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. METHODS AND 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.
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. METHODS AND 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: Andreas Keller; Angela Graefen; Markus Ball; Mark Matzas; Valesca Boisguerin; Frank Maixner; Petra Leidinger; Christina Backes; Rabab Khairat; Michael Forster; Björn Stade; Andre Franke; Jens Mayer; Jessica Spangler; Stephen McLaughlin; Minita Shah; Clarence Lee; Timothy T Harkins; Alexander Sartori; Andres Moreno-Estrada; Brenna Henn; Martin Sikora; Ornella Semino; Jacques Chiaroni; Siiri Rootsi; Natalie M Myres; Vicente M Cabrera; Peter A Underhill; Carlos D Bustamante; Eduard Egarter Vigl; Marco Samadelli; Giovanna Cipollini; Jan Haas; Hugo Katus; Brian D O'Connor; Marc R J Carlson; Benjamin Meder; Nikolaus Blin; Eckart Meese; Carsten M Pusch; Albert Zink Journal: Nat Commun Date: 2012-02-28 Impact factor: 14.919
Authors: Håkan Lövkvist; Sandra Olsson; Peter Höglund; Olle Melander; Christina Jern; Marketa Sjögren; Gunnar Engström; J Gustav Smith; Bo Hedblad; Gunnar Andsberg; Hossein Delavaran; Katarina Jood; Ulf Kristoffersson; Holger Luthman; Bo Norrving; Arne Lindgren Journal: Eur J Hum Genet Date: 2012-01-25 Impact factor: 4.246
Authors: Christin E Burd; William R Jeck; Yan Liu; Hanna K Sanoff; Zefeng Wang; Norman E Sharpless Journal: PLoS Genet Date: 2010-12-02 Impact factor: 5.917
Authors: M G Heckman; A I Soto-Ortolaza; N N Diehl; S Rayaprolu; T G Brott; Z K Wszolek; J F Meschia; O A Ross Journal: Eur J Neurol Date: 2012-08-06 Impact factor: 6.089