The plasminogen activator inhibitor-1-675 4G/5G genotype influences the risk of myocardial infarction associated with elevated plasma proinsulin and insulin concentrations in men from Europe: the HIFMECH Study
The plasminogen activator inhibitor-1-675 4G/5G genotype influences the risk of myocardial infarction associated with elevated plasma proinsulin and insulin concentrations in men from Europe: the HIFMECH Study
复制标题
DOI：
10.1046/j.1538-7836.2003.00458.x
复制
发表时间：
2003-11-01
影响因子：
10.4
通讯作者：
Humphries, SE
中科院分区：
文献类型：
--
作者：
Juhan-Vague, I;Morange, PE;Humphries, SE
尽管纤溶酶原激活物抑制剂-1 （PAI-1）在冠状动脉疾病发展中的潜在作用得到其生物学特性的有力支持，但临床研究结果仍存在争议。目的：探讨血浆PAI-1浓度及PAI-1基因-675 4G/5G多态性是否可构成心肌梗死（MI）的危险标志。患者和方法：我们使用了一项欧洲病例对照研究，HIFMECH研究，比较了598名男性心肌梗死患者和653名年龄匹配的对照组。结果：胰岛素抵抗解释了PAI-1变化的主要部分（24%），而炎症仅占很小的贡献（0.01%）。对于这两个病例和对照组，血浆PAI-1浓度在北方明显高于南方，在这两个地区，心肌梗死患者的浓度都高于对照组[1个标准差增加的总优势比(OR) = 1.54, 95%可信区间（CI） 1.34, 1.77]。在所有研究中心都观察到这种差异。总体而言，在控制炎症变量后，病例与对照组之间的差异仍然显著（OR = 1.30, 95% CI 1.08, 1.57），但在控制胰岛素抵抗变量后，差异失去显著性（OR = 1.17, 95% CI 0.98, 1.40）。在病例中，4G等位基因与PAI-1水平显著升高相关，但在对照组中没有，并且，单独考虑，没有改变心肌梗死的风险（P = 0.9）。然而，胰岛素或胰岛素原与心肌梗死风险之间存在显著的相互作用（P分别= 0.05和0.02），但与甘油三酯或体重指数（BMI）无关。仅在4G/4G基因型携带者中观察到胰岛素或胰岛素原对风险的影响。这种相互作用似乎不受血浆PAI-1抗原浓度的介导（调整血浆PAI-1水平后P = 0.01和0.02）。在进一步调整与胰岛素抵抗相关的其他因素（甘油三酯和BMI）和c反应蛋白（P = 0.01）后，与胰岛素原而非胰岛素的相互作用仍具有统计学意义（P = 0.01）。结论：本研究提示PAI-1在存在潜在胰岛素抵抗的心肌梗死风险中起作用。胰岛素或胰岛素原与-675 4G/5G多态性之间的显著相互作用在心肌梗死风险中被观察到。这些相互作用的机制仍有待确定。
Although the potential role of plasminogen activator inhibitor-1 (PAI-1) in the development of coronary artery disease is strongly supported by its biological characteristics, results of clinical studies remain controversial. Objectives: To investigate whether plasma PAI-1 concentrations and the -675 4G/5G polymorphism located in the PAI-1 gene could constitute risk markers for myocardial infarction (MI). Patients and methods: We used a European case-control study, the HIFMECH study, comparing 598 men with MI and 653 age-matched controls. Results: Insulin resistance explained a major part of the variation in PAI-1 (24%) whereas inflammation had only a minor contribution (0.01%). For both cases and controls plasma PAI-1 concentrations were significantly higher in the North than the South, and in both regions were higher in individuals with MI compared with control subjects [overall odds ratio (OR) for a 1 SD increase = 1.54, 95% confidence interval (CI) 1.34, 1.77]. This difference was observed in all the centers studied. Overall, the difference between cases and control subjects remained significant after controlling for inflammation variables (OR = 1.30, 95% CI 1.08, 1.57), but lost significance after controlling for insulin resistance variables (OR = 1.17, 95% CI 0.98, 1.40). The 4G allele was associated with significantly higher PAI-1 levels in cases but not controls and, taken independently, did not modify the risk of MI (P = 0.9). However, a significant interaction was observed with both insulin or proinsulin and the risk of MI (P = 0.05 and 0.02, respectively), but not with triglycerides or body mass index (BMI). The insulin or proinsulin effect on risk was observed only in the carriers of the 4G/4G genotype. This interaction appeared not to be mediated by plasma PAI-1 antigen concentrations (P = 0.01 and 0.02 after adjustment for PAI-1 plasma levels). The interaction with proinsulin but not insulin remained statistically significant after further adjustment for other factors associated with insulin resistance (triglycerides and BMI) and C-reactive protein (P = 0.01). Conclusion: This study suggests that PAI-1 has a role in risk of MI in the presence of underlying insulin resistance. A significant interaction between insulin or proinsulin and the -675 4G/5G polymorphism was observed in risk for MI. The mechanisms for these interactions remain to be determined.