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Gene polymorphisms for plasminogen activator inhibitor-1/tissue plasminogen activator and development of allograft
R L Benza1, H E Grenett, R C Bourge
1Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, Alabama, USA. rbenza@cardio.dom.uab.edu
Insights
Donor PAI-1 2/2 genotype is linked to increased risk of allograft vasculopathy (Tx CAD) after cardiac transplantation. This genetic marker may help predict Tx CAD development in recipients.
Area of Science:
- Cardiology
- Transplantation Immunology
- Genetics
Background:
- Impaired fibrinolytic activity is associated with allograft vasculopathy (Tx CAD) severity.
- Fibrinolytic protein gene polymorphisms may contribute to this impairment.
Purpose of the Study:
- To investigate the association between donor fibrinolytic protein genotypes and Tx CAD.
- To determine if specific genotypes predict Tx CAD development.
Main Methods:
- Identified donor plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (TPA) genotypes using Southern blot analysis in 48 cardiac allograft recipients.
- Correlated genotypes with the development of Tx CAD.
Main Results:
- No association found between donor TPA genotypes and Tx CAD.
- Donor PAI-1 2/2 genotype was associated with significantly lower freedom from CAD at 12 and 24 months (75% and 45%) compared to other genotypes (P=0.03).
- Recipients with a 2/2 PAI-1 genotyped allograft had longer ischemic times.
Conclusions:
- The donor 2/2 PAI-1 genotype is a significant risk factor for developing Tx CAD.
- This genotype can potentially serve as a screening tool for predicting Tx CAD risk.
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 (P=0.03). Recipients with a diseased 2/2 PAI-1 genotyped allograft had longer ischemic times (P=0.02) 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.