Objective Recent studies have identified a major locus for risk of coronary artery disease (CAD) and myocardial infarction (MI) on chromosome 9p21.3. Stroke, in particular ischemic stroke (IS) due to atherosclerotic disease, shares common mechanisms with MI. We investigated whether the 9p21 region contributes to IS risk. Methods In an initial screen, 15 single nucleotide polymorphisms (SNPs) covering the critical genetic interval on 9p21 were genotyped in samples from Southern Germany (1090 cases, 1244 controls) and the United Kingdom (758 cases, 872 controls, 3 SNPs). SNPs significantly associated with IS or individual stroke subtypes in either of the screening samples were subsequently genotyped in 2528 additional cases and 2189 additional controls from Europe and North America. Results Genotyping of the screening samples revealed associations between seven SNPs and atherosclerotic stroke (all p<0.05). Analysis of the full sample confirmed associations between six SNPs and atherosclerotic stroke in multivariate analyses controlling for demographic variables, CAD, MI, and vascular risk factors (all p<0.05). The odds ratios (OR) for the lead SNP (rs1537378-C) were similar in the various subsamples with a pooled OR of 1.21 (95%CI=1.07-1.37) under both fixed and random effects models (p=0.002). The point estimate for the population attributable risk is 20.1% for atherosclerotic stroke. Interpretation The chromosome 9p21.3 region represents a major risk locus for atherosclerotic stroke. The effect of this locus on stroke seems to be independent of its relationship to CAD and other stroke risk factors. Our findings support a broad role of the 9p21 region in arterial disease.

Background and Purpose Recently, a novel locus at 17q25 was associated with white matter hyperintensities (WMH) on MRI in stroke-free individuals. We aimed to replicate the association with WMH volume (WMHV) in patients with ischemic stroke. If the association acts by promoting a small vessel arteriopathy, it might be expected to also associate with lacunar stroke. Methods We quantified WMH on MRI in the stroke-free hemisphere of 2588 ischemic stroke cases. Association between WMHV and 6 single-nucleotide polymorphisms at chromosome 17q25 was assessed by linear regression. These single-nucleotide polymorphisms were also investigated for association with lacunar stroke in 1854 cases and 51 939 stroke-free controls from METASTROKE. Meta-analyses with previous reports and a genetic risk score approach were applied to identify other novel WMHV risk variants and uncover shared genetic contributions to WMHV in community participants without stroke and ischemic stroke. Results Single-nucleotide polymorphisms at 17q25 were associated with WMHV in ischemic stroke, the most significant being rs9894383 (P=0.0006). In contrast, there was no association between any single-nucleotide polymorphism and lacunar stroke. A genetic risk score analysis revealed further genetic components to WMHV shared between community participants without stroke and ischemic stroke. Conclusions This study provides support for an association between the 17q25 locus and WMH. In contrast, it is not associated with lacunar stroke, suggesting that the association does not act by promoting small-vessel arteriopathy or the same arteriopathy responsible for lacunar infarction.

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