Alu-repeat polymorphism in the tissue-type plasminogen activator (t-PA) gene, t-PA levels and risk of familial myocardial infarction (MI)

Several authors have suggested that increased t-PA antigen levels were associated to thrombotic events in coronary, cerebral and peripheral arteries. Baseline and stimulated levels of t-PA in plasma appear highly heritable, therefore, it could be of interest to evaluate the role of genetic variations in the t-PA locus in determining its plasma levels and its association with a parental history of thrombosis. We studied an insertion deletion polymorphism located in the first Alu sequence in intron h of the t-PA gene, in a sample of the population, including 327 subjects (202 M,125 F, aged 20-78 years) from all over Italy. Genotype analysis was also performed on 114 patients with MI and at least one first degree relative affected by MI or stroke before 65 years compared with 145 controls, aged over 45 years. The genotype distribution in all groups were in Hardy-Weinberg equilibrium. The I and D allele frequencies in the Italian sample were 0.55 and 0.45 respectively. There were no differences in genotype distribution between MI patients with familial history of thrombosis and controls (29 and 31%, 51 and 50%, 20 and 20% for I/I, I/D and D/D, respectively in cases and controls). There was no significant interaction of sex or age on the association between t-PA polymorphism and familial MI. The levels of t-PA and PAI-1 (both antigen and activity) were not differently distributed among the t-PA genotypes in the healthy Italian population sample. However, an association between t-PA polymorphisms and PAI-1 antigen was found in patients with MI. Patients carrying the genotype I/I showed the higher levels of PAI-1 antigen (31 ± 17 in I/I vs. 20 ± 15 and 21 ± 14, respectively in I/D and D/D, P < 0.01). These data do not support a role for the Alu repeat polymorphism of t-PA gene in determining the blood levels of t-PA and the risk of familial MI in the Italian population. The relation found between t-PA polymorphism and PAI-1 antigen levels in Italian patients should be further clarified.