Abstracts

INFLUENCE OF TGF-ß1 GENE POLYMORPHISMS ON ACUTE AND CHRONIC REJECTION AFTER PEDIATRIC HEART TRANSPLANTATION

Sylvie Di Filippo, Steve Webber, Kevin McDade, Susan Miller, Adriana Zeevi Transplant Pathology, Biomedical Science Tower, Pittsburgh, PA, USA; Pediatric Cardiology, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA

Background: Calcineurin inhibitors may induce intragraft upregulation of the fibrogenic factor TGF-ß1. Since TGF-ß1 production is genetically determined, the aim of this study was to assess the influence of TGF-ß1 gene polymorphisms on the incidence of acute rejection and graft coronary disease in pediatric heart transplant recipients.

Material and Methods: Patients were classified as ‘Rejectors’ if they had recurrent (> 2 grade 3A episodes) or at least one steroid resistant or severe acute rejection (AR), and ‘Non-Rejectors’ if none of these events. Coronary artery disease (CAD) was diagnosed by angiography or on examination of the explanted graft. Genotyping using PCR specific primers were performed for the TGF-ß1codon 10, TGF-ß1 codon 25 and TGF-ß1 in the association of codon 10 and 25. A total of 111 patients under tacrolimus-based immunosuppression were evaluated: 39 were Rejectors and 31 developed CAD, 22 to 149 (median 82) months post-transplant.

Results: The proportion of TGF-ß1 codon 10-25 high-producers was higher in Rejectors (36/39= 92.3% versus 54/72= 75% in Non-rejectors p= 0.026). TGF-ß1 codon 25 gene polymorphism alone was not different between Rejectors and Non Rejectors (p= 0.21). TGF-ß1 codon10 allele frequencies were similar between Rejectors and Non-Rejectors (p= 0.11). TGF-ß1 codon10-25 high-production was associated with a higher frequency of CAD (29/31= 93.5% in CAD group versus 61/80= 76.2% in no CAD group, p= 0.037). TGF-ß1 codon 25 high-production separately correlated with CAD (31/31 high- producers in CAD = 100% versus 69/80 in no CAD= 86.2%, p= 0.03). TGF-ß1 codon10 gene polymorphisms were not associated with CAD.

Conclusion: High-expressors of TGF-ß1 codon10-25 have an increased risk of acute rejection and CAD, while TGF-ß1 codon 25 high-production is associated with a higher occurrence of graft coronary disease. Genetic polymorphism may reveal patients at higher risk in whom therapies and monitoring should be adjusted.