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Original Articles

Common Genetic Variants on Chromosome 9p21 Confers Risk of Ischemic Stroke

A Large-Scale Genetic Association Study

J. Gustav Smith, MD; Olle Melander, MD, PhD; Håkan Lövkvist, MSc; Bo Hedblad, MD, PhD; Gunnar Engström, MD, PhD; Peter Nilsson, MD, PhD; Joyce Carlson, MD, PhD; Göran Berglund, MD, PhD; Bo Norrving, MD, PhD and Arne Lindgren, MD, PhD

From the Program in Medical and Population Genetics (J.G.S.), Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Mass; Departments of Clinical Sciences (J.G.S., H.L., B.N., A.L.) and Laboratory Medicine (J.C.), Lund University, Lund, Sweden; and Department of Clinical Sciences (J.G.S., O.M., B.H., G.E., P.N., G.B.), Lund University, Malmö, Sweden.

Correspondence to Arne Lindgren, MD, PhD, Department of Neurology, Lund University Hospital, SE-221 85, Lund, Sweden. E-mail arne.lindgren{at}med.lu.se

Received November 11, 2008; accepted January 29, 2009.

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.

Key Words: genetics • atherosclerosis • cardiovascular diseases • cerebral infarction • stroke

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Related Article

Common Genetic Variants on Chromosome 9p21 Confers Risk of Ischemic Stroke: A Large-Scale Genetic Association Study

J. Gustav Smith, Olle Melander, Håkan Lövkvist, Bo Hedblad, Gunnar Engström, Peter Nilsson, Joyce Carlson, Göran Berglund, Bo Norrving, and Arne Lindgren
Circ Cardiovasc Genet 2009 2: 159-164. [Abstract] [Full Text] [PDF]