Risk stratification of organ-specific GVHD can be improved by single-nucleotide polymorphism-based risk models

Abstract

We aimed to develop a risk model, based on single-nucleotide polymorphism (SNP) markers associated with an increased risk of organ-specific GVHD in 394 transplant pairs. A total of 259 SNPs were genotyped in 53 genes and evaluated for their associated risk of organ-specific GVHD. Risk models were generated using both clinical factors and genetic SNP markers. Patients were stratified by quartiles according to their risk scores and then categorized into three groups (low, intermediate and high risk) according to this model. We compared the risk of overall and organ-specific GVHD amongst these groups. Several SNP markers in the cytokine-, apoptosis-, TGF-b-and PDGF-mediated pathways were identified as correlative markers of acute and chronic GVHD. Each organspecific GVHD shared some common biologic pathway such as cytokine, TGF-b-or PDGF-mediated pathways. However, we also identified different SNP markers that correlated with increased risk of organ-specific GVHD (for example, FCGR2A SNP for oral GVHD, and FAS and TGFB1 SNP for lung GVHD). The incorporation of genetic risk factors into the clinical factors risk model improved stratification power for organ-specific GVHD. The SNP-based approach was suggested to improve risk stratification of organ-specific GVHD.

Polymorphism in TGFB1 is associated with worse non-relapse mortality and overall survival after stem cell transplantation with unrelated donors

“…13 Finally, in two recent reports analyzing relatively large cohorts of mostly related donor transplants, TGFB1 -1347 TT and CT patients showed increased incidence of aGvHD, but no effect on OS, EFS, or NRM. 14,15 TGFB1 -1347T was found to be a risk factor for skin aGvHD but protective against lung cGvHD.…”

Interleukin-6 in Allogeneic Stem Cell Transplantation: Its Possible Importance for Immunoregulation and As a Therapeutic Target

“…Kim et al (129, 130) investigated the effects of 259 different SNPs on outcome after ASCT. While they did not observe any effect of SNPs in the IL-6 gene, patients with an SNP in the IL-6R gene (rs4845617) showed decreased relapse-free survival.…”

Association analysis between SUFU polymorphism rs17114808 and acute graft versus host disease after hematopoietic stem cell transplantation

“…Furthermore, different genetic polymorphisms affect the risk for GvHD, especially genes encoding for cytokines or chemokines, pharmacogenes and costimulatory molecules [5]. For example, Kim et al discovered an association between the presence of a specific single-nucleotide polymorphisms (SNP) in the NFKBIA or in the FAS gene of the recipient with increased risk of acute GvHD and the group suggested a SNP-based approach to improve the risk stratification of GvHD [6,7]. In addition, various SNPs in donors' or recipients' genes were associated with an effect on the risk and/or the outcome of GvHD after HSCT, e.g., ABCB1, CYP3A, thrombomodulin, Interleukin-17, methylenetetrahydrofolate reductase, B-cell activating factor, Interleukin-2, tumor necrosis factor-α, and heparanase [8][9][10][11][12][13][14].…”