Genetic Variations in the Mycophenolate Mofetil Target Enzyme Are Associated with Acute GVHD Risk after Related and Unrelated Hematopoietic Cell Transplantation

Inosine monophosphate dehydrogenase (IMPDH) is the target enzyme of mycophenolate mofetil (MMF). Single nucleotide polymorphisms (SNPs) in the IMPDHI gene are reportedly relevant to acute rejection in renal transplant patients receiving MMF. The objective of this study was to identify the impact of IMPDH I gene polymorphisms on the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Four IMPDH I gene SNPs (IVS7 +125 G>A, IV58-106 G>A, exon15 1572 G>A, and 5' flanking intron-exon region C>T) were analyzed in 240 consecutive pairs of transplant recipients and their donors. The presence of the IMPDHI IVS8-106 GIG genotype in recipients was associated with a significantly higher incidence of acute graft-versus-host disease (aGVHD) than other genotypes, in both unrelated and sibling transplantation cohorts (unrelated cohort: 83.3% vs 63.9%, P = .048; sibling cohort: 47.6% vs 17.3%, P = .008). Multivariate analysis confirmed that recipients with the IVS8-106 GIG genotype were at significantly higher risk of developing aGVHD (relative risk [RR] = 2.018, 95% confidence interval [CI]: 1.354-3.009, P = .001) and grades II-IV aGVHD (RR = 2.232, 95% CI: 1.352-3.685, P = .002). There was no association among IVS7 +125, exon15 1572, and 5' flanking intron-exon region genotypes and the risk of aGVHD. These results represent the first report of an association between IMPDHI gene polymorphisms and the risk of aGVHD in allo-HSCT.