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. 2009 Dec;41(12):1341-4.
doi: 10.1038/ng.490.

Donor-recipient Mismatch for Common Gene Deletion Polymorphisms in Graft-Versus-Host Disease

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Free PMC article

Donor-recipient Mismatch for Common Gene Deletion Polymorphisms in Graft-Versus-Host Disease

Steven A McCarroll et al. Nat Genet. .
Free PMC article

Abstract

Transplantation and pregnancy, in which two diploid genomes reside in one body, can each lead to diseases in which immune cells from one individual target antigens encoded in the other's genome. One such disease, graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT, or bone marrow transplant), is common even after transplants between HLA-identical siblings, indicating that cryptic histocompatibility loci exist outside the HLA locus. The immune system of an individual whose genome is homozygous for a gene deletion could recognize epitopes encoded by that gene as alloantigens. Analyzing common gene deletions in three HSCT cohorts (1,345 HLA-identical sibling donor-recipient pairs), we found that risk of acute GVHD was greater (odds ratio (OR) = 2.5; 95% confidence interval (CI) 1.4-4.6) when donor and recipient were mismatched for homozygous deletion of UGT2B17, a gene expressed in GVHD-affected tissues and giving rise to multiple histocompatibility antigens. Human genome structural variation merits investigation as a potential mechanism in diseases of alloimmunity.

Figures

Figure 1
Figure 1
(a) Initial screen for association of acute GVHD with donor-recipient mismatch for common gene deletions, in Cohort A. Six common gene-deletion polymorphisms were screened by typing in donors and recipients; data represent association of donor-recipient mismatch (donor −, recipient +) with the development of GVHD after transplantation. Odds ratios and 95% confidence intervals are shown. (b) Analysis in additional patient cohorts of the association of donor-recipient mismatch at UGT2B17 with acute GVHD. (c) Association of UGT2B17 deletion in donor and recipient with GVHD risk. The group of transplants in which both donor and patient were UGT2B17-positive is used as the reference group for analysis. Odds ratios and confidence intervals were calculated using the Cochran-Mantel-Haenszel test to combine data from the 1,345 donor-recipient pairs from Cohorts A, B, and C.
Figure 2
Figure 2
Cumulative incidence of acute GVHD during the first 100 days after HSCT (Cohort C). In this analysis, death and recurring malignancy before the onset of grades II – IV GVHD were treated as competing risks.
Figure 3
Figure 3
Multiple histocompatibility antigens derived from UGT2B17. An antibody response to the UGT2B17-derived peptide VLLADAVNP was detected in the serum of a UGT2B17-positive GVHD patient whose donor was UGT2B17-negative. Responses of T-cell clones against multiple antigens derived from UGT2B17 and presented by three distinct HLA alleles have been detected in other GVHD patients ,,.

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