Nikolopoulos Georgios K, Bagos Pantelis G, Tsangaris Iraklis, Tsiara Chrissa G, Kopterides Petros, Vaiopoulos Aristides, Kapsimali Violetta, Bonovas Stefanos, Tsantes Argirios E
Clin Chem Lab Med. 2014 Jul;52(7):937-50. doi: 10.1515/cclm-2013-1124.
The circulating levels of plasminogen activator inhibitor type 1 (PAI-1) are increased in individuals carrying the 4G allele at position -675 of the PAI-1 gene. In turn, overexpression of PAI-1 has been found to affect both atheroma and thrombosis. However, the association between PAI-1 levels and the incidence of myocardial infarction (MI) is complicated by the potentially confounding effects of well-known cardiovascular risk factors. The current study tried to investigate in parallel the association of PAI-1 activity with the PAI-1 4G/5G polymorphism, with MI, and some components of metabolic syndrome (MetS).
Using meta-analytical Mendelian randomization approaches, genotype-disease and genotype-phenotype associations were modeled simultaneously.
According to an additive model of inheritance and the Mendelian randomization approach, the MI-related odd ratio for individuals carrying the 4G allele was 1.088 with 95% confidence interval (CI) 1.007, 1.175. Moreover, the 4G carriers had, on average, higher PAI-1 activity than 5G carriers by 1.136 units (95% CI 0.738, 1.533). The meta-regression analyses showed that the levels of triglycerides (p=0.005), cholesterol (p=0.037) and PAI-1 (p=0.021) in controls were associated with the MI risk conferred by the 4G carriers.
The Mendelian randomization meta-analysis confirmed previous knowledge that the PAI-1 4G allele slightly increases the risk for MI. In addition, it supports the notion that PAI-1 activity and established cardiovascular determinants, such as cholesterol and triglyceride levels, could lie in the etiological pathway from PAI-1 4G allele to the occurrence of MI. Further research is warranted to elucidate these interactions.
在纤溶酶原激活物抑制剂1（PAI-1）基因-675位携带4G等位基因的个体中，PAI-1的循环水平升高。反过来，已发现PAI-1的过表达会影响动脉粥样硬化和血栓形成。然而，PAI-1水平与心肌梗死（MI）发生率之间的关联因众所周知的心血管危险因素的潜在混杂效应而变得复杂。当前研究试图同时调查PAI-1活性与PAI-1 4G/5G多态性、MI以及代谢综合征（MetS）某些成分之间的关联。
使用荟萃分析孟德尔随机化方法，同时对基因型-疾病和基因型-表型关联进行建模。
根据遗传的加性模型和孟德尔随机化方法，携带4G等位基因个体的MI相关比值比为1.088，95%置信区间（CI）为1.007，1.175。此外，4G携带者的PAI-1活性平均比5G携带者高1.136个单位（95%CI为0.738，1.533）。荟萃回归分析表明，对照组中的甘油三酯水平（p=0.005）、胆固醇水平（p=0.037）和PAI-1水平（p=0.021）与4G携带者赋予的MI风险相关。
孟德尔随机化荟萃分析证实了先前的认识，即PAI-1 4G等位基因会轻微增加MI风险。此外，它支持这样一种观点，即PAI-1活性以及既定的心血管决定因素，如胆固醇和甘油三酯水平，可能存在于从PAI-1 4G等位基因到MI发生的病因途径中。有必要进行进一步研究以阐明这些相互作用。
