TY - JOUR
T1 - Sequence variants on chromosome 9p21.3 confer risk for atherosclerotic stroke
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 - Mueller-Myhsok, Bertram
AU - Dichgans, Martin
AU - Int Stroke Genetics Consortium
PY - 2009/5
Y1 - 2009/5
N2 - Objective: Recent studies have identified a major locus for risk for coronary artery disease and myocardial infiarction 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.
AB - Objective: Recent studies have identified a major locus for risk for coronary artery disease and myocardial infiarction 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.
KW - genome-wide association
KW - coronary-artery-disease
KW - transient ischemic attack
KW - smooth-muscle-cells
KW - myocardial-infarction
KW - cardiovascular events
KW - plaque vulnerability
KW - media thickness
KW - metaanalysis
KW - replication
U2 - 10.1002/ana.21590
DO - 10.1002/ana.21590
M3 - Article
SN - 0364-5134
VL - 65
SP - 531
EP - 539
JO - Annals of Neurology
JF - Annals of Neurology
IS - 5
ER -