Casas Juan P, Hingorani Aroon D, Bautista Leonelo E, Sharma Pankaj
Centre for Clinical Pharmacology, British Heart Foundation Laboratories at University College London, London, England.
Arch Neurol. 2004 Nov;61(11):1652-61. doi: 10.1001/archneur.61.11.1652.
Ischemic stroke is thought to have a polygenic basis, but identification of stroke susceptibility genes and quantification of associated risks have been hampered by conflicting results from underpowered case-control studies. We performed a meta-analysis of all candidate gene association studies in ischemic stroke. Electronic databases were searched up until January 2003 for all case-control and nested case-control studies in English-language journals relating to the investigation of any candidate gene for ischemic stroke in humans. Cases were required to have neuroimaging evidence of the diagnosis. To maintain genetic homogeneity, only studies in white adults were included. Studies that evaluated quantitative traits or intermediate phenotypes were excluded. Data from 120 case-control studies were included. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) from random- and fixed-effects models were calculated. Of 32 genes studied, 15 polymorphisms were identified for which at least 3 studies had been conducted. Statistically significant associations with ischemic stroke were identified for factor V Leiden Arg506Gln (OR, 1.33; 95% CI, 1.12-1.58), methylenetetrahydrofolate reductase C677T (OR, 1.24; 95% CI, 1.08-1.42), prothrombin G20210A (OR, 1.44; 95% CI, 1.11-1.86), and angiotensin-converting enzyme insertion/deletion (OR, 1.21; 95% CI, 1.08-1.35). These were also the most investigated candidate genes, including 4588, 3387, 3028, and 2990 cases, respectively. No statistically significant association with ischemic stroke was detected for the 3 next most investigated genes (factor XIII, apolipoprotein E, and human platelet antigen type 1). There is a genetic component to common stroke. No single gene with major effect was identified; rather, common variants in several genes, each exerting a modest effect, contribute to the risk of stroke. These findings have important implications for the design of future genetic studies and for predictive genetic testing for stroke and other multifactorial diseases.
缺血性中风被认为具有多基因基础，但由于样本量不足的病例对照研究结果相互矛盾，中风易感基因的识别以及相关风险的量化一直受到阻碍。我们对所有关于缺血性中风的候选基因关联研究进行了荟萃分析。检索电子数据库直至2003年1月，查找英文期刊中所有与人类缺血性中风任何候选基因研究相关的病例对照研究和巢式病例对照研究。病例需有神经影像学诊断证据。为保持基因同质性，仅纳入白人成年人的研究。排除评估数量性状或中间表型的研究。纳入了120项病例对照研究的数据。计算了随机效应模型和固定效应模型的合并比值比（OR）及95%置信区间（CI）。在所研究的32个基因中，鉴定出15个多态性位点，针对这些位点至少进行了3项研究。发现因子V Leiden Arg506Gln（OR，1.33；95%CI，1.12 - 1.58）、亚甲基四氢叶酸还原酶C677T（OR，1.24；95%CI，1.08 - 1.42）、凝血酶原G20210A（OR，1.44；95%CI，1.11 - 1.86）和血管紧张素转换酶插入/缺失多态性（OR，1.21；95%CI，1.08 - 1.35）与缺血性中风存在统计学显著关联。这些也是研究最多的候选基因，分别包括4588、3387、3028和2990例病例。对于接下来研究最多的3个基因（因子XIII、载脂蛋白E和人类血小板抗原1型），未检测到与缺血性中风有统计学显著关联。常见中风存在遗传因素。未发现有主要作用的单个基因；相反，几个基因中的常见变异各自发挥适度作用，共同导致中风风险。这些发现对未来基因研究的设计以及中风和其他多因素疾病的预测性基因检测具有重要意义。
