remains unclear whether 4q25 associates with all the stroke subtypes or with cardioembolic stroke in particular, which is often attributable to atrial fibrillation. Methods-We performed a large case-control association study in 4199 ischemic stroke patients, all subtyped according to Trial of Org 10172 in Acute Stroke Treatment criteria, and 3750 controls derived from 6 studies conducted in Australia, Austria, Belgium, Poland, Spain, and Sweden. Two variants on chromosome 4q25, rs1906591 and rs10033464, were genotyped. Results-Within cases, the A-allele of rs1906591 was associated with atrial fibrillation (odds ratio, 1.64 [95% CI, 1.43 to 1.90]; Pϭ9.2 ⅐ 10 Ϫ12 ), whereas rs10033464 was only marginally associated. There was an association between overall ischemic stroke and rs1906591 (odds ratio, 1.20 [95% CI, 1.09 to 1.32]; Pϭ1.2 ⅐ 10 Ϫ4 ). However, this was probably caused by the large effect of stroke of cardioembolic etiology because no relation was obtained in any other subgroup of stroke. The rs10033464 variant failed to show any relationship with ischemic stroke. Conclusions-We replicated the association of the rs1906591 variant on chromosome 4q25 with atrial fibrillation and ischemic stroke of cardioembolic etiology. The 4q25 locus failed to associate with noncardiac subtypes of ischemic stroke. (Stroke.

Mechanisms and treatment of ischaemic stroke—insights from genetic associations

“…16 PITX2 encodes a transcription factor regulated by β-catenin, whereas ZFHX3 encodes a zinc finger protein. Furthermore, a genetic variant at the 9p21 locus on the short arm of chromosome 9 that has a widely reported association with myocardial infarction and coronary artery disease 17 was associated with ischaemic stroke in a meta-analysis across multiple cohorts.…”

Wellcome Trust Genome-Wide Association Study of Ischemic Stroke

“…5,6 These associations were only apparent with cardioembolic stroke and not with other stroke subtypes. 7 An association between SNPs in the chromosome 9p21 region and coronary artery disease has been reported by many groups. 8 A meta-analysis across multiple ischemic stroke populations demonstrated an association with large artery stroke independently of vascular risk factors and coronary artery disease.…”

Genomewide Association Studies in Cardiovascular Disease—An Update 2011

“…Prospective trials will be important for determining whether such genetic variants carry clinical implications. For atrial fibrillation, it is worth noting that the 4q25 and 16q22 GWAS loci are also associated significantly with the risk of embolic stroke (59,60 ), results that fit the underlying etiology linking atrial fibrillation with embolic stroke.…”