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Sequence variants on chromosome 9p21.3 confer risk for atherosclerotic stroke
Author(s) -
Gschwendtner Andreas,
Bevan Steve,
Cole John W.,
Plourde Anna,
Matarin Mar,
RossAdams 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.,
MüllerMyhsok Bertram,
Dichgans Martin
Publication year - 2009
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21590
Subject(s) - single nucleotide polymorphism , odds ratio , medicine , stroke (engine) , myocardial infarction , cardiology , coronary artery disease , case control study , confidence interval , locus (genetics) , population , genetics , genotype , biology , mechanical engineering , gene , engineering , environmental health
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