Life-threatening risks associated with HLA-mismatched unrelated donor hematopoietic cell transplantation (HCT) limit its general application for the treatment of blood diseases. In CA100019, we have taken a haplotype approach to investigate the MHC as a source of untyped variation. We mapped haplotype effects of acute or chronic graft-versus-host disease (GVHD), relapse, or mortality after HLA-mismatched unrelated donor HCT to 12 single nucleotide polymorphisms (SNPs). SNP-associated risks were conferred by either patient or donor genotype or by patient-donor mismatching. Risks after transplantation increased with increasing numbers of unfavorable SNPs. SNPs affected acute GVHD independently from chronic GVHD. SNPs also lowered relapse independently of GVHD. Haplotype-specific content for candidate genes can be used clinically to assess risks in patients and to select donors with optimal MHC genetics.
The aims of CA100019 are to: 1) confirm the impact of the 12 SNPs in HLA-mismatched transplants;2) determine the content of homozygous HLA haplotypes for candidate transplant genes;3) identify specific polymorphisms associated with risks after mismatched unrelated HCT, and 4) identify risks associated with HLA mismatches. CA100019 will contribute novel information on the genes and putative pathways involved in GVHD and graft- versus-leukemia, and provide clinicians with a haplotype-based approach for optimizing HLA-mismatched unrelated donor HCT.

Public Health Relevance

We are discovering the genes that are responsible for the success of blood and marrow transplantation from unrelated donors. Information on these genes will help physicians to choose better donors and to lower risks for patients who need a transplant to cure diseases of the blood system.

National Institute of Health (NIH)
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Cancer Immunopathology and Immunotherapy Study Section (CII)
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Merritt, William D
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Fred Hutchinson Cancer Research Center
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