Analysis of Relationships between Immune Checkpoint and Methylase Gene Polymorphisms and Outcomes after Unrelated Bone Marrow Transplantation

Abstract

Unrelated bone marrow transplantation (uBMT) is performed to treat blood disorders, and it uses bone marrow from an unrelated donor as the transplant source. Although the importance of HLA matching in uBMT has been established, that of other genetic factors, such as single-nucleotide polymorphisms (SNPs), remains unclear. The application of immunoinhibitory receptors as anticancer drugs has recently been attracting attention. This prompted us to examine the importance of immunoinhibitory receptor SNPs in uBMT. We retrospectively genotyped five single-nucleotide polymorphisms (SNPs) in the immune checkpoint genes, BTLA, PD-1, LAG3, and CTLA4, and two SNPs in the methylase genes, DNMT1 and EZH2, in 999 uBMT donor–recipient pairs coordinated through the Japan Marrow Donor Program matched at least at HLA-A, -B, and -DRB1. No correlations were observed between these SNPs and post-uBMT outcomes (p > 0.005). This result questions the usefulness of these immune checkpoint gene polymorphisms for predicting post-BMT outcomes. However, the recipient EZH2 histone methyltransferase gene SNP, which encodes the D185H substitution, exhibited a low p-value in regression analysis of grade 2–4 acute graft-versus-host disease (p = 0.010). Due to a low minor allele frequency, this SNP warrants further investigation in a larger-scale study.

LAG3 genotype of the donor and clinical outcome after allogeneic transplantation from HLA-identical sibling donors

“…In contrast, a recent Japanese study explored the relationship between transplant outcome and polymorphisms in the immune checkpoint genes, including the LAG3 rs870849 SNP in patients receiving an unrelated alloHSCT, and the authors failed to find any correlation (28). There are some aspects that need to be considered to explain this discrepancy: Takahasi et al explored Japanese patients transplanted from unrelated donors whereas our study is performed in Caucasian patients transplanted from HLA-identical sibling donors, avoiding hidden or even known HLA mismatches and with less genetic differences potentially influencing the development of GVHD.…”