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Study Suggests SNP Screening Could Improve Outcomes in Blood Stem Cell Transplants Between Unrelated Individuals

NEW YORK (GenomeWeb News) – A variant in a major histocompatibility complex, or MHC, region on chromosome 6 appears to hold promise for predicting which individuals will develop graft versus host disease (GVHD) after receiving blood stem cell transplants from non-relatives, according to a new study.

In Science Translational Medicine, researchers from the Fred Hutchinson Cancer Research Center, the University of Washington, and elsewhere profiled 1,120 MHC region SNPs in thousands of individuals with blood, bone marrow, or lymph node cancers who had received hematopoietic stem cell transplants from unrelated individuals sharing the same human leukocyte antigen, or HLA, type.

Results of the study suggest that donor-recipient mismatches at one of the MHC SNPs examined can influence disease-free survival, while mismatches at a second, independent variant in the region influences the risk of a transplant recipient developing acute GVHD.

"Two SNPs were validated as robust markers for disease-free survival and acute GVHD risk," corresponding author Effie Petersdorf, a researcher affiliated with the Hutch and the University of Washington, and colleagues wrote. "These results demonstrate that the transplant barrier is defined not only by classical HLA genes but also by non-HLA genetic variation within the MHC."

The study offered a retrospective look at potential MHC-related genetic contributors affecting outcomes and/or GVHD risk during hematopoietic stem cell transplants.

For the first phase of the study, the researchers focused on 2,492 transplants between 2,107 donor-recipient pairs and another 385 unpaired donors or patients, using the Illumina FastTrack genotyping service to assess more than 1,200 SNPs spread across 4.9 million bases in the MHC region. After quality control steps, they were left with information at 1,120 SNPs for 4,599 of the samples.

The team did not find statistically significant differences related to the overall percentage of these SNPs that were shared between a transplant recipient and their unrelated blood stem cell donor, indicating that donor-recipient mismatches across the complete MHC SNP set are not especially informative when it comes to clinical outcomes.

On the other hand, the team found eight SNPs with apparent ties to clinical outcomes. And donor-recipient mismatches at two SNPs in a chromosome 6 MHC region remained associated with outcomes after a replication testing analysis of 1,713 transplants. These involved 1,654 donor-recipient pairs and 59 donors or recipients that weren't part of a pair.

One of these, known as rs887464, was linked to disease-free survival following the blood stem cell transplants, while donor-recipient mismatch at an independent SNP called rs2281389 was associated with acute GVHD risk, researchers reported.

Although further fine-mapping studies are needed to better understand these findings, those involved with the study argued that genotyping at one or both of the newly identified SNPs might serve as a strategy for improving the outcomes of individuals slated to receive blood stem cell transplants from unrelated, but HLA-matched, donors.

"The identification of MHC-resident transplantation determinants provides clinicians with tools to lower post-transplant risks through comprehensive donor matching," they wrote, "and to identify patients at highest risk for complications who might benefit from directed preventive measures that include optimization of GVHD prophylaxis."

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