Tumor necrosis factor genetic polymorphisms correlate with infections after renal transplantation

Background. Nonimmunosuppressed individuals possessing a NcoI restriction enzyme site in the tumor necrosis factor (TNF) gene locus produce less TNF-α in vitro and in vivo than do individuals lacking this site. We have previously shown that this NcoI+/low TNF-α genotype is independently associated with increased rates of infection for liver transplant recipients. Methods. In this study, we performed polymerase chain reaction amplification and restriction fragment length polymorphism analysis of the TNF locus from 45 renal transplant recipients to determine whether the presence of the NcoI site is associated with the frequency of rejection, infection, time to rejection or infection, and patient or graft survival. Results. Twenty-six recipients were typed with the NcoI+/low TNF-α genotype, whereas 19 recipients had the NcoI^-/high TNF-α genotype. Age, sex, donor type, secondary immunosuppression, use of anti-lymphocyte preparations, graft ischemia time, and year of transplant were evenly distributed in the two groups. There was no difference between the genotype groups in the rate of, or time to, rejection. In contrast, significantly more patients with the NcoI+/low TNF-α site developed infections (46% vs. 10% P=0.01). In bivariable models, each controlling for donor type, ischemia time, recipient age, use of antilymphocyte agents, and secondary immunosuppresion, the NcoI+/low TNF-α genotype was still independently associated with increased numbers of infections (relative risk, 5.38; confidence interval, 1.20-23.8). Conclusion. We conclude that in individuals genetically predetermined to be low TNF-α producers, the additional inhibition of TNF-α production by routine immunosuppression may be excessive, rendering these individuals less able to respond to infectious stimuli. These patients may benefit from lower doses or withdrawal of corticosteroids, which are known inhibitors of TNF-α transcription.