Jern C, Ladenvall P, Wall U, Jern S
Clinical Experimental Research Laboratory, Heart and Lung Institute, and Department of Neurology, Institute of Clinical Neuroscience, Sahlgrenska University Hospital, Göteborg University, Sweden.
Arterioscler Thromb Vasc Biol. 1999 Feb;19(2):454-9. doi: 10.1161/01.atv.19.2.454.
We have observed marked interindividual differences in release rates of tissue-type plasminogen activator (t-PA) among healthy subjects. The objective of the current study was to test the hypothesis that there is an association between a genetic variation at the t-PA locus and the in vivo release rate of t-PA. Fifty-one healthy males were studied at rest in the morning and 27 of these were also subjected to a mental stress test. Net release rates of total t-PA across the forearm vascular bed were calculated as the product of the venoarterial concentration gradient and forearm plasma flow. Zygosity for an Alu-repeat polymorphism in intron 8 of the t-PA gene was determined by a polymerase chain reaction. Basal t-PA release rates differed markedly by genotype (ANOVA, P<0.05); subjects homozygous for the insertion had a significantly higher release rate (mean 10.9 ng. min-1. L-1, n=19) than both heterozygotes (4.5 ng. min-1. L-1, n=26) and subjects homozygous for the deletion (0.9 ng. min-1. L-1, n=6). After 2 minutes of mental stress release rates had increased approximately 2-fold in all groups. Arterial and venous plasma levels of t-PA were unrelated to genotype. In conclusion, the current results provide the first evidence of an association between a common genetic variation at the t-PA locus and interindividual differences in net release rates of t-PA in vivo. The relationship is not reflected by circulating steady-state plasma levels and can thus not be disclosed by conventional venous plasma sampling.
我们观察到健康受试者之间组织型纤溶酶原激活物（t-PA）的释放速率存在显著的个体差异。本研究的目的是检验t-PA基因座的基因变异与t-PA体内释放速率之间存在关联的假设。对51名健康男性进行了早晨静息状态下的研究，其中27人还接受了心理应激测试。通过静脉-动脉浓度梯度与前臂血浆流量的乘积计算前臂血管床总t-PA的净释放速率。采用聚合酶链反应确定t-PA基因第8内含子Alu重复多态性的纯合性。基础t-PA释放速率因基因型而异（方差分析，P<0.05）；插入纯合子受试者的释放速率（平均10.9 ng·min-1·L-1，n=19）显著高于杂合子（4.5 ng·min-1·L-1，n=26）和缺失纯合子受试者（0.9 ng·min-1·L-1，n=6）。心理应激2分钟后，所有组的释放速率均增加了约2倍。t-PA的动脉和静脉血浆水平与基因型无关。总之，目前的结果首次证明了t-PA基因座常见的基因变异与t-PA体内净释放速率的个体差异之间存在关联。这种关系未反映在循环稳态血浆水平中，因此无法通过传统的静脉血浆采样来揭示。
