Peck George, Smeeth Liam, Whittaker John, Casas Juan Pablo, Hingorani Aroon, Sharma Pankaj
Imperial College Cerebrovascular Research Unit (ICCRU), Department of Clinical Neuroscience, Imperial College London & Hammersmith Hospitals, London, UK.
PLoS One. 2008;3(11):e3691. doi: 10.1371/journal.pone.0003691. Epub 2008 Nov 14.
The genetic basis of haemorrhagic stroke has proved difficult to unravel, partly hampered by the small numbers of subjects in any single study. A meta-analysis of all candidate gene association studies of haemorrhagic stroke (including ruptured subarachnoid haemorrhage and amyloid angiopathy-related haemorrhage) was performed, allowing more reliable estimates of risk.
A systematic review and meta-analysis of all genetic studies in haemorrhagic stroke was conducted. Electronic databases were searched until and including March 2007 for any candidate gene in haemorrhagic stroke. Odds ratio (OR) and 95% confidence intervals (CI) were determined for each gene disease association using fixed and random effect models.
Our meta-analyses included 6,359 cases and 13,805 controls derived from 55 case-control studies, which included 12 genes (13 polymorphisms). Statistically significant associations with haemorrhagic stroke were identified for those homozygous for the ACE/I allele (OR, 1.48; 95% CI, 1.20-1.83; p = 0.0003) and for the 5G allele in the SERPINE1 4G/5G polymorphism (OR, 1.42; 95% CI, 1.03-1.96; p = 0.03). In addition, both epsilon2 and epsilon4 alleles of APOE were significantly associated with lobar haemorrhage (OR, 1.81; 95% CI, 1.26-2.62; p = 0.002 and OR, 1.49; 95% 1.08-2.05; p = 0.01 respectively). Furthermore, a significant protective association against haemorrhagic stroke was found for the factor V Leiden mutation (OR, 0.30; 95% CI, 0.10-0.87; p = 0.03).
Our data suggests a genetic contribution to some types of haemorrhagic stroke, with no overall responsible single gene but rather supporting a polygenic aetiology . However, the evidence base is smaller compared to ischaemic stroke. Importantly, for several alleles previously found to be associated with protection from ischaemic stroke, there was a trend towards an increased risk of haemorrhagic stroke.
事实证明，出血性中风的遗传基础难以厘清，部分原因是任何一项单独研究中的受试者数量较少。我们对所有出血性中风（包括破裂性蛛网膜下腔出血和淀粉样血管病相关性出血）的候选基因关联研究进行了荟萃分析，以便更可靠地评估风险。
我们对出血性中风的所有基因研究进行了系统评价和荟萃分析。检索电子数据库至2007年3月（包括该月），查找出血性中风的任何候选基因。使用固定效应模型和随机效应模型确定每个基因与疾病关联的比值比（OR）和95%置信区间（CI）。
我们的荟萃分析纳入了来自55项病例对照研究的6359例病例和13805例对照，其中包括12个基因（13个多态性）。对于ACE/I等位基因纯合子（OR，1.48；95%CI，1.20 - 1.83；p = 0.0003）以及SERPINE1 4G/5G多态性中的5G等位基因（OR，1.42；95%CI，1.03 - 1.96；p = 0.03），发现与出血性中风存在统计学显著关联。此外，APOE的ε2和ε4等位基因均与脑叶出血显著相关（OR分别为1.81；95%CI，1.26 - 2.62；p = 0.002和OR，1.49；95%CI，1.08 - 2.05；p = 0.01）。此外，发现因子V莱顿突变对出血性中风有显著的保护关联（OR，0.30；95%CI，0.10 - 0.87；p = 0.03）。
我们的数据表明某些类型的出血性中风存在遗传因素，不存在单一的总体致病基因，而是支持多基因病因学。然而，与缺血性中风相比，证据基础较小。重要的是，对于先前发现与预防缺血性中风相关的几个等位基因，存在出血性中风风险增加的趋势。
