PTLD risk and IFNG polymorphisms

First, we would like to thank Thomas and colleagues for their interest in our work, their provision of additional data, and their commentary regarding genotyping studies and clinical posttransplantation lymphoproliferative disorder (PTLD). A central component of our prospective preclinical study using the human peripheralblood leukocyte severe combined immunodeficient (hu PBL SCID) mouse model of Epstein-Barr virus (EBV) lymphoproliferative disease was the demonstration of a statistically significant association of the adenosine (A)/A interferon (IFNG) genotype with the spontaneous development of EBV lymphoproliferative disease. As part of our discussion, we mentioned that our prospective preclinical studies were in line with our retrospective clinical observation in a group of renal transplant patients showing that the same A/A IFNgenotype was statistically more prevalent in renal transplant patients who developed PTLD (n 12) when compared with renal transplant patients who did not develop PTLD (n 135, P .02). This suggests that the A/A IFNG genotype may be a risk factor for the development of PTLD in renal transplant patients. Thomas and colleagues did not observe an association of IFNG genotype with the development of PTLD in their transplant patients. However, as pointed out by Professor Thomas, our PTLD patients were all renal transplant recipients, while their cohort consisted of a heterogeneous group who had undergone renal, lung, heart, hematopoietic stem cell, and liver transplantations, the latter with or without small-bowel transplantations. Further, the control population in our retrospective analysis consisted entirely of renal-transplant patients who did not develop PTLD. It is unclear if the transplant-recipient controls in the Thomas et al study were matched for the organ transplanted, immunosuppression, race, or ethnicity. Assuming that the variables were not matched, the results from our analysis are not comparable with the data from Thomas et al. If the Thomas et al study was properly controlled and the results were as reported, it is conceivable that our hypothesis holds true for renal-transplant patients but not for other solid-organ transplant recipients who receive different regimens of immune suppression and have a different incidence of PTLD. The hypothesis that an IFNG genotype is associated with the development of clinical PTLD is an active area of investigation. We do agree with Thomas and colleagues that a larger patient cohort is needed to properly assess this association in a statistically robust fashion. Most transplant centers have only a few PTLD patients each year, often of different organ types, making it difficult to perform well-controlled analyses. For this reason, we have joined with several medical centers to compare transplant patients with PTLD to transplant patients without PTLD that are matched for age, ethnicity, immune suppression, and for the transplanted organ. By our calculation, this analysis will require 65 PTLD organ transplant patients and 130 matched non-PTLD organ transplant patients to achieve 80% power. This study was recently funded by the US National Cancer Institute, and we would welcome the participation of other centers to assist us in determining if the IFNG genotype is a risk factor for the development of clinical PTLD.