Abstract
The outcome of hematopoietic stem cell transplantation (HSCT) is controlled by genetic factors among which the leukocyte antigen human leukocyte antigen (HLA) matching is most important. In addition, minor histocompatibility antigens and non-HLA gene polymorphisms in genes controlling immune responses are known to contribute to the risks associated with HSCT. Besides single-nucleotide polymorphisms (SNPs) in protein coding genes, SNPs in regulatory elements such as microRNAs (miRNAs) contribute to these genetic risks. However, genetic risks require for their realization the expression of the respective gene or miRNA. Thus, gene and miRNA expression studies may help to identify genes and SNPs that indeed affect the outcome of HSCT. In this review, we summarize gene expression profiling studies that were performed in recent years in both patients and animal models to identify genes regulated during HSCT. We discuss SNP–mRNA–miRNA regulatory networks and their contribution to the risks associated with HSCT in specific examples, including forkheadbox protein 3 and regulatory T cells, the role of the miR-155 and miR-146a regulatory network for graft-versus-host disease, and the function of MICA and its receptor NKG2D for the outcome of HSCT. These examples demonstrate how SNPs affect expression or function of proteins that modulate the alloimmune response and influence the outcome of HSCT. Specific miRNAs targeting these genes and directly affecting expression of mRNAs are identified. It might be valuable in the future to determine SNPs and to analyze miRNA and mRNA expression in parallel in cohorts of HSCT patients to further elucidate genetic risks of HSCT.
Highlights
A considerable proportion of the risk of adverse outcome after hematopoietic stem cell transplantation (HSCT) is genetically determined and can be attributed to various factors including human leukocyte antigen (HLA) matching, killer-immunoglobulin-like receptor matching, minor histocompatibility antigens, and non-HLA gene polymorphisms. Outcomes such as acute and chronic graftversus-host disease, relapse, and survival have been shown to be modified by Genetic Association of HSCT Outcome functionally relevant polymorphisms in non-HLA genes that are involved in immune responses [1, 2]
In addition other genes associated with Acute graft-versushost disease (aGvHD), IL2, methylene tetrahydrofolate reductase (MTHFR), Heparanase (HPSE), and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) were identified in this GENOME-WIDE ASSOCIATION STUDIES (GWAS) cohort and illustrate (Figure 6) the fact that genomic control of immunoregulatory cytokines could alter the function of cells which in turn aid or reduce successful transplant outcome [170]
We have shown the differential expression patterns of a variety of mRNA, different miRNAs and single-nucleotide polymorphisms (SNPs) in specific genes that have a significant impact on transplant outcome and development of GvHD
Summary
A considerable proportion of the risk of adverse outcome after hematopoietic stem cell transplantation (HSCT) is genetically determined and can be attributed to various factors including human leukocyte antigen (HLA) matching, killer-immunoglobulin-like receptor matching, minor histocompatibility antigens (miHAg), and non-HLA gene polymorphisms. Outcomes such as acute and chronic graftversus-host disease (aGvHD and cGvHD), relapse, and survival have been shown to be modified by Genetic Association of HSCT Outcome functionally relevant polymorphisms in non-HLA genes that are involved in immune responses [1, 2]. MiR-146a regulation of TRAF6 and IRAK1 was associated with aGvHD, since upregulation of miR146a expression was observed in T cells of mice developing aGvHD compared to untreated mice [52].
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