Potential conflict of interest: Nothing to report.
Sequence variants on chromosome 9p21.3 confer risk for atherosclerotic stroke†
Version of Record online: 18 MAR 2009
Copyright © 2009 American Neurological Association
Annals of Neurology
Volume 65, Issue 5, pages 531–539, May 2009
How to Cite
Gschwendtner, A., Bevan, S., Cole, J. W., Plourde, A., Matarin, M., Ross-Adams, H., Meitinger, T., Wichmann, E., Mitchell, B. D., Furie, K., Slowik, A., Rich, S. S., Syme, P. D., MacLeod, M. J., Meschia, J. F., Rosand, J., Kittner, S. J., Markus, H. S., Müller-Myhsok, B. and Dichgans, M. (2009), Sequence variants on chromosome 9p21.3 confer risk for atherosclerotic stroke. Ann Neurol., 65: 531–539. doi: 10.1002/ana.21590
- Issue online: 11 JUN 2009
- Version of Record online: 18 MAR 2009
- Accepted manuscript online: 18 MAR 2009 12:00AM EST
- Manuscript Accepted: 31 OCT 2008
- Manuscript Revised: 19 OCT 2008
- Manuscript Received: 31 AUG 2008
- German Research Foundation. Grant Numbers: Di722/3-1, KFGK1027, KFGK1028
- German Ministry of Education and Research. Grant Numbers: PGE-S04T13, PGE-S04T10
- National Institute of Neurologic Disorders and Stroke. Grant Numbers: K23NS042720, P50NS051343, R01NS42733
- Deane Institute for Integrative Research in Atrial Fibrillation and Stroke
- The Stroke Association. Grant Number: TSA2007/04
- Scottish Chief Scientist's Office. Grant Number: CZG/4/1/26
Recent studies have identified a major locus for risk for coronary artery disease and myocardial infarction on chromosome 9p21.3. Stroke, in particular, ischemic stroke caused by atherosclerotic disease, shares common mechanisms with myocardial infarction. We investigated whether the 9p21 region contributes to ischemic stroke risk.
In an initial screen, 15 single nucleotide polymorphisms (SNPs) covering the critical genetic interval on 9p21 were genotyped in samples from Southern Germany (1,090 cases, 1,244 control subjects) and the United Kingdom (758 cases, 872 control subjects, 3 SNPs). SNPs significantly associated with ischemic stroke or individual stroke subtypes in either of the screening samples were subsequently genotyped in 2,528 additional cases and 2,189 additional control subjects from Europe and North America.
Genotyping of the screening samples demonstrated 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, coronary artery disease, myocardial infarction, and vascular risk factors (all p < 0.05). The odds ratios for the lead SNP (rs1537378-C) were similar in the various subsamples with a pooled odds ratio of 1.21 (95% confidence interval, 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.
The chromosome 9p21.3 region represents a major risk locus for atherosclerotic stroke. The effect of this locus on stroke appears to be independent of its relation to coronary artery disease and other stroke risk factors. Our findings support a broad role of the 9p21 region in arterial disease. Ann Neurol 2009;65:531–539