Donor C3435T Polymorphism in the Multidrug Resistance 1 (MDR1) Gene Is Associated with the Incidence of Acute and Chronic Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Shimoni Avichai , Ostrovsky Olga , Galski Hanan , Hardan Izhar , Shem-Tov Noga , Yerushalmi Ronit , Papatryphonos Antonis , Nagler Arnon 
Published: October 2019

Abstract
Graft-versus-Host disease (GVHD) is the most significant treatment-related complication after allogeneic stem cell transplantation (alloSCT). HLA, KIR and cytokine gene polymorphisms were previously reported to be involved in determining the risk of GVHD after alloSCT. The current study was designed to explore the role of polymorphism in the multi-drug resistance 1 (MDR1) gene in predicting GVHD. Single nucleotide polymorphisms at C3435T and G2677T were determined in patients (pts) and donors using RFLP- based assay and correlated with the occurrence of acute and chronic GVHD after alloSCT. The study included 115 pts with various hematological malignancies after alloSCT from related (n=73) or unrelated (n=42) donors. Fifty pts had myeloablative and 65 had reduced-intensity conditioning. C3435T polymorphism included CC, CT and TT genotypes. CC genotype was detected in 36% and 34% of pts and donors, respectively. CT and TT genotypes were detected in 47%/47%, and 17%/19% respectively. G2677T polymorphism included GG, GT and TT genotypes that were detected in 29%/34%, 55%/49%, and 16%/17% of pts and donor pairs, respectively. The incidence of acute and chronic GVHD were found to be increased after alloSCT in pt-donor pairs when the donor had CC in the C3435T site. The cumulative incidence of acute GVHD grade II–IV after alloSCT was 53% (95%CI, 37–74), 40% (28–57) and 42% (25–71) when the donors had CC, CT and TT in the C3435T site, respectively (p=NS), while the cumulative incidence of acute GVHD grade III–IV was 38% (24–62), 18% (9–35) and 18% (6–50), respectively (p=0.02). Multivariable analysis determined donor CC (HR 2.4, p=0.05) and alloSCT from female to male (HR 5.1, p=0.03) as the most significant factors predicting for severe acute GVHD while donor, disease and conditioning types were not significant. Pt C3435T polymorphism and pt or donor G2677T polymorphisms had no correlation with GVHD. Similarly the cumulative incidence of chronic GVHD was 84% (95%CI, 68–100), 53% (38–75) and 38% (39–63) when the donors had CC, CT and TT in the C3435T site, respectively (p=0.02). Multivariable analysis determined donor CC (HR 2.2, p=0.01), alloSCT from female to male (HR 2.5, p=0.03) and alloSCT from unrelated donor (HR 1.8, p=0.05) as the most significant factors predicting for chronic GVHD. The same three factors predicted for extensive chronic GVHD. The CC genotype in C3435T is known to be associated with higher expression level of P-glycoprotein (Pgp). We speculate that increased Pgp may result in lower intracellular levels of cyclosporine in donor T-cells leading to higher incidence of GVHD. Furthermore, Pgp may be involved in transporting Th1 and Th2 cytokines that are critical to the pathogenesis of acute and chronic GVHD, respectively. Further studies will be required to determine the mechanism of the association of C3435T polymorphism, Pgp expression and GVHD. In conclusion, C3435T polymorphism in the MDR1 gene may be an important factor in predicting GVHD and may be considered when selecting the most suitable donor.