High-resolution HLA phased haplotype frequencies to predict the success of unrelated donor searches and clinical outcome following hematopoietic stem cell transplantation

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Abstract

HLA matching is a critical factor for successful allogeneic hematopoietic stem cell transplantation. For unrelated donor searches, matching is usually based on high-resolution typing at five HLA loci, looking for a 10/10 match. Some studies have proposed that further matching at the haplotype level could be beneficial for clinical outcome. In this study, we determined the phased haplotypes of 291 patients using family members and segregation analysis. The sum of ranks of the haplotypes carried by patients was used as a surrogate predictor of a successful unrelated donor search. The putative impact of haplotypes was then analyzed in a cohort of 211 recipients transplanted with 10/10 matched unrelated donors. A logistic regression analysis showed a highly significant effect of the haplotypes in the outcome of a search, but we did not find any significant effect on overall survival, graft versus host disease or relapse/progression following HSCT. This study provides useful data for the optimization of unrelated bone marrow donor searches, but does not confirm previous reports that matching at the haplotype level has a clinical impact following HSCT. Due to the extreme polymorphism of HLA genes, further studies are warranted to better understand the many factors at play.

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Most cited references 44

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High-resolution HLA alleles and haplotypes in the United States population.

Martin Maiers, Loren Gragert, William Klitz (2007)

We extract and present high-resolution HLA allele and haplotype frequency data available from the National Marrow Donor Program databases from four major U.S. census categories of race and ethnicity. Population-based high-resolution HLA frequencies defined on the basis of from one to five loci are presented and made available online (http://bioinformatics.nmdp.org/haplotype2006). In addition, a discriminatory classification of HLA allelic variation on the basis of observed population allele frequencies (common, rare and unseen) for HLA A, C, B, DRB1, DQA1, and DQB1 is introduced. The electronic availability of this information will be useful for projects central to the typing and use of population data in HLA applications.

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Determination of HLA‐A, ‐C, ‐B, ‐DRB1 allele and haplotype frequency in Japanese population based on family study

N Ikeda, H Kojima, Marília M Nishikawa … (2015)

Abstract The present study investigates the human leucocyte antigen (HLA) allele and haplotype frequencies in Japanese population. We carried out the frequency analysis in 5824 families living across Japanese archipelago. The studied population has mainly been typed for the purpose of transplant, especially the hematopoietic stem cell transplantation (HSCT). We determined HLA class I (A, B, and C) and HLA class II (DRB1) using Luminex technology. The haplotypes were directly counted by segregation. A total of 44 HLA‐A, 29 HLA‐C, 75 HLA‐B, and 42 HLA‐DRB1 alleles were identified. In the HLA haplotypes of A‐C‐B‐DRB1 and C‐B, the pattern of linkage disequilibrium peculiar to Japanese population has been confirmed. Moreover, the haplotype frequencies based on family study was compared with the frequencies estimated by maximum likelihood estimation (MLE), and the equivalent results were obtained. The allele and haplotype frequencies obtained in this study could be useful for anthropology, transplantation therapy, and disease association studies.

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How to select the best available related or unrelated donor of hematopoietic stem cells?

Jean-Marie Tiercy (2016)

Recognition of HLA incompatibilities by the immune system represents a major barrier to allogeneic hematopoietic stem cell transplantation. HLA genotypically identical sibling donors are, therefore, the gold standard for transplantation purposes, but only 30% patients have such a donor. For the remaining 70% patients alternative sources of stem cells are a matched unrelated adult volunteer donor, a haploidentical donor or a cord blood unit. The definition of 'HLA matching' depends on the level of resolution and on which loci are tested. The development of HLA molecular typing technologies and the availability of more than 27 million donors in the international database has greatly facilitated unrelated donor searches. The gold standard is high resolution typing at the HLA-A, -B, -C, -DRB1, and -DQB1 loci (10/10 match). Single disparities for HLA-A, -B, - C, or -DRB1 are associated with increased risk of post-transplant complications, but less so in patients with advanced disease, and in those undergoing T-cell-depleted allografting. HLA-DQB1 mismatches seem to be better tolerated and some HLA-C, -DRB1 and -DPB1 disparities are potentially less immunogenic. HLA typing by next-generation sequencing methods is likely to change matching algorithms by providing full sequence information on all HLA loci in a single step. In most European populations a 10/10 matched donor can be found for at least 50% of patients and an additional 20-30% patients may have a 9/10 matched donor. Genetic factors that help in identifying donors with less immunogenic mismatches are discussed. Haploidentical donors are increasingly used as an alternative source of stem cells for those patients lacking a matched unrelated donor.

