We have observed marked interindividual differences in release rates of tis
sue-type plasminogen activator (t-PA) among healthy subjects. The objective
of the current study was to test the hypothesis that there is an associati
on between a genetic variation at the t-PA locus and the in vivo release ra
te 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 produ
ct of the venoarterial concentration gradient and forearm plasma flow. Zygo
sity for an Alu-repeat polymorphism in intron 8 of the t-PA gene was determ
ined by a polymerase chain reaction. Basal t-PA release rates differed mark
edly by genotype (ANOVA, P < 0.05); subjects homozygous for the insertion h
ad a significantly higher release rate (mean 10.9 ng.min(-1).L-1, n = 19) t
han 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 st
ress release rates had increased approximately 2-fold in all groups. Arteri
al and venous plasma levels of t-PA were unrelated to genotype. In conclusi
on, the current results provide the first evidence of an association betwee
n a common genetic variation at the t-PA locus and interindividual differen
ces 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.