Tissue plasminogen activator genetic polymorphisms do not influence tissue plasminogen activator release in patients with coronary heart disease.
OBJECTIVE
To determine if polymorphisms of the tissue plasminogen activator (t-PA) gene influence acute endogenous t-PA release in patients with coronary heart disease (CHD).


METHODS
Forearm blood flow and plasma t-PA concentrations were measured in response to intra-brachial infusion of substance P and sodium nitroprusside in 96 patients with stable CHD. Genotyping was performed using a Taqman polymerase chain reaction assay specifically designed to detect the polymorphisms of interest: (i) Alu-repeat insertion/deletion sequence; (ii) C-->T substitution in an upstream enhancer region (-7351 C/T); (iii) T-->C in exon 6 (20 099 T/C); and (iv) T-->A (27 445 T/A) in intron 10.


RESULTS
Substance P and sodium nitroprusside caused dose-dependent increases in forearm blood flow in all patients (P < 0.001 for all) that were independent of the four genetic polymorphisms. Similarly, there were no differences in basal plasma t-PA antigen concentrations or net t-PA release between genotypes. Compared to non-smokers, smokers exhibited impaired substance P-induced vasodilatation (P < 0.001) and t-PA release (P = 0.05).


CONCLUSIONS
Despite confirming our previous findings in cigarette smokers, we have found no effect of polymorphisms of the t-PA gene on two complementary aspects of endothelial function. We conclude that genetic variation of the t-PA locus is unlikely to have a major influence on acute t-PA release in subjects with established CHD.
Robinson
S D
SD
Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK. simon.robinson@ed.ac.uk
Ludlam
C A
CA
Boon
N A
NA
Newby
D E
DE
D000368:Aged; D003327:Coronary Disease / Q000235:genetics* / Q000473:pathology*; D005260:Female; D005342:Fibrinolysis / Q000235:genetics; D017353:Gene Deletion; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009599:Nitroprusside / Q000494:pharmacology; D011110:Polymorphism, Genetic; D013373:Substance P / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology
D009599:Nitroprusside; D013373:Substance P; D010959:Tissue Plasminogen Activator