Gene polymorphism of t-PA is associated with forearm vascular release rate of t-PA.
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.
Jern
C
C
Clinical Experimental Research Laboratory, Heart and Lung Institute, and Department of Neurology, Institute of Clinical Neuroscience, Sahlgrenska University Hospital, Göteborg University, Sweden. christina.jern@pediat.gu.se
Ladenvall
P
P
Wall
U
U
Jern
S
S
D000328:Adult; D001158:Arteries / Q000502:physiology; D001808:Blood Vessels / Q000378:metabolism; D005542:Forearm / Q000098:blood supply*; D014644:Genetic Variation / Q000502:physiology; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic / Q000502:physiology*; D012039:Regional Blood Flow / Q000502:physiology; D013315:Stress, Psychological; D010959:Tissue Plasminogen Activator / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D014680:Veins / Q000502:physiology