Single-Nucleotide Polymorphisms Within Non-HLA Regions Are Associated With Engraftment Effectiveness for Patients With Unrelated Cord Blood Transplantation

Abstract

Clinically, stem cells with matched human leukocyte antigens (HLAs) must be selected for allogeneic transplantation to avoid graft rejection. However, adverse reactions still occur after cord blood transplantation (CBT). It was inferred that the HLA system is not the only regulatory factor that may influence CBT outcomes. Therefore, we plan to investigate whether the single-nucleotide polymorphisms (SNPs) located in non-HLA genes are associated with the effectiveness of CBT. In this study, the samples of 65 donors from CBT cases were collected for testing. DNA sequencing was focused on the SNPs of non-HLA genes, cytotoxic T-lymphocyte-associated protein 4 (CTLA4), CD28, tumor necrosis factor ligand superfamily 4 (TNFSF4), and programmed cell death protein 1 (PDCD1), which were selected in regard to the literatures published in 2017 and 2018, which indicated that they were related to stem cell transplantation. Then, in combination with the detailed follow-up transplantation tracking database, these SNPs were analyzed with the risk of mortality, relapse, cytomegalovirus (CMV) infection, and graft-versus-host disease (GVHD). We found that there were 2 SNPs of CTLA4, 1 SNP of TNFSF4, and 2 SNPs of PDCD1 associated with the effectiveness of unrelated CBT. These statistically significant SNPs and haplotypes would be used in clinical to choose the best donor for the patient receiving CBT. Moreover, the polygenic risk scores (PRSs) with these SNPs could be used to predict the risk of CBT adverse reactions with an area under the receiver operating characteristic curve (AUC) of 0.7692. Furthermore, these SNPs were associated with several immune-related diseases or cancer susceptibility, which implied that SNPs play an important role in immune regulation.

Keywords: CD28; CTLA4; PDCD1; TNFSF4; cord blood transplantation (CBT); non-HLA genes; single-nucleotide polymorphism (SNP).

Figure 1

Kaplan–Meier curves of overall survival with statistical significance based on the mortality-related SNPs and event-free survival based on the GVHD-related SNPs and relapse-related SNPs. (A) The survival time had a significant difference between the 3 genotypes of rs733618. (B) The survival time had a significant difference between the 3 genotypes of rs1234314. (C) The survival time had a significant difference between the 2 genotype groups of rs1234314. (D) The survival time had a significant difference between the 3 genotypes of rs36084323. (E) The survival time had a significant difference between the 2 genotype groups of rs36084323. (F) The survival time had a significant difference between the 3 genotypes of rs2227982.

Figure 2

The ROC curve of the PRS for predicting the risk of CBT adverse reactions.