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Direct HLA Genetic Comparisons Identify Highly Matched Unrelated Donor-Recipient Pairs with Improved Transplantation Outcome. Biol Blood Marrow Transplant 2019 05;25(5):921-931

Date

12/12/2018

Pubmed ID

30537549

DOI

10.1016/j.bbmt.2018.12.006

Scopus ID

2-s2.0-85060298203   7 Citations

Abstract

HLA matching by allele-level genotyping is largely based on genetic similarity between a few exons that encode the antigen recognition domain (ARD) of the HLA protein. Next-generation sequencing (NGS) can identify HLA genetic polymorphisms in non-ARD-encoding exons, introns, and untranslated regions, but the impact of these polymorphisms on hematopoietic cell transplantation (HCT) outcome is unclear. We performed NGS-based sequencing of 11 HLA loci on a well-characterized retrospective cohort of 166 unrelated donor-recipient HCT pairs. Genetic differences between HCT pairs were identified and visualized using a novel bioinformatics approach that directly compares phased full-length HLA sequences. Our approach was able to correctly classify HCT pairs without known HLA allele-level mismatches and also to identify a subset of HLA allele-matched HCT pairs with very few to no genetic differences in the sequenced HLA regions. This highly HLA genetically matched unrelated HCT group shows improved overall survival and reduced acute graft-versus-host disease compared with HCT pairs with HLA allele-level mismatches. These results suggest that direct genetic matching of HLA loci may offer an additional means of HCT donor selection beyond traditional HLA allele comparisons and suggests that genetic similarity as defined by HLA sequencing may have a novel role in unrelated HCT donor selection. Finally, our approach can enable larger cohort studies with adequate power to detect differences in other HCT outcomes based on genetic similarity within the HLA loci.

Author List

Vazirabad I, Chhabra S, Nytes J, Mehra V, Narra RK, Szabo A, Jerkins JH, Dhakal B, Hari P, Anderson MW

Authors

Matthew W. Anderson MD, PhD Assistant Professor in the Pathology department at Medical College of Wisconsin
Saurabh Chhabra MD Associate Professor in the Medicine department at Medical College of Wisconsin
Binod Dhakal MD Associate Professor in the Medicine department at Medical College of Wisconsin
Parameswaran Hari MD Chief, Professor in the Medicine department at Medical College of Wisconsin
James H. Jerkins MD Assistant Professor in the Medicine department at Medical College of Wisconsin
Aniko Szabo PhD Professor in the Institute for Health and Equity department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adult
Alleles
Female
Graft vs Host Disease
HLA Antigens
Hematopoietic Stem Cell Transplantation
High-Throughput Nucleotide Sequencing
Histocompatibility
Histocompatibility Testing
Humans
Male
Middle Aged
Retrospective Studies
Survival Rate
Unrelated Donors
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a