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Graft-versus-host Disease

Novel HLA-DP region susceptibility loci associated with severe acute GvHD

Bone Marrow Transplantation volume 52, pages 95–100 (2017)Cite this article

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Abstract

Despite HLA allele matching, significant acute GvHD remains a major barrier to successful unrelated donor BMT. We conducted a genome-wide association study (GWAS) to identify recipient and donor genes associated with the risk of acute GvHD. A case–control design (grade III–IV versus no acute GvHD) and pooled GWA approach was used to study European-American recipients with hematological malignancies who received myeloablative conditioning non-T-cell-depleted first transplantation from HLA-A, -B, -C, -DRB1, -DQB1 allele level (10/10) matched unrelated donors. DNA samples were divided into three pools and tested in triplicate using the Affymetrix Genome-wide SNP Array 6.0. We identified three novel susceptibility loci in the HLA-DP region of recipient genomes that were associated with III–IV acute GvHD (rs9277378, P=1.58E−09; rs9277542, P=1.548E−06 and rs9277341, P=7.718E−05). Of these three single nucleotide polymorphisms (SNPs), rs9277378 and rs9277542 are located in non-coding regions of the HLA-DPB1 gene and the two are in strong linkage disequilibrium with two other published SNPs associated with acute GvHD, rs2281389 and rs9277535. Eighteen other recipient SNPs and 3 donor SNPs with a high level of significance (8E−07 or lower) were found. Our report contributes to emerging data showing clinical significance of the HLA-DP region genetic markers beyond structural matching of DPB1 alleles.

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Acknowledgements

We would like to thank Dan Scheller for research repository management, Deborah Hollingshead for coordinating the GWAS experiments, and Dr A Kim Ritchey for his support and guidance for this project.

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Author notes

  1. M Trucco

    Present address: Institute of Cellular Therapeutics, 11th Floor South Tower, Allegheny Health Network, 320 East North Avenue, Pittsburgh, PA 15212, USA.,

Authors and Affiliations

  1. Department of Pediatric of Blood and Marrow Transplantation and Cellular Therapies, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA

    R K Goyal

  2. Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    R K Goyal

  3. Division of Hematology, Department of Pediatrics, Oncology and Blood and Marrow Transplantation, Children’s Mercy Hospital, Kansas City, MO, USA

    R K Goyal

  4. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    S J Lee

  5. Department of Biostatistics, Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI, USA

    S J Lee & T Wang

  6. Division of Immunogenetics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA, USA

    M Trucco

  7. Department of Immunobiology and Observational Research, Center for International Blood and Marrow Transplant Research, Minneapolis, MN, USA

    M Haagenson & S R Spellman

  8. Department of Pediatric BMT, University of Minnesota, Minneapolis, MN, USA

    M Verneris

  9. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA

    R E Ferrell

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Correspondence to R K Goyal.

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Goyal, R., Lee, S., Wang, T. et al. Novel HLA-DP region susceptibility loci associated with severe acute GvHD. Bone Marrow Transplant 52, 95–100 (2017). https://doi.org/10.1038/bmt.2016.210

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