title: Common genetic variants on chromosome 9p21 confers risk of ischemic stroke: a large-scale genetic association study.
abstract: BACKGROUND
  Epidemiological studies indicate a genetic contribution to ischemic stroke risk, but specific genetic variants remain unknown, with the exception of a few rare variants. Recent genome-wide association studies identified and replicated common genetic variants on chromosome 9p21 to confer risk of coronary heart disease. We examined whether these variants are associated with ischemic stroke.
  
  
  RESULTS
  We genotyped 6 common genetic variants on chromosome 9p21, previously associated with coronary artery disease in genome-wide association studies, in 2 population-based studies in southern Sweden, the Lund Stroke Register (n=1837 cases, 947 controls) and the Malmö Diet and Cancer study (MDC; n=888 cases, 893 controls). We examined association in each study and in the pooled dataset. Adjustments were made for cardiovascular risk factors and further for previous myocardial infarction in MDC. We found a modest increase in ischemic stroke risk for 2 common (minor allele frequencies 0.46 to 0.49) variants, rs2383207 (P=0.04 in Lund Stroke Register, P=0.01 in MDC) and rs10757274 (P=0.03 in Lund Stroke Register, P=0.03 in MDC), in each sample independently. The strength of the association increased when samples were pooled with an odds ratio of 1.15 (95% CI, 1.05 to 1.25; P=0.002) for the strongest variant rs2383207. Results were similar after adjustment for clinical covariates. rs1333049 also showed significant association in MDC, which increased in the pooled sample (P=0.004).
  
  
  CONCLUSIONS
  In this large sample (n=4565), we detected common genetic determinants for ischemic stroke on chromosome 9p21. Our findings indicate that ischemic stroke shares pathophysiological determinants with coronary heart disease and other arterial diseases and highlight the need for large sample sizes in stroke genetics.
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: J Gustav
authors.initials: JG
authors.lastname: Smith
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
authors.forename: Håkan
authors.initials: H
authors.lastname: Lövkvist
authors.forename: Bo
authors.initials: B
authors.lastname: Hedblad
authors.forename: Gunnar
authors.initials: G
authors.lastname: Engström
authors.forename: Peter
authors.initials: P
authors.lastname: Nilsson
authors.forename: Joyce
authors.initials: J
authors.lastname: Carlson
authors.forename: Göran
authors.initials: G
authors.lastname: Berglund
authors.forename: Bo
authors.initials: B
authors.lastname: Norrving
authors.forename: Arne
authors.initials: A
authors.lastname: Lindgren
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D007511:Ischemia / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012307:Risk Factors; D020521:Stroke / Q000235:genetics*; D013548:Sweden