Exploring Genetic Basis of GVHD by Whole-Genome Association Studies in a Large Series from the Japan Marrow Donation Program (JMDP).

Allogeneic stem cell transplantation (allo-HSCT) has been established as one of the most effective therapeutic options for hematopoietic malignancies. Its major therapeutic benefits are obtained from allo-immunity directed against patients’ tumor cells (graft-versus-tumor effects, GVT). However, the same kind of allo-immune reactions can also be directed to normal host tissues resulting in graft-versus-host disease (GVHD) and subsequently offset the potential benefit from GVT. Because both reactions are initiated by donor T-cells that recognize minor histocompatibility antigens (mHA) that are incompatible between donor and recipient, the knowledge of these mHA is of particular importance to develop a new measure to prevent GVHD while harnessing the antitumor potential of allo-HSCT. On the other hand, the incompatibility of mHAs, as well as other predispositions to development of GVHD, is basically determined genetically, and thus, are plausible targets of genetic association studies, which have recently been enabled with the advent of large-scale genotyping technology. In the current study, we explored genetic basis of GVHD by whole genome association studies, in which relevant SNPs to GVHD development were explored by genotyping a large cohort of GVHD-positive and negative transplantations performed through the Japan Marrow Donor Program (JMDP). Among 7,800 transplants genotyped for HLA types, we selected 1856 transplants (3712 donors/recipients) for large scale genotyping of more than 500,000 SNPs using Affymetrix® GeneChip® 500K arrays, according to the following criteria:

1. HLA A, B, C, DR, DQ loci were completely matched at the DNA level

2. Short term MTX (stMTX) + CyA or stMTX + FK506 was employed as GVHD prophylaxis, and

3. Genome DNA from both donor and recipient and record of clinical course was available.

Based on the genotyping data, possible association was tested for each SNP in donors and recipients with regard to the development of GVHD. Association of genotype incompatibilities was also investigated for major HLA subtypes to identify the mHA loci that are relevant to GVHD pathogenesis. In the intermediate analysis, a number of candidate polymorphisms in donors and recipients have been identified together with possible mHA loci.