Influence of tumor necrosis factor-α gene-308 polymorphism on the development of coronary vasculopathy after cardiac transplantation

Abstract

Background Tumor necrosis factor-α (TNF-α) has been implicated in cardiovascular disease. Polymorphism of the TNF-α gene promoter region (position -308) influences an individual’s production of TNF-α. This affects susceptibility to acute rejection after cardiac transplantation. Because the highest serum levels of TNF-α have been found in recipients with cardiac transplant vasculopathy and because TNF-α blockade can prevent the disease in rabbits, we investigated the effect of TNF-α promoter polymorphism on the development of vasculopathy in human cardiac allograft recipients Methods Using sequence-specific primers to the TNF-α gene and polymerase chain reaction, the genotypes of 147 cardiac transplant recipients and 134 heart donors were identified. An association was sought between the presence of high-producing (A homozygotes, GA heterozygotes) or low-producing (G homozygotes) TNF-α genotype and the development of coronary vasculopathy, diagnosed by routine surveillance coronary angiography. Results We found that 31.9% of recipients and 27.0% of donors were high TNF-α producers. The presence of the high-producing TNF-α allele led to an earlier diagnosis of vasculopathy; 3.42 years (± 91.3 days) vs 3.84 years (± 76.3 days) for high- and low-producing cardiac graft recipients, respectively; 3.52 years (± 87.3 days) vs 3.78 years (± 77.4 days) for high- and low-producing donor grafts, respectively. However, neither of these differences were significant. By Kaplan Meier actuarial analysis and log-rank test, TNF-α polymorphism had no effect on the freedom from vasculopathy when considering either recipient ( p = 0.99) or donor ( p = 0.86) TNF-α genotype. Multivariate analysis identified increasing donor age and the number of acute rejection episodes of International Society for Heart and Lung Transplantation grade 3 or greater as independent risk factors for vasculopathy in both the recipient and donor cohorts. Conclusions Polymorphism at position -308 in the promoter region of the TNF-α gene fails to predict the development of cardiac transplant-related vasculopathy and cannot be used as a genetic risk marker. This may be because of the effects of immunosuppressive treatment.