Smith J Gustav, Melander Olle, Lövkvist Håkan, Hedblad Bo, Engström Gunnar, Nilsson Peter, Carlson Joyce, Berglund Göran, Norrving Bo, Lindgren Arne
Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.
Circ Cardiovasc Genet. 2009 Apr;2(2):159-64. doi: 10.1161/CIRCGENETICS.108.835173. Epub 2009 Feb 12.
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.
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).
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.
流行病学研究表明，遗传因素对缺血性中风风险有影响，但除少数罕见变异外，具体的遗传变异仍不清楚。近期的全基因组关联研究已识别并重复验证了位于9号染色体短臂2区1带（9p21）上的常见遗传变异与冠心病风险相关。我们研究了这些变异是否与缺血性中风有关。
我们对瑞典南部两项基于人群的研究（隆德中风登记处研究，n = 1837例病例，947例对照；马尔默饮食与癌症研究，MDC，n = 888例病例，893例对照）中9p21染色体上6个先前在全基因组关联研究中与冠状动脉疾病相关的常见遗传变异进行了基因分型。我们在每项研究以及合并的数据集中研究了关联性。对心血管危险因素进行了校正，在MDC研究中还进一步对既往心肌梗死进行了校正。我们发现，在每个样本中，两个常见（次要等位基因频率为0.46至0.49）变异rs2383207（在隆德中风登记处研究中P = 0.04，在MDC研究中P = 0.01）和rs10757274（在隆德中风登记处研究中P = 0.03，在MDC研究中P = 0.03）的缺血性中风风险有适度增加。当合并样本时，最强变异rs2383207的关联强度增加，比值比为1.15（95%可信区间，1.05至1.25；P = 0.002）。校正临床协变量后结果相似。rs1333049在MDC研究中也显示出显著关联，在合并样本中关联性增强（P = 0.004）。
在这个大样本（n = 4565）中，我们在9p21染色体上检测到了缺血性中风的常见遗传决定因素。我们的研究结果表明，缺血性中风与冠心病及其他动脉疾病具有共同的病理生理决定因素，并突出了中风遗传学研究中需要大样本量的必要性。
