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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:454-459.)
© 1999 American Heart Association, Inc.

Original Contribution

Gene Polymorphism of t-PA is Associated With Forearm Vascular Release Rate of t-PA

Christina Jern; Per Ladenvall; Ulrika Wall; Sverker Jern

From the Clinical Experimental Research Laboratory (C.J., P.L., U.W., S.J.), Heart and Lung Institute, and Department of Neurology (C.J.), Institute of Clinical Neuroscience, Sahlgrenska University Hospital, Göteborg University, Göteborg, Sweden.

Correspondence to Christina Jern, MD, PhD, Clinical Experimental Research Laboratory, Sahlgrenska University Hospital/Östra, CK, S-416 85 Göteborg, Sweden. E-mail christina.jern{at}pediat.gu.se

Abstract—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.

Key Words: genetics • tissue-type plasminogen activator • blood flow • secretion • stress

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