Common Gene Deletions and Graft-Versus-Host Disease after Hematopoietic Stem Cell Transplantation

Graft-versus-host disease (GVHD) is a serious and common complication of allogeneic hematopoetic stem cell transplantation (HSCT). GVHD results from genetic incompatibilities between donor and host. Although matching of donor and recipient human leukocyte antigens (HLA) is critical to transplant outcomes, GVHD is common even in transplants involving HLA-identical sibling donors. The additional determinants of graft compatibility are poorly understood, though a small number of minor histocompatibility antigens have been reported. The human genome has recently been found to show large-scale structural variation, including large gene deletions sufficiently common to appear as homozygous gene deletions in many patients. We investigated whether donor-recipient disparity for common gene deletion polymorphisms (homozygous gene deletion in donor but not in recipient) was associated with GVHD following allogeneic HSCT in 821 HLA-identical sibling donor-recipient pairs. Patient samples and clinical outcomes data were assembled collaboratively from institutions in Finland and North America, in strict compliance with ethical standards and IRB-approved protocols. Donors and patients were typed for the presence of six common gene deletions using real-time PCR. Donor-recipient disparities were then assessed for association with acute and chronic GVHD. Donor-recipient disparities in the expected direction (-/- in donor, +/- or +/+ in recipient) for two common gene deletions, UGT2B28 and UGT2B17, were associated with chronic GVHD (OR > 4, P=0.001; and OR=2.0, P=0.05 respectively). Donor-recipient disparity for UGT2B17 was also associated with acute GVHD (OR=2.0, P=0.05). In the cohorts assembled for this study, we also observed an expected robust association for sex mismatch with chronic GVHD (OR=1.6, p=0.001) and a non-significant trend toward association with acute GVHD (OR=1.1, p=0.30). No significant association with acute or chronic GVHD was observed for the other four common gene deletion polymorphisms (GSTT1, GSTM1, OR51A2, and LCE3C). Consistent with prior studies of minor histocompatibility antigens on the Y-chromosome, we observed evidence of serologic immunoreactivity to a nine residue peptide on UGT2B17 in an HSCT recipient with mismatch at this locus. Because disparities for UGT2B17 and UGT2B28 occur in fewer than 6% of sibling-donor transplants in populations with European ancestry, they can explain only a fraction of the genetically attributable risk of GVHD. Of note, deletion of UGT2B28 appears to be more common in individuals with African and Latin American ancestry (allele frequency of 25–35%), and therefore merits investigation as a potential contributor to transplant outcome in those populations. We conclude that variation in genome structure associates with graft-versus-host disease and merits further investigation as a cause of minor histocompatibility barriers to hematopoietic stem cell transplantation. For the Transplant Structural Genetics Consortium: David Altshuler, Shannon Chilewski, Steven McCarroll (Broad Institute of Harvard and MIT, Cambridge, MA); Joseph Antin, James Bradner, Stephanie Lee, Jerome Ritz, Robert Soiffer (Dana-Farber Cancer Institute, Boston, MA); Aarno Palotie (Finnish Genome Center, Helsinki, Finland); Jukka Partanen, Hannu Turpeinen (Finnish Red Cross, Helsinki, Finland); Tapani Ruutu, Liisa Volin (Helsinki University Central Hospital, Helsinki, Finland); David Ginsburg, David Siemeniak (University of Michigan, Ann Arbor, MI).