Imperial College Cerebrovascular Research Unit, Clinical Neurosciences, Charing Cross Hospital, Imperial College London, London, United Kingdom.
PLoS One. 2010 Feb 9;5(2):e9136. doi: 10.1371/journal.pone.0009136.
Interrelationships between genetic and biochemical factors underlying ischemic stroke and ischemic heart disease are poorly understood. We: 1) undertook the most comprehensive meta-analysis of genetic polymorphisms in ischemic stroke to date; 2) compared genetic determinants of ischemic stroke with those of ischemic heart disease, and 3) compared effect sizes of gene-stroke associations with those predicted from independent biochemical data using a mendelian randomization strategy. Electronic databases were searched up to January 2009. We identified: 1) 187 ischemic stroke studies (37,481 cases; 95,322 controls) interrogating 43 polymorphisms in 29 genes; 2) 13 meta-analyses testing equivalent polymorphisms in ischemic heart disease; and 3) for the top five gene-stroke associations, 146 studies (65,703 subjects) describing equivalent gene-biochemical relationships, and 28 studies (46,928 subjects) describing biochemical-stroke relationships. Meta-analyses demonstrated positive associations with ischemic stroke for factor V Leiden Gln506, ACE I/D, MTHFR C677T, prothrombin G20210A, PAI-1 5G allele and glycoprotein IIIa Leu33Pro polymorphisms (ORs: 1.11 - 1.60). Most genetic associations show congruent levels of risk comparing ischemic stroke with ischemic heart disease, but three genes--glycoprotein IIIa, PAI-1 and angiotensinogen--show significant dissociations. The magnitudes of stroke risk observed for factor V Leiden, ACE, MTHFR and prothrombin, but not PAI-1, polymorphisms, are consistent with risks associated with equivalent changes in activated protein C resistance, ACE activity, homocysteine, prothrombin, and PAI-1 levels, respectively. Our results demonstrate causal relationships for four of the most robust genes associated with stroke while also showing that PAI-1 4G/5G polymorphism influences cardiovascular risk via a mechanism not simply related to plasma levels of PAI-1 (or tPA) alone.
遗传和生化因素之间的相互关系是导致缺血性中风和缺血性心脏病的基础，但目前人们对此知之甚少。我们：1）进行了迄今为止针对缺血性中风的基因多态性最全面的荟萃分析；2）比较了缺血性中风的遗传决定因素与缺血性心脏病的遗传决定因素，3）使用孟德尔随机化策略，比较了基因-中风关联的效应大小与独立生化数据预测的效应大小。电子数据库搜索截至 2009 年 1 月。我们确定了：1）187 项缺血性中风研究（37481 例病例；95322 例对照）检测了 29 个基因中的 43 个基因多态性；2）13 项荟萃分析检验了缺血性心脏病中相同的多态性；3）对于前五个基因-中风关联，有 146 项研究（65703 例受试者）描述了相同的基因-生化关系，有 28 项研究（46928 例受试者）描述了生化-中风关系。荟萃分析显示，因子 V Leiden Gln506、ACE I/D、MTHFR C677T、凝血酶原 G20210A、PAI-1 5G 等位基因和糖蛋白 IIIa Leu33Pro 多态性与缺血性中风呈正相关（ORs：1.11-1.60）。大多数遗传关联表明，缺血性中风与缺血性心脏病的风险水平一致，但有三个基因——糖蛋白 IIIa、PAI-1 和血管紧张素原——存在显著差异。因子 V Leiden、ACE、MTHFR 和凝血酶原的中风风险观察到的幅度与相应的 APC 抵抗、ACE 活性、同型半胱氨酸、凝血酶原和 PAI-1 水平的变化相关，而 PAI-1 多态性则不一致。我们的研究结果表明，在与中风相关的最具影响力的四个基因中存在因果关系，同时也表明 PAI-1 4G/5G 多态性通过一种不仅仅与 PAI-1（或 tPA）单独的血浆水平相关的机制影响心血管风险。
