Meta-Analysis of Genome-Wide Association and Gene Expression Studies Implicates Donor T Cell Function and Cytokine Pathways in Acute GvHD

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.

Effect of NK cell receptor genetic variation on allogeneic stem cell transplantation outcome and in vitro NK cell cytotoxicity

“…As the year of transplantation was one of the covariates, the division into the discovery and replication cohorts according to the transplantation year should not explain the results. It is of note that the genome-wide association [24][25][26][27][28] or matching analyses have not pointed to the role of NK cell receptor gene polymorphisms. It was, nevertheless, of interest to nd out that the putative GVHD and relapse protective alleles reported in the present study had effects on NK cell function in vitro.…”

Review of Genetic Variation as a Predictive Biomarker for Chronic Graft-Versus-Host-Disease After Allogeneic Stem Cell Transplantation

“…mortality, relapse and acute GvHD, but for cGvHD only a matching effect could be seen (see section "Histocompatibility or matching of genetic variation as predictive biomarker for cGvHD"). In the GWAS performed on Finnish and Spanish allo-HSCT, including over 5000 SNPs in the MHC region, no evidence for genetic association between cGvHD and MHC-linked SNPs was found at the genome-wide level (58). Based on these studies and that of Ritari et al (59) it is likely that the genetic risk to cGvHD may be more related to overall genomic matching, as opposed to associations with single markers.…”

A genome-wide association study on hematopoietic stem cell transplantation reveals novel genomic loci associated with transplant outcomes

“…A first genome-wide association study (GWAS) associated genotype mismatch at HLA-DPB1 ( 10 ) and rs17473423 (12p12.1, now listed as rs1137282, located in the Kirsten rat sarcoma virus ( KRAS ) gene encoding K-Ras, a part of the RAS/MAPK pathway, were associated with GvHD in a Japanese population ( 11 ). Combining GWAS on a Finnish and a Spanish cohort with gene expression studies revealed further 51 genes potentially associated with GvHD ( 12 ). However, despite plausible molecular biological explanations, replication often fails, often due to incompatibilities between patient and donor cohorts with regards to HSCT treatment regimens and patient and donor characteristics ( 9 , 13 – 15 ).…”