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Author and article information

Contributors

Stéphane Buhler: stephane.buhler@hcuge.ch

Journal

Journal ID (nlm-ta): Bone Marrow Transplant

Journal ID (iso-abbrev): Bone Marrow Transplant

Title: Bone Marrow Transplantation

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 0268-3369

ISSN (Electronic): 1476-5365

Publication date (Electronic): 5 April 2019

Publication date PMC-release: 5 April 2019

Publication date (Print): 2019

Volume: 54

Issue: 10

Pages: 1701-1709

Affiliations

[1 ]ISNI 0000 0001 0721 9812, GRID grid.150338.c, Transplantation Immunology Unit and National Reference Laboratory for Histocompatibility, Department of Diagnostic, , Geneva University Hospitals, ; Geneva, Switzerland

[2 ]ISNI 0000 0001 2322 4988, GRID grid.8591.5, Anthropology Unit, AGP Laboratory, Department of Genetics and Evolution, , University of Geneva, ; Geneva, Switzerland

[3 ]GRID grid.410567.1, Division of Hematology, Basel University Hospital, ; Basel, Switzerland

[4 ]Institute of Genetics and Genomics in Geneva (iGE3), Geneva, Switzerland

[5 ]ISNI 0000 0001 0721 9812, GRID grid.150338.c, Division of Hematology, Department of Oncology, Geneva University Hospitals, ; Geneva, Switzerland

[6 ]ISNI 0000 0004 0478 9977, GRID grid.412004.3, Division of Hematology, University Hospital of Zurich, ; Zurich, Switzerland

[7 ]ISNI 0000 0001 0726 4330, GRID grid.412341.1, Department of Stem Cell Transplantation, , University Children’s Hospital Zurich, ; Zurich, Switzerland

[8 ]ISNI 0000 0001 1017 1290, GRID grid.452284.d, Swiss Blood Stem Cells Registry, Swiss Transfusion SRC, ; Bern, Switzerland

Author information

Grazia Nicoloso http://orcid.org/0000-0001-6783-0349

Article

Publisher ID: 520

DOI: 10.1038/s41409-019-0520-6

PMC ID: 7198472

PubMed ID: 30953025

SO-VID: 3062ad42-b5ea-4595-b38b-d18692e67f88

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 30 November 2018

Date accepted : 18 March 2019

Funding

Funded by: FundRef https://doi.org/10.13039/501100001711, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation);

Award ID: 310030_173237/1

Award Recipient : Stéphane Buhler

Funded by: FundRef https://doi.org/10.13039/501100007606, Société Académique de Genève (Academic Society of Geneva);

Funded by: Ernest Boninchi Foundation, International Research Group on unrelated Haematopietic Stem Cell Transplantation, Dr Henri Dubois-Ferrière Dinu Lippatti foundation and the Philantropy Settlement.

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ScienceOpen disciplines: Transplantation

Keywords: bone marrow transplantation,transplant immunology

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ScienceOpen disciplines: Transplantation

Keywords: bone marrow transplantation, transplant immunology

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High-resolution HLA phased haplotype frequencies to predict the success of unrelated donor searches and clinical outcome following hematopoietic stem cell transplantation

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Regulatory T cell (Treg) therapy

Most cited references 44

High-resolution HLA alleles and haplotypes in the United States population.

Determination of HLA‐A, ‐C, ‐B, ‐DRB1 allele and haplotype frequency in Japanese population based on family study

How to select the best available related or unrelated donor of hematopoietic stem cells?

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