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Background: Single-nucleotide polymorphisms (SNPs) at the chromosome 9p21.3 locus are associated with coronary artery disease (CAD). An association of this genomic region with ischemic stroke independent of its effect on CAD could suggest an additional, stroke-specific pathophysiological relationship., Methods: Medical record review was used to identify 548 patients without a history of cerebrovascular disease and 232 who had a verified ischemic stroke or transient ischemic attack (TIA) from the Duke CATHGEN biorepository of patients who had a cardiac catheterization. ANCOVA and multivariable logistic regression modeling were performed to determine independent genetic associations between the key chromosome 9p21.3 SNP, rs10757278, and ischemic stroke by comparing allele frequencies between 229 patients with stroke or TIA and an equal number of matched nonstroke controls, adjusting for other risk factors. In a secondary analysis, controls were further divided based on the presence (n = 353) or absence (n = 195) of angiographic CAD., Results: Allele frequencies were similar between patients with and without a history of ischemic stroke in both additive (p = 0.83) and dominant (p = 0.92) models of genetic risk. There was no association between rs10757278 allele frequency and stroke status based on the presence or absence of angiographically demonstrated CAD in nonstroke controls (ANCOVA, p = 0.99)., Conclusion: These results provide no evidence of a stroke-specific association of the 9p21.3 locus regardless of the presence or absence of angiographic CAD and highlight the need for larger studies to further evaluate this hypothesized relationship., (Copyright © 2010 S. Karger AG, Basel.)