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

Abstract

Simple SummaryHematopoietic stem-cell transplantation (HSCT) is a curative therapy for blood disorders. Unrelated bone marrow transplantation (uBMT) is a type of allogeneic HSCT that uses the bone marrow of an unrelated donor. While HLA mismatch is a risk factor for poor outcomes in HSCT, such as graft-versus-host disease (GVHD), the importance of non-HLA single-nucleotide polymorphisms (SNPs) remains unclear. The clinical application of immune checkpoint and chromatin methylation inhibitors to cancer has been attracting attention. In the present study, we retrospectively genotyped five SNPs in four immune checkpoint genes, BTLA, PD-1, LAG3, and CTLA4, and two SNPs in methylase genes, DNMT1 and EZH2, in 999 uBMT pairs. Although no correlations were observed between these SNPs and post-uBMT outcomes, recipient EZH2 SNP exhibited a low p-value in the analysis of grade 2–4 acute GVHD (p = 0.010). This SNP may be useful for outcome predictions and needs to be confirmed in a larger-scale study.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.