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Abstract
Despite detailed human leukocyte antigen (HLA) matching and modern immunosuppressive therapy, severe graft-versus-host disease (GvHD) remains a major hurdle for successful allogeneic hematopoietic stem cell transplantation (HSCT). As the genetic diversity in GvHD complicates the systematic discovery of associated variants across populations, we studied 122 GvHD-associated single nucleotide polymorphisms (SNPs) in 492 HLA-matched sibling HSCT donor-recipient pairs from Finland and Spain. The association between these candidate SNPs and grade III–IV acute GvHD and extensive chronic GvHD was assessed. The functional effects of the variants were determined using expression and cytokine quantitative trait loci (QTL) database analyses. Clear heterogeneity was observed in the associated markers between the two populations. Interestingly, the majority of markers, such as those annotated to IL1, IL23R, TLR9, TNF, and NOD2 genes, are related to the immunological response by monocytes-macrophages to microbes, a step that precedes GvHD as a result of intestinal lesions. Furthermore, cytokine QTL analysis showed that the GvHD-associated markers regulate IL1β, IFNγ, and IL6 responses. These results support a crucial role for the anti-microbial response in GvHD risk. Furthermore, despite apparent heterogeneity in the genetic markers associated with GvHD, it was possible to identify a biological pathway shared by most markers in both populations.
Highlights
Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established curative treatment for many hematological malignancies
In the Finnish cohort, we evaluated the association between 50 candidate single nucleotide polymorphisms (SNPs) and both acute graft-versus-host disease (GvHD) and chronic GvHD outcomes
To systematically identify genetic loci that are associated with GvHD, we screened previously reported SNPs for their genetic associations with acute GvHD (aGvHD) and chronic GvHD (cGvHD) in a total of 492 human leukocyte antigen (HLA)-matched sibling HSCT recipient-donor pairs
Summary
Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established curative treatment for many hematological malignancies. GvHD is mediated by donor immune cells in the graft, which recognize the patient’s tissues as foreign and destroy them. The outcome of HSCT is strongly influenced by the genetic differences between recipient/donor pairs[4]. The golden rule is genetic similarity or identity in the human leukocyte antigen (HLA) genes located in the major histocompatibility complex (MHC) on chromosome 6. We can assume GvHD as a multifactorial trait with a genetic component, in which the HLA matching is a crucial but not sufficient factor. One challenge for GWA studies in HSCT is diagnostic and treatment heterogeneity and the fact that the outcome may depend on properties of both the donor and recipient. We evaluated the previously reported GvHD-associated single nucleotide polymorphisms (SNPs) in two HLA-matched sibling allogeneic HSCT cohorts derived from Finnish and Spanish populations. We further analyzed the downstream functional effects of the associated SNPs to identify the disease-related biological pathways involved
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