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BACKGROUND:The genes underlying the risk of stroke in the general population remain undetermined. METHODS:We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [+/-SD] age, 63+/-8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons. RESULTS:Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5x10(-8)). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95% confidence interval [CI], 1.19 to 1.42) and 1.33 (95% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11% and 12% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95% CI, 1.01 to 1.79; P=0.04) and 1.42 (95% CI, 1.06 to 1.91; P=0.02) in the large cohort of black persons and 1.17 (95% CI, 1.01 to 1.37; P=0.03) and 1.19 (95% CI, 1.01 to 1.41; P=0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant. CONCLUSIONS:A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.

Original publication

DOI

10.1056/NEJMoa0900094

Type

Journal article

Journal

The New England journal of medicine

Publication Date

15/04/2009

Volume

360

Pages

1718 - 1728

Addresses

Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Keywords

Chromosomes, Human, Pair 12, Humans, Genetic Predisposition to Disease, Genetic Markers, Proportional Hazards Models, Risk Factors, Cohort Studies, Genotype, Polymorphism, Single Nucleotide, Aged, Middle Aged, African Continental Ancestry Group, European Continental Ancestry Group, Female, Male, Stroke, Genome-Wide Association Study