Sequence variants on chromosome 9p21.3 confer risk for atherosclerotic stroke†
Andreas Gschwendtner MD
Department of Neurology, Klinikum Großhadern, Ludwig-Maximilians-Universität, Munich, Germany
Search for more papers by this authorSteve Bevan PhD
Centre for Clinical Neuroscience, St. George's, University of London, London, United Kingdom
Search for more papers by this authorJohn W. Cole MD, MS
Department of Neurology, University of Maryland, School of Medicine, and Veterans Affairs Medical Center, Baltimore, MD
Search for more papers by this authorAnna Plourde BA
Stroke Service and Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA
Search for more papers by this authorMar Matarin PhD
Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD
Search for more papers by this authorHelen Ross-Adams PhD
Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen, United Kingdom
Search for more papers by this authorThomas Meitinger MD
Institute of Human Genetics, Ludwig-Maximilians-Universität, Munich, Germany
Search for more papers by this authorErich Wichmann MD, PhD
Institute of Epidemiology, Helmholtz Zentrum München, Ludwig-Maximilians-Universität, Munich, Germany
Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany
Search for more papers by this authorBraxton D. Mitchell PhD
Department of Neurology, University of Maryland, School of Medicine, and Veterans Affairs Medical Center, Baltimore, MD
Search for more papers by this authorKaren Furie MD, MPH
Stroke Service and Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA
Search for more papers by this authorAgnieszka Slowik MD, PhD
Department of Neurology, Jagiellonian University, Medical College, Kraków, Poland
Search for more papers by this authorStephen S. Rich PhD
Center for Public Health Genomics, University of Virginia, Charlottesville, VA
Search for more papers by this authorPaul D. Syme MD
Department of Clinical and Surgical Sciences, University of Edinburgh, Edinburgh, United Kingdom
Search for more papers by this authorMary J. MacLeod PhD
Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen, United Kingdom
Search for more papers by this authorJames F. Meschia MD
Department of Neurology, Mayo Clinic, Jacksonville, FL
Search for more papers by this authorJonathan Rosand MD, MSc
Stroke Service and Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA
Search for more papers by this authorSteve J. Kittner MD, MPH
Department of Neurology, University of Maryland, School of Medicine, and Veterans Affairs Medical Center, Baltimore, MD
Search for more papers by this authorHugh S. Markus FRCP
Centre for Clinical Neuroscience, St. George's, University of London, London, United Kingdom
Search for more papers by this authorBertram Müller-Myhsok MD
Max-Planck-Institute of Psychiatry, Munich, Germany
Search for more papers by this authorCorresponding Author
Martin Dichgans MD
Department of Neurology, Klinikum Großhadern, Ludwig-Maximilians-Universität, Munich, Germany
Marchioninistrasse 15, 81377 München, GermanySearch for more papers by this authorAndreas Gschwendtner MD
Department of Neurology, Klinikum Großhadern, Ludwig-Maximilians-Universität, Munich, Germany
Search for more papers by this authorSteve Bevan PhD
Centre for Clinical Neuroscience, St. George's, University of London, London, United Kingdom
Search for more papers by this authorJohn W. Cole MD, MS
Department of Neurology, University of Maryland, School of Medicine, and Veterans Affairs Medical Center, Baltimore, MD
Search for more papers by this authorAnna Plourde BA
Stroke Service and Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA
Search for more papers by this authorMar Matarin PhD
Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD
Search for more papers by this authorHelen Ross-Adams PhD
Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen, United Kingdom
Search for more papers by this authorThomas Meitinger MD
Institute of Human Genetics, Ludwig-Maximilians-Universität, Munich, Germany
Search for more papers by this authorErich Wichmann MD, PhD
Institute of Epidemiology, Helmholtz Zentrum München, Ludwig-Maximilians-Universität, Munich, Germany
Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany
Search for more papers by this authorBraxton D. Mitchell PhD
Department of Neurology, University of Maryland, School of Medicine, and Veterans Affairs Medical Center, Baltimore, MD
Search for more papers by this authorKaren Furie MD, MPH
Stroke Service and Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA
Search for more papers by this authorAgnieszka Slowik MD, PhD
Department of Neurology, Jagiellonian University, Medical College, Kraków, Poland
Search for more papers by this authorStephen S. Rich PhD
Center for Public Health Genomics, University of Virginia, Charlottesville, VA
Search for more papers by this authorPaul D. Syme MD
Department of Clinical and Surgical Sciences, University of Edinburgh, Edinburgh, United Kingdom
Search for more papers by this authorMary J. MacLeod PhD
Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen, United Kingdom
Search for more papers by this authorJames F. Meschia MD
Department of Neurology, Mayo Clinic, Jacksonville, FL
Search for more papers by this authorJonathan Rosand MD, MSc
Stroke Service and Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA
Search for more papers by this authorSteve J. Kittner MD, MPH
Department of Neurology, University of Maryland, School of Medicine, and Veterans Affairs Medical Center, Baltimore, MD
Search for more papers by this authorHugh S. Markus FRCP
Centre for Clinical Neuroscience, St. George's, University of London, London, United Kingdom
Search for more papers by this authorBertram Müller-Myhsok MD
Max-Planck-Institute of Psychiatry, Munich, Germany
Search for more papers by this authorCorresponding Author
Martin Dichgans MD
Department of Neurology, Klinikum Großhadern, Ludwig-Maximilians-Universität, Munich, Germany
Marchioninistrasse 15, 81377 München, GermanySearch for more papers by this authorPotential conflict of interest: Nothing to report.
Abstract
Objective
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.
Methods
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.
Results
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.
Interpretation
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
Supporting Information
Additional Supporting Information may be found in the online version of this article.
| Filename | Description |
|---|---|
| ANA_21590_sm_SupDoc.doc48 KB | SUPPLEMENTARY MATERIALS |
| ANA_21590_sm_SupFig1.tif4.2 MB | Supplementary Figure 1 |
| ANA_21590_sm_SupFig2.tif1.7 MB | Supplementary Figure 2 |
| ANA_21590_sm_SupFig3a.tif3.8 MB | Supplementary Figure 3a |
| ANA_21590_sm_SupFig3b.tif3.8 MB | Supplementary Figure 3b |
| ANA_21590_sm_SupTable1.doc61.5 KB | Supplementary Table 1: Association to Atherosclerotic Stroke on 9p21 in the Screening Samples |
| ANA_21590_sm_SupTable2.doc140.5 KB | Supplementary Table 2: Association to Atherosclerotic Stroke on 9p21 in Subsamples |
| ANA_21590_sm_SupTable3.doc94.5 KB | Supplementary Table 3: Association to overall IS and other stroke subtypes on 9p21 in the overall sample |
| ANA_21590_sm_SupTable4.doc75.5 KB | Supplementary Table 4: Association to MI and CAD on 9p21 in the overall sample |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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