Impact of Homozygous Deletion of UGT2B17 on Outcome of Allogeneic BMT.
Authors: Terakura Seitaro , Murata Makoto , Nishida Tetsuya , Emi Nobuhiko , Akatsuka Yoshiki , Riddell Stanley R. , Morishima Yasuo , Kodera Yoshihisa , Naoe Tomoki 
Published: October 2019

Abstract
We recently identified a human minor histocompatibility (H) antigen encoded by the UDP glycosyltransferase 2 family, polypeptide B17 (UGT2B17) gene. UGT2B17 is a metabolic enzyme that is highly expressed in liver and colon, and at low levels in hematopoietic cells. UGT2B17 conjugates exogenous and endogenous compounds including steroid hormones and facilitates their elimination. The immunogenicity of the UGT2B17 was due to differential expression of the protein in donor and recipient cells as a consequence of a homozygous deletion of the UGT2B17 gene in the recipient. Deletion of this gene in a subset of normal individuals suggested two mechanisms by which UGT2B17 could affect the outcome of allogeneic BMT. First, the expression of UGT2B17 in recipient but not donor cells could provide minor H antigens and increase GVHD. Second, the presence of UGT2B17 in the donor or recipient could affect the metabolism, function, or toxicity related to endogenous hormones or drugs administered with BMT. The purposes of this study were to determine the frequency of homozygous UGT2B17 deletion in healthy individuals and patients with hematological disease and whether a deficiency of UGT2B17 in donor and/or recipient affected the outcome of allogeneic BMT. A total of 435 recipients were selected from the patients who received unrelated BMT through the Japanese Marrow Donor Program between January 1993 and March 2000. Selection criteria were (1) matched at HLA-A, B, C and DRB1 genotypes, (2) unmanipulated marrow graft, (3) cyclosporine A or tacrolimus as GVHD prophylaxis, and (4) available DNA was stored. DNA from a total of 358 of the donors was also available. Homozygous deletion of the UGT2B17 gene determined by SSP-PCR was found in 320 (84.8%) of 377 donors and 358 (82.3%) of 435 patients (P=0.32, χ2 test). These frequencies of UGT2B17 deletion were substantially higher than the 11% observed in the Caucasian population in a previous study. A multivariate analysis (Cox proportional hazard model) showed no significant association between UGT2B17-mismatch in the GVHD direction and the incidence of acute GVHD (grade II-IV or III-IV), chronic GVHD, relapse, or survival. However, a deletion of UGT2B17 in the donor was a favorable factor for transplant-related mortality (TRM) (relative risk, 0.530; 95% CI, 0.334 to 0.841; P=0.007), survival (0.567; 0.387 to 0.831; P=0.036) and disease-free survival (DFS) (0.647; 0.443 to 0.945; P=0.024). We also analyzed these outcomes in the subset of patients with standard-risk malignant disease by the Kaplan-Meier method. TRM, survival, and DFS at eight years after transplantation were 23.7% for patients transplanted from a UGT2B17-deleted donor vs 52.9% for patients with a UGT2B17-positive donor (P=0.001); 68.3% vs 37.5% (P=0.0009); and 66.9% vs 37.5% (P=0.0009), respectively. These data suggest that the UGT2B17 enzyme in donor-derived blood cells may affect the metabolism of exogenously administered or endogenous molecules and adversely influence the outcome of unrelated BMT. Analysis in another patient population will be important to confirm our results.