Key Points Array genotyping enables extensive blood cell antigen typing with >99.9% reproducibility across international laboratories.

Accurate antigen genotyping by array in diverse populations provides an opportunity to reduce alloimmunization by extended matching.

Category: Transfusion Medicine

Blood transfusions save millions of lives worldwide each year, yet formation of antibodies against non-self antigens remains a significant problem, particularly in frequently transfused patients. We designed and tested the Universal Blood Donor Typing (UBDT_PC1) array for automated high-throughput simultaneous typing of human erythroid, platelet, leukocyte, and neutrophil antigens (HEA, HPA, HLA, and HNA, respectively) to support selection of blood products matched beyond ABO/Rh. Typing samples from 6946 donors of European, African, Admixed American, South Asian, and East Asian ancestry at two different laboratories showed a genotype reproducibility of ≥99% for 17 244 variants, translating to 99.98%, 99.90%, and 99.93% concordance across 338 372 HEA, 53 270 HPA, and 107 094 HLA genotypes, respectively. Compared to previous clinical typing data, concordance was 99.9% and 99.6% for 245 874 HEA and 3726 HPA comparisons, respectively. HLA types were 99.1% concordant with clinical typing across 8130 comparisons, with imputation accuracy higher in Europeans versus non-Europeans. Seven variant RHD alleles, a GYPB deletion underlying the U− phenotype, and 14 high-frequency antigen negative types were also detected. Beyond blood typing, hereditary hemochromatosis-associated HFE variants were identified in 276 donors. We found that the UBDT_PC1 array can reliably type a wide range of blood cell antigens across diverse ancestries. Reproducibility and accuracy were retained when transfusion-relevant targets from the UBDT_PC1 array were incorporated into the UKBB_v2.2 genome-wide typing array. The results represent the potential for significant advancement towards improved patient care by reducing harm in transfused patients through extended matching.

Thermo Fisher Scientific (TFS) provides research funding to the Blood transfusion Genomics Consortium and is one of its founding members. J.G. and R.V. are TFS employees and N.S.G. and W.J.L. have consultancy agreements with TFS to provide computational and scientific support for research and development. A complete list of the BGC members appears in the supplemental Information. E.D.A. holds an NIHR Senior Investigator Award.

The participation by blood donors as study subjects is gratefully acknowledged. Samples and data from NHSBT donors were made available through the STRIDES NIHR BioResource, which is part of the STRIDES trial. A complete list of the investigators and contributors to the STRIDES trial is provided in reference.44 The trial was funded by NHS Blood and Transplant and the NIHR Blood and Transplant Research Unit in Donor Health and Behaviour (NIHR203337) (formerly Donor Health and Genomics; NIHR BTRU_2014_10024) and NHS Blood & Transplant (17_01_GEN). The academic coordinating centre of STRIDES at the Department of Public Health and Primary Care at the University of Cambridge received core support from the NIHR Blood and Transplant Research Unit (NIHR203337 and NIHR BTRU_2014_10024), British Heart Foundation (RG/13/13/30194; RG/18/13/33946) and NIHR Cambridge Biomedical Research Centre (BRC_1215_20014). The NIHR BioResource receives funding from the NIHR and the NIHR Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust, amongst others. Further funding for the study was received from NHSBT (grants 17_01_GEN; 20_01_GEN; G120400) for J.M. and N.S.G. and NIHR (grant G111294) for O.R. and O.S. We thank NIHR BioResource volunteers for their participation and acknowledge the funding from NIHR. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. The support provided by the Sanquin Blood Supply Foundation and National Screening laboratory of Sanquin is much appreciated, and the funding from Sanquin to support the study is acknowledged. We also acknowledge the contribution by the Australian government's funds for Lifeblood, which provides blood, blood products, and services to the Australian community. We also acknowledge the Finnish Red Cross Blood Service Biobank, and Drs. Satu Koskela and Jarmo Ritari for their help in providing samples from the Finnish blood donors. Research projects of J.P. are supported by the Finnish Research Council, VTR Funding from the Finnish Government, Cancer Foundation Finland, and Business Finland. Finally, we appreciate the support and resources provided by the South African National Blood Service.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Permission for the use of DNA samples and accompanying data was obtained from the respective internal review boards (IRB) for ARCLB (Daly-08052020); CBS (2020.062-REB-20210225); FRCBS (002-2018-1); NYBC (NY-JA-190 - SOP-0210); Sanquin (EAR-250920) and SANBS (SANBS-150920). NHS research ethics committee (REC) approval was granted for the use of the samples and data from NHSBT blood donors, who were enrolled in the STRIDES NIHR BioResource Research Tissue Bank (REC-22/EE/0230; NIHR BioResