Livia Varga1,2, Petra Kövy1,2, Nora Meggyesi2, Andras Bors2, Katalin Balassa2, Eva Torbagyi2, Melinda Paksi2, Laszlo Gopcsa2, Attila Tordai1, Tamas Masszi1, Peter Remenyi2, Hajnalka Andrikovics2
1Semmelweis University (SE), Budapest
2Central Hospital of Southern Pest (DPC) Budapest
Introduction: The endothelial membrane protein, thrombomodulin is an important regulator of coagulation and innate immunity. Functional single-nucleotide polymorphisms (SNPs) within the thrombomodulin gene (THBD) of the recipient might contribute to endothelial dysfunction, abnormal reactivity during graft versus host disease (GvHD) thereby subsequent mortality after allogeneic hematopoietic stem cell transplantation (HSCT).
Aims: The role of recipient’s THBD SNPs (rs1962, rs1042579 and rs1042580) was analyzed in the outcome after HSCT.
Method: We genotyped 528 recipients with malignant hematopoietic diseases treated with HSCT. HLA-matched sibling (n=207), HLA-matched unrelated individuals (n=193) or haploidentical relatives (n=128) were served as donors. Conditioning types were the following: myeloablative (MAC, n=370) or reduced intensity conditioning (RIC=158). Calcineurin inhibitors (CNI, n=171); or CNI+mTOR inhibitor (n=234) or post-transplant cyclophosphamide (PTCy, n=110) were used as GvHD prophylaxis. (No GvHD prophylaxis was applied in 13 cases with T-cell depleted graft.) THBD SNPs (rs1962, rs1042579 and rs1042580) were genotyped from genomic DNA by melting curve analysis on LightCycler instrument.
Results: In case of MAC conditioning THBD homozygosity for either SNP influenced overall survival (OS) differentially depending on GvHD prophylaxis applied. If CNI±mTOR inhibitor was applied in HLA-matched sibling or MUD HSCT, favorable OS was observed in THBD homozygous patients (OS at 24 months: 73.7±5.6% vs. 51.0±3.5%, p=0.004). A tendency for the opposite effect was detectable in haploidentical HSCT with PTCy (OS at 24 months: 21.1±11.9% vs. 58.2±7.4%, p=0.063). THBD homozygosity did not influenced survival in RIC.
Our results suggest that recipient’s THBD rs1962, rs1042579 or rs1042580 genotypes have altered effect in different HSCT settings. THDB homozygosity may propitiously influence overall survival in case of myeloablative conditioning with calcineurin & mTOR inhibitor GvHD prophylaxis. In case of post-transplant cyclophosphamide, the same genetic constellation exerts an adverse effect. THBD homozygosity may be a predictive biomarker for HSCT outcome.
Doctoral School: Clinical Medicine
Program: Clinical Haematology
Supervisor: Hajnalka Andrikovics MD, PhD
E-mail address: firstname.lastname@example.org