Department of Biology and Genetics for Medical Sciences, University of Milan, Milano, Italy.
Thromb Haemost. 2011 Oct;106(4):655-64. doi: 10.1160/TH11-04-0247. Epub 2011 Sep 8.
Occlusive coronary thrombus formation superimposed on an atherosclerotic plaque is the ultimate event leading to myocardial infarction (MI). Therefore, haemostatic proteins may represent important players in the pathogenesis of MI. It was the objective of this study to evaluate, in a comprehensive way, the role of haemostatic gene polymorphisms in predisposition to premature MI. A total of 810 single nucleotide polymorphisms (SNPs) in 37 genes were assessed for association with MI in a large cohort (1,670 males, 210 females) of Italian patients who suffered from an MI event before the age of 45, and an equal number of controls. Thirty-eight SNPs selected from the literature were genotyped using the SNPlex technology, whereas genotypes for the remaining 772 SNPs were extracted from a previous genome-wide association study. Genotypes were analysed by a standard case-control analysis corrected for classical cardiovascular risk factors, and by haplotype analysis. A weighted Genetic Risk Score (GRS) was calculated. Evidence for association with MI after covariate correction was found for 35 SNPs in 12 loci: F5, PROS1, F11, ITGA2, F12, F13A1, SERPINE1, PLAT, VWF, THBD, PROCR, and F9. The weighted GRS was constructed by including the top SNP for each of the 12 associated loci. The GRS distribution was significantly different between cases and controls, and subjects in the highest quintile had a 2.69-fold increased risk for MI compared with those in the lowest quintile. Our results suggest that a GRS, based on the combined effect of several risk alleles in different haemostatic genes, is associated with an increased risk of MI.
在动脉粥样硬化斑块上形成的闭塞性冠状动脉血栓是导致心肌梗死 (MI) 的最终事件。因此，止血蛋白可能是 MI 发病机制中的重要因素。本研究旨在全面评估止血基因多态性在易患早发性 MI 中的作用。在一个由意大利患者组成的大队列中（1670 名男性，210 名女性），评估了 37 个基因中的 810 个单核苷酸多态性 (SNP) 与 MI 的关联，这些患者在 45 岁之前发生了 MI 事件，且数量相等的对照者。使用 SNPlex 技术对从文献中选择的 38 个 SNP 进行基因分型，而其余 772 个 SNP 的基因型则从之前的全基因组关联研究中提取。通过标准病例对照分析，对经过经典心血管危险因素校正后的基因型进行分析，并进行单体型分析。计算加权遗传风险评分 (GRS)。在对协变量进行校正后，在 12 个基因座中的 35 个 SNP 中发现与 MI 相关的证据：F5、PROS1、F11、ITGA2、F12、F13A1、SERPINE1、PLAT、VWF、THBD、PROCR 和 F9。通过包含 12 个相关基因座中每个基因座的最佳 SNP 来构建 GRS。病例组和对照组之间的 GRS 分布存在显著差异，最高五分位组的 MI 风险是最低五分位组的 2.69 倍。我们的研究结果表明，基于不同止血基因中多个风险等位基因的综合效应构建的 GRS 与 MI 风险增加相关。
