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


CONCLUSIONS
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.
Gschwendtner
Andreas
A
Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians-Universität, Marchioninistrasse 15, Munich, Germany.
Bevan
Steve
S
Cole
John W
JW
Plourde
Anna
A
Matarin
Mar
M
Ross-Adams
Helen
H
Meitinger
Thomas
T
Wichmann
Erich
E
Mitchell
Braxton D
BD
Furie
Karen
K
Slowik
Agnieszka
A
Rich
Stephen S
SS
Syme
Paul D
PD
MacLeod
Mary J
MJ
Meschia
James F
JF
Rosand
Jonathan
J
Kittner
Steve J
SJ
Markus
Hugh S
HS
Müller-Myhsok
Bertram
B
Dichgans
Martin
M
D002874:Chromosome Mapping; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D003324:Coronary Artery Disease / Q000150:complications* / Q000235:genetics; D005006:Ethnicity; D005060:Europe / Q000453:epidemiology; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D009656:North America / Q000453:epidemiology; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D018570:Risk Assessment; D012307:Risk Factors; D020521:Stroke / Q000209:etiology* / Q000235:genetics*