Gene Polymorphisms for Plasminogen Activator Inhibitor-1/Tissue Plasminogen Activator and Development of Allograft Coronary Artery Disease

Abstract

Background-Impaired fibrinolytic activity has been linked to the presence and severity of allograft vasculopathy (Tx CAD). This impairment may be associated with the presence of certain fibrinolytic protein gene polymorphisms. Methods and Results-To investigate the relation between donor-specific fibrinolytic protein genotypes and Tx CAD, we identified donor plasminogen activator inhibitor-1 (PAI-1) HindIII and tissue plasminogen activator (TPA) EcoRI restriction fragment length polymorphisms-based genotypes by Southern blot analysis in 48 recipients of cardiac allografts and correlated these genotypes with the development of CAD. No association was found between donor TPA genotypes and the presence of Tx CAD. Among the 48 patients, 17% were homozygous for the 1/1 PAI-1 genotype, 51% for the 2/2 PAI-1 genotype, and 32% for the 1/2 PAI-1 genotype. The actuarial freedom from any CAD for the recipients with each respective donor PAI-1 genotype at 12 and 24 months was 100% and 100% for the 1/1 PAI-1 genotype, 92% and 92% for the 1/2 PAI-1 genotype, and 75% and 45% for the 2/2 PAI-1 genotype (Pϭ0.03). Recipients with a diseased 2/2 PAI-1 genotyped allograft had longer ischemic times (Pϭ0.02) than those recipients with a Tx CAD-free allograft. Conclusions-These data suggest that recipients with a 2/2 PAI-1 genotype are at a significant risk of developing Tx CAD.This genotype may serve as a useful screening tool for predicting the future development of Tx CAD. (Circulation. 1998;98:2248-2254.)

Plasminogen activator inhibitor-1 C/G polymorphism in relation to plasma levels in rheumatoid arthritis

“…To our knowledge, there are not previous association studies of this polymorphism with RA susceptibility. To date, only three studies have been published related to PAI-1 HindIII C/G polymorphism and risk of MI and CAD [16,18,19]. In these previous studies, the homozygous (C/C and G/G) genotypes were associated with the angiographic extent of CAD whereas in other studies only the G/G genotype was associated with the same condition [18,19].…”

“…To date, only three studies have been published related to PAI-1 HindIII C/G polymorphism and risk of MI and CAD [16,18,19]. In these previous studies, the homozygous (C/C and G/G) genotypes were associated with the angiographic extent of CAD whereas in other studies only the G/G genotype was associated with the same condition [18,19]. However, in MI the PAI-1 HindIII C/G polymorphism was not associated, but the PAI-1 plasma levels were increased in patients and controls carriers of the C/C genotype [16].…”

“…In relation to this information, the PAI-1 HindIII polymorphism has been used as marker for genetic variation, and it has been related to higher PAI-1 plasma levels in C/C genotype carriers than C/G and G/G genotypes carriers in two independent control populations and young patients post-myocardial infarction (MI) [16,17]. Moreover, the PAI-1 HindIII polymorphism homozygote forms have been associated with the angiographic extent of coronary artery disease (CAD) [18,19]. Based on this knowledge, the aim of this study was to investigate the relationship between PAI-1 HindIII C/G polymorphism and PAI-1 plasma levels in RA patients.…”

Alterations in the Fibrinolytic Cascade Post-transplant: Evidence of a Bimodal Expression Pattern

“…Among the nonimmune factors, alterations in fibrinolytic activity (FA) appear to be important (12)(13)(14)(15)(16). Impaired FA usually results from diminished levels of the plasminogen activators (PAs), t-PA and urokinase (u-PA) and/or the presence of excess PAI-1, the inhibitor of these PAs.…”

Population variability in some genes involving the haemostatic system: data on the general population of Corsica (France), Sardinia and Sicily (Italy)

“…The I (Insertion) and H7 (HVR4) alleles have been reported to be associated with low Factor VII plasma concentration, which is interpreted as conferring protection against the risk of cardiovascular disease (Iacoviello et al, 1998;Girelli et al, 2000;Geng et al, 2003). Moreover, the typed RFLP/HindIII polymorphism in the 3' region of the fibrinolytic protein plasminogen activator inhibitor (PAI1) influences the plasma levels (PAI-1) and has been associated with the development of cardiovascular disease (Benza et al, 1998;Lee et al, 1999). The only exception to the lack of population studies is the Alu insertion polymorphism, located within intron 8 of the PLAT gene, the geographic distribution of which has been extensively studied (Ludwig et al, 1992;Tishkoff et al, 2000).…”