Tumor necrosis factor genetic polymorphisms correlate with infections after renal transplantation

Background Nonimmunosuppressed individuals possessing a NcoI restriction en zyme site in the tumor necrosis factor (TNF) gene locus produce less TNF-al pha in vitro and in vivo than do individuals lacking this site. We have pre viously shown that this NcoI+/low TNF-alpha genotype is independently assoc iated with increased rates of infection for liver transplant recipients. Methods. In this study, we performed polymerase chain reaction amplificatio n and restriction fragment length polymorphism analysis of the TNF locus fr om 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-alpha geno type, whereas 19 recipients had the NcoI(-)/high TNF-alpha genotype, Age, s ex, donor type, secondary immunosuppression, use of anti-lymphocyte prepara tions, graft ischemia time, and year of transplant were evenly distributed in the two groups. There was no difference between the genotype groups in t he rate of, or time to, rejection. In contrast, significantly more patients with the NcoI+/low TNF-alpha site developed infections (46% vs. 10% P=0.01 ). In bivariable models, each controlling for donor type, ischemia time, re cipient age, rise of antilymphocyte agents, and secondary immunosuppression , the NcoI+/low TNF-alpha 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-alpha producers, the additional inhibition of TNF-alpha: productio n by routine immunosuppression may be excessive, rendering these individual s less able to respond to infectious stimuli. These patients may benefit fr om lower doses or withdrawal of corticosteroids, which are known inhibitors of TNF-alpha transcription.