Sequence variants on chromosome 9p21.3 confer risk for atherosclerotic stroke

Andreas Gschwendtner, Steve Bevan, John W. Cole, Anna Plourde, Mar Matarin, Helen Ross-Adams, Thomas Meitinger, Erich Wichmann, Braxton D. Mitchell, Karen Furie, Agnieszka Slowik, Stephen S. Rich, Paul D. Syme, Mary J. MacLeod, James F Meschia, Jonathan Rosand, Steve J. Kittner, Hugh S. Markus, Bertram Müller-Myhsok, Martin Dichgans

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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.

Original languageEnglish (US)
Pages (from-to)531-539
Number of pages9
JournalAnnals of Neurology
Volume65
Issue number5
DOIs
StatePublished - May 2009

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Chromosomes
Stroke
Single Nucleotide Polymorphism
Coronary Artery Disease
Myocardial Infarction
Odds Ratio
North America
Germany
Multivariate Analysis
Demography
Confidence Intervals
Population

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Gschwendtner, A., Bevan, S., Cole, J. W., Plourde, A., Matarin, M., Ross-Adams, H., ... Dichgans, M. (2009). Sequence variants on chromosome 9p21.3 confer risk for atherosclerotic stroke. Annals of Neurology, 65(5), 531-539. https://doi.org/10.1002/ana.21590

Sequence variants on chromosome 9p21.3 confer risk for atherosclerotic stroke. / Gschwendtner, Andreas; Bevan, Steve; Cole, John W.; Plourde, Anna; Matarin, Mar; Ross-Adams, Helen; Meitinger, Thomas; Wichmann, Erich; Mitchell, Braxton D.; Furie, Karen; Slowik, Agnieszka; Rich, Stephen S.; Syme, Paul D.; MacLeod, Mary J.; Meschia, James F; Rosand, Jonathan; Kittner, Steve J.; Markus, Hugh S.; Müller-Myhsok, Bertram; Dichgans, Martin.

In: Annals of Neurology, Vol. 65, No. 5, 05.2009, p. 531-539.

Research output: Contribution to journalArticle

Gschwendtner, A, Bevan, S, Cole, JW, Plourde, A, Matarin, M, Ross-Adams, H, Meitinger, T, Wichmann, E, Mitchell, BD, Furie, K, Slowik, A, Rich, SS, Syme, PD, MacLeod, MJ, Meschia, JF, Rosand, J, Kittner, SJ, Markus, HS, Müller-Myhsok, B & Dichgans, M 2009, 'Sequence variants on chromosome 9p21.3 confer risk for atherosclerotic stroke', Annals of Neurology, vol. 65, no. 5, pp. 531-539. https://doi.org/10.1002/ana.21590
Gschwendtner A, Bevan S, Cole JW, Plourde A, Matarin M, Ross-Adams H et al. Sequence variants on chromosome 9p21.3 confer risk for atherosclerotic stroke. Annals of Neurology. 2009 May;65(5):531-539. https://doi.org/10.1002/ana.21590
Gschwendtner, Andreas ; Bevan, Steve ; Cole, John W. ; Plourde, Anna ; Matarin, Mar ; Ross-Adams, Helen ; Meitinger, Thomas ; Wichmann, Erich ; Mitchell, Braxton D. ; Furie, Karen ; Slowik, Agnieszka ; Rich, Stephen S. ; Syme, Paul D. ; MacLeod, Mary J. ; Meschia, James F ; Rosand, Jonathan ; Kittner, Steve J. ; Markus, Hugh S. ; Müller-Myhsok, Bertram ; Dichgans, Martin. / Sequence variants on chromosome 9p21.3 confer risk for atherosclerotic stroke. In: Annals of Neurology. 2009 ; Vol. 65, No. 5. pp. 531-539.
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AU - Gschwendtner, Andreas

AU - Bevan, Steve

AU - Cole, John W.

AU - Plourde, Anna

AU - Matarin, Mar

AU - Ross-Adams, Helen

AU - Meitinger, Thomas

AU - Wichmann, Erich

AU - Mitchell, Braxton D.

AU - Furie, Karen

AU - Slowik, Agnieszka

AU - Rich, Stephen S.

AU - Syme, Paul D.

AU - MacLeod, Mary J.

AU - Meschia, James F

AU - Rosand, Jonathan

AU - Kittner, Steve J.

AU - Markus, Hugh S.

AU - Müller-Myhsok, Bertram

AU - Dichgans, Martin

PY - 2009/5

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N2 - 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.

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