Influence of IFN-gamma polymorphism on the development of coronary vasculopathy after cardiac transplantation.

Abstract

The development of coronary vasculopathy (CV) limits survival after cardiac transplantation. Interferon (IFN)-gamma is an important immunomodulator affecting the growth and function of T cells and macrophages, free radical formation, adhesion molecule, and MHC class I and II expression, which are important processes for CV formation. IFN-gamma is expressed early after transplantation and neutralization or genetic absence of the cytokine can abrogate CV development. The expression of IFN-gamma is influenced by a dinucleotide repeat in the first intron of the IFN-gamma gene. We investigated the effect of this polymorphism on the development of CV. Using sequence specific primers to the IFN-gamma polymorphic region, polymerase chain reaction (PCR) and gel electrophoresis identified the genotype in 144 cardiac transplant recipients and 134 donors. An association was sought between the presence of a high, intermediate or low IFN-gamma producing genotype and the development of CV diagnosed by routine surveillance posttransplant angiography. High, intermediate, and low IFN-gamma producers made up 29.2%, 44.4%, 26.4% and 24.6%, 40.3%, 35.1% of recipients and donors respectively (p = NS). IFN-gamma polymorphism in cardiac graft recipients had no impact on the time to first diagnosis of CV; high producers 4.03 years (+/- 129.9 days), intermediate producers 3.40 years (+/- 79.7 days), low producers 4.01 years (+/- 102.9 days); p = 0.16. Similar results were found on investigating donor polymorphism; high producers (3.68 years +/- 120.1 days), intermediate producers (3.83 years +/- 105.9 days), low producers (3.3 years +/- 77.7 days); p = 0.35. Multivariate analysis identified the number of rejection episodes of ISHLT grade 3 or greater and increasing donor age to be independent risk factors for CV development. Dinucleotide repeat polymorphism in the first intron of the human IFN-gamma gene does not influence CV development and cannot be used as a genetic risk marker.