Abstract
Graft-vs.-host disease (GvHD) is a major complication after allogeneic hematopoietic stem cell transplantation that causes mortality and severe morbidity. Genetic disparities in human leukocyte antigens between the recipient and donor are known contributors to the risk of the disease. However, the overall impact of genetic component is complex, and consistent findings across different populations and studies remain sparse. To gain a comprehensive understanding of the genes responsible for GvHD, we combined genome-wide association studies (GWAS) from two distinct populations with previously published gene expression studies on GvHD in a single gene-level meta-analysis. We hypothesized that genes driving GvHD should be associated in both data modalities and therefore could be detected more readily through their combined effects in the integrated analysis rather than in separate analyses. The meta-analysis yielded a total of 51 acute GvHD-associated genes (false detection rate [FDR] <0.1). In support of our hypothesis, this number was significantly higher than that in a permutation meta-analysis involving the whole data set, as well as in separate meta-analyses on the GWAS and gene expression data sets. The genes indicated by the meta-analysis were significantly enriched in 277 Gene Ontology terms (FDR < 0.05), such as T cell function and cytokine-mediated signaling pathways, and the results highlighted several established immune mediators, such as interleukins and JAK-STAT signaling, and presented TRAF6 and TERT as potential effector candidates. Altogether, the results support the chosen methodological approach, implicate a role of gene-level variation in donors' key immunological regulators predisposing patients to acute GVHD, and present potential targets for therapeutic intervention.
Highlights
Allogeneic hematopoietic stem cell transplantation (HSCT) is utilized as a curative treatment for life-threatening hematological malignancies
We explore the cooperative relationship between genome-wide association studies (GWAS) signals mapped into genes and published gene expression profiles in acute GvHD (aGvHD) and chronic GvHD (cGvHD)
The SNP associated P-values of donor aGvHD grades II–IV vs. 0 and cGvHD limited-extensive vs. 0 GWASs from all three study cohorts were mapped into genes using MAGMA [33] v1.07b with the default 1000 Genomes GRCh37 LD data and gene annotation data provided with MAGMA
Summary
Allogeneic hematopoietic stem cell transplantation (HSCT) is utilized as a curative treatment for life-threatening hematological malignancies. Mismatching recipient and donor for HLA-molecules is a well-established risk factor for GvHD and overall survival [5, 6] Both HLA and minor histocompatibility antigen disparities have been shown to result in the beneficial graft- vs.-leukemia effect reducing the risk of relapse [7, 8]. Sato-Otsubo et al studied unrelated HSCT in a Japanese population and identified an association between HLA-DPB1 allele disparity and aGvHD. They discovered three novel loci, including one in HLA-DP region, linked to severe aGvHD. A genomewide approach was employed by Martin et al [20] and Ritari et al [21, 22], who both studied the effect of genome-wide recipient-donor mismatching. We sought to determine whether the two data modalities lend support to each other and to understand the functional categories that may explain the outcome of HSCT in terms of GvHD pathogenesis
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