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

Abstract

In addition to the classical human leukocyte antigen (HLA) genes, the outcomes of post-hematopoietic stem cell transplantation (HSCT) are associated with human leukocyte antigen (HLA)-related genes and non-HLA genes involved in immune regulation. HLA-G gene plays an important role in immune tolerance, assisting immune escape of tumor cells, and decrease of transplant rejection. In this study, we explored the association of genetic variants at the 3’-untranslated region (3’-UTR) and 5’-upstream regulatory region (5’-URR) of HLA-G gene with the adverse outcomes of patients with leukemia receiving HSCT. The genomic DNAs of 164 patients who had acute leukemia and received HSCT were collected for analysis. Nine single nucleotide polymorphisms (SNPs) and six haplotypes in the 3’-UTR and 27 SNPs and 6 haplotypes in the 5’-URR were selected to investigate their relationship with the development of adverse outcomes for patients receiving HSCT, including mortality, relapse, and graft-versus-host disease. Our results revealed that two SNPs (rs371194629 and rs9380142) and one haplotype (UTR-3) located in the 3’-UTR and two SNPs (rs3823321 and rs1736934) and one haplotype (G0104a) located in the 5’-URR of HLA-G were associated with the occurrence of chronic GVHD or development of any forms of GVHD. No SNP was found to associate with the occurrence of mortality and relapse for patients receiving HSCT. These SNPs and haplotypes may play important roles in regulating immune tolerance of allografts post-HSCT that can be used to predict the risk of poor outcomes after receiving HSCT and giving preventive treatment to patients on time.

Association of HLA‐E single nucleotide polymorphisms with human myeloid leukemia

“…28,29 For example, SNPs in the regulatory region of HLA-G gene were found relative to cancers. [14][15][16] However, whether the SNP in regulatory region of HLA-E gene is associated with diseases, it remains unclear. In our study, we found the correlation between rs76971248 SNP in the regulatory region and myeloid leukemia.…”

“…Few studies have reported the SNPs in regulatory region of HLA‐E gene among healthy individuals 28,29 . For example, SNPs in the regulatory region of HLA‐G gene were found relative to cancers 14–16 . However, whether the SNP in regulatory region of HLA‐E gene is associated with diseases, it remains unclear.…”

“…Most of SNPs associated with complex diseases identified by GWAS are located in the noncoding regions of genes 13 . The SNPs in the regulatory region of other HLA gene families, such as HLA‐G correlating to various diseases, have been reported 14–16 . SNPs in the regulation region can affect gene expression through different mechanisms, such as differential binding of transcription factors or microRNAs 17,18 .…”

“…13 The SNPs in the regulatory region of other HLA gene families, such as HLA-G correlating to various diseases, have been reported. [14][15][16] SNPs in the regulation region can affect gene expression through different mechanisms, such as differential binding of transcription factors or microRNAs. 17,18 However, there are limited reports regarding SNPs in the noncoding regions of HLA-E gene in association with diseases, and the role of these SNPs affecting gene expression remains unknown.…”

Relationships between Polymorphisms in HLA-G 3’UTR Region and COVID- 19 Disease Severity

“…Genetic polymorphisms in the 3'-untranslated region (UTR) of HLA-G have been linked to posttranscriptional alteration of HLA-G expression and a wide range of clinical complications, including autoimmunity, chronic in ammation, viral infections, allografting, and cancer (Chen et al 2023). Harmful effects that HLA-G triggers include immunological escape mechanisms, while it positively in uences innate and adaptive immune responses and tolerance development (Jasinski-Bergner, Eckstein, et al…”