Friday, April 17, 2009
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.
Stroke is the leading neurologic cause of death and disability.1 Twin and familial aggregation studies suggest that the risk of stroke has a substantial genetic component,2,3,4 but the genes underlying this risk in the general population remain undetermined. Studies of candidate genes or studies that use classical linkage approaches have yielded inconsistent findings.5
Genomewide association studies have uncovered previously unsuspected common variants underlying the risk of complex diseases such as diabetes6 and coronary disease.7,8 Two previous genomewide association studies of stroke were limited by a case–control design that is more susceptible to survival and selection biases than the design of prospective cohort studies.9,10 We combined data derived from four large, prospective, population-based cohorts consisting predominantly of white persons: the Atherosclerosis Risk in Communities (ARIC) cohort,11 the Cardiovascular Health Study cohort,12 the Framingham Heart Study cohort,13,14 and the Rotterdam Study cohort.15 The four cohorts are part of a consortium, the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE),16 formed to generate a discovery sample of 19,602 participants. We also present the findings from three replication samples, a prospectively evaluated cohort of 2430 black participants in the ARIC study, a second small, prospectively evaluated cohort of 574 black participants in the Cardiovascular Health Study, and a case–control sample of 4265 self-reported Caucasian (hereafter called white) Dutch persons.
