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.
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Acknowledgements
We wish to thank the patients, donors and clinical care teams at Helsinki University Central Hospital, the Dana-Farber Cancer Institute and the Fred Hutchinson Cancer Research Center. We also wish to thank D. Sese and colleagues at the Brigham and Women's Hospital Tissue Typing Laboratory; the Ted and Eileen Pasquarello Tissue Bank; Q. Yang and colleagues at the Quality Assurance Office for Clinical Trials at Dana-Farber Cancer Institute; E. Lander, Y. Ofran, J. Chien and M. Daly for helpful conversations on the project and data; and B. Blazar, C. Keever-Taylor and D. Senitzer for providing patient samples for the Nichols et al. cohort further studied here. This work was supported by the Broad Institute of MIT and Harvard (D.A., S.A.M.), the Academy of Finland (L.V., H.T., J.P.), the Helsinki University Central Hospital Research Fund (L.V.), the Fred Hutchinson Cancer Research Center, a Lilly Life Sciences Research fellowship (S.A.M.), the S. Juselius Foundation (J.P.), the Center of Excellence Program of the Finnish Academy (A.P.) and the National Institutes of Health (HA070149 to J.H.A.; AI29530 to J.R.; AI33484, CA18029 and HL087690 to J.A.H.).
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S.A.M., J.E.B. and D.A. developed an initial study plan and refined this plan with insights from R.J.S., J.R., A.P., E.H.W. and P.J.M. Patient collections including DNA samples were established and/or further developed by L.V., H.T., T.R. and J.P. in Helsinki; J.E.B., S.J.L., J.H.A., J.R. and R.J.S. in Boston; D.G. in Michigan; and P.J.M., S.J.L., B.S. and J.A.H. in Seattle. Analyses of patient clinical data were led, performed and/or further analyzed by L.V. and T.R. at Helsinki University Central Hospital; S.J.L., J.E.B., J.H.A., R.J.S. and J.R. at Dana-Farber Cancer Institute; and B.S., P.J.M., S.J.L., E.H.W. and J.A.H. at the Fred Hutchinson Cancer Research Center (FHCRC). Deletion polymorphisms were genotyped by S.A.M., H.T. and S.D.C., using molecular assays developed by S.A.M. B.Z. and L.P.Z. analyzed array-based data to genotype deletions and analyzed association and time course in the FHCRC cohort. S.A.M. performed statistical analyses of genotype-phenotype correlation with feedback from other authors, especially P.J.M., A.P. and D.A. S.D.C. and H.T. performed ELISA experiments. S.A.M. wrote the manuscript with extensive input and feedback from coauthors.
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McCarroll, S., Bradner, J., Turpeinen, H. et al. Donor-recipient mismatch for common gene deletion polymorphisms in graft-versus-host disease. Nat Genet 41, 1341–1344 (2009). https://doi.org/10.1038/ng.490
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DOI: https://doi.org/10.1038/ng.490
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