The Association Between Single-Nucleotide Polymorphisms of Co-Stimulatory Genes Within Non-HLA Region and the Prognosis of Leukemia Patients With Hematopoietic Stem Cell Transplantation

Abstract

To avoid graft rejection, the hematopoietic stem cells with matched classical human leukocyte antigen (HLA) alleles are the primary choice for clinical allogeneic transplantation. However, even if the fully HLA-matched hematopoietic stem cells are used for transplantation, some patients still have poor prognosis after hematopoietic stem cell transplantation (HSCT), suggesting that the HLA system was not the only determinant of the outcomes of HSCT. In this study, we investigated whether the single-nucleotide polymorphisms (SNPs) of the co-stimulatory genes within non-HLA regions were related to the outcomes of HSCT. The genomic DNAs of 163 patients who had acute leukemia and received HSCT and their respective donors were collected for analysis. Thirty-four SNPs located in the four co-stimulatory genes including cytotoxic T-lymphocyte associated protein 4 (CTLA4), CD28, tumor necrosis factor ligand superfamily 4 (TNFSF4), and programmed cell death protein 1 (PDCD1) were selected to explore their relationship with the adverse outcomes after transplantation, including mortality, cytomegalovirus infection, graft-versus-host disease, and relapse. Our results revealed that nine SNPs in the CTLA4 gene, five SNPs in the PDCD1 gene, two SNPs in the TNFSF4 gene, and four SNPs in the CD28 gene were significantly associated with the occurrence of adverse outcomes post-HSCT. These SNPs may play important roles in immune response to allografts post-HSCT and can be the targets for developing strategy to identify appropriate donors.

Association between the side effect induced by COVID-19 vaccines and the immune regulatory gene polymorphism

“…Next, nociception occurs when cytokines, prostaglandins or ATP released by these immune cells interact with nociceptors and the threshold is reached ( 8 ). Combining the results of the present study with our previous finding, we found that rs11571315 and rs16840252 of CTLA4 were associated with the adverse reaction of post-haematopoietic stem cell transplantation in patients with acute lymphocytic leukemia ( 27 ) and immune thrombocytopenia ( 28 ). Moreover, such SNPs were associated with vaccine-induced side effects.…”

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

“…The average survival time was 44.46 months ( Figure 1F ). These significant SNPs were also associated with the outcomes of post-bone marrow transplantation (BMT) in our previous study ( 22 ), which was summarized in Table 7 .…”

“…The data showed that there were 5 SNPs in these four genes associated with the outcomes of post-CBT. Integrating the research results of the literature published in the Frontiers in Immunology journal in 2021 by our team that explored the association between immune regulatory gene polymorphism and the outcomes of post-HSCT ( 22 ), it was found that the rs1234314 of TNFSF4, the rs36084323 and rs2227982 of PDCD1, and the rs733618 and rs3087243 of CTLA4 were also associated with the outcomes of post-bone marrow transplantation (BMT) in adults in addition to the CBT case in children. These SNPs affected mortality, GVHD, and relapse in both BMT cases and CBT cases.…”

The association between genetic variants at 3’-UTR and 5’-URR of HLA-G gene and the clinical outcomes of patients with leukemia receiving hematopoietic stem cell transplantation

“…The definition of outcomes post-HSCT has been described previously (26). Briefly, mortality was referred to the state of patients who died in the duration of study.…”

“…The associations of genotypes and haplotypes in the 3'-UTR and 5'-URR of HLA-G gene with the outcomes of patients post-HSCT (i.e. Grade I-II aGVHD, Grade III-IV aGVHD, cGVHD, any forms of GVHD, mortality, and relapse) were evaluated by analysis of genotype groups (AA, Aa, and aa) using various genetic models including additive, homozygous, heterozygous, dominant and recessive models and logistic regression analysis as described previously (26). Briefly, the allele with higher frequency was referred to major allele "A" and the other was minor allele "a".…”