Ye Zheng, Liu Eugene H C, Higgins Julian P T, Keavney Bernard D, Lowe Gordon D O, Collins Rory, Danesh John
Department of Public Health and Primary Care, University of Cambridge, Strangeways Site, Wort's Causeway, Cambridge CB1 8RN, UK.
Lancet. 2006 Feb 25;367(9511):651-8. doi: 10.1016/S0140-6736(06)68263-9.
Variants of certain haemostatic genes (such as that encoding factor V Leiden) are involved in the development of venous thrombosis, but studies of such variants in coronary disease have reported apparently conflicting results. We did meta-analyses on seven such haemostatic genetic variants for which the available evidence on each comprises at least 5000 coronary disease cases and at least 5000 controls.
Meta-analyses were done of 191 studies in relation to factor V G1691A (ie, factor V Leiden), factor VII G10976A, prothrombin G20210A, plasminogen activator inhibitor-1 (PAI-1) [-675] 4G/5G, and three platelet glycoprotein (GP) receptor variants (GPIa C807T, GPIbalpha T[-5]C, GPIIIa C1565T), involving a total of 66 155 coronary disease cases and 91 307 controls. We explored potential sources of heterogeneity.
In a combined analysis of all studies, the per-allele relative risks (RR) for coronary disease of factor V 1691A and of prothrombin 20210A were 1.17 (95% CI 1.08-1.28) and 1.31 (1.12-1.52), respectively. Combined analyses of studies of the PAI-1 [-675] 4G variant yielded a per-allele relative risk for coronary disease of 1.06 (1.02-1.10), but there was an indication of publication bias in these studies. Combined analyses of the factor VII 10976A, GPIa 807T, GPIbalpha [-5]C, and GPIIIa 1565T variants showed no significant overall associations with coronary disease, yielding per-allele RRs of 0.97 (0.91-1.04), 1.02 (0.97-1.08), 1.05 (0.96-1.13), and 1.03 (0.98-1.07), respectively.
The 1691A variant of the factor V gene and the 20210A variant of the prothrombin gene, both of which increase circulating thrombin generation, might each be moderately associated with the risk of coronary disease. Further studies are merited to assess these associations in greater detail (including any gene-gene and gene-environment interactions) and to determine any implications with regard to potential therapies designed to reverse patients' prothrombotic phenotype, such as selective plasma factor V or factor Xa inhibition.
某些止血基因的变异体（如编码因子V莱顿的基因）与静脉血栓形成有关，但关于这些变异体在冠心病中的研究报告结果明显相互矛盾。我们对七种此类止血基因变异体进行了荟萃分析，每种变异体的现有证据均包含至少5000例冠心病病例和至少5000例对照。
对191项关于因子V G1691A（即因子V莱顿）、因子VII G10976A、凝血酶原G20210A、纤溶酶原激活物抑制剂-1（PAI-1）[-675] 4G/5G以及三种血小板糖蛋白（GP）受体变异体（GPIa C807T、GPIbalpha T[-5]C、GPIIIa C1565T）的研究进行荟萃分析，共涉及66155例冠心病病例和91307例对照。我们探究了异质性的潜在来源。
在所有研究的综合分析中，因子V 1691A和凝血酶原20210A的冠心病等位基因相对风险（RR）分别为1.17（95%可信区间1.08 - 1.28）和1.31（1.12 - 1.52）。对PAI-1 [-675] 4G变异体研究的综合分析得出冠心病等位基因相对风险为1.06（1.02 - 1.10），但这些研究存在发表偏倚迹象。因子VII 10976A、GPIa 807T、GPIbalpha [-5]C和GPIIIa 1565T变异体的综合分析显示与冠心病无显著总体关联，等位基因RR分别为0.97（0.91 - 1.04）、1.02（0.97 - 1.08）、1.05（0.96 - 1.13）和1.03（0.98 - 1.07）。
因子V基因的1691A变异体和凝血酶原基因的20210A变异体均增加循环凝血酶生成，可能各自与冠心病风险中度相关。值得进一步研究以更详细地评估这些关联（包括任何基因 - 基因和基因 - 环境相互作用），并确定对于旨在逆转患者血栓前状态的潜在疗法（如选择性血浆因子V或因子Xa抑制）的任何影响。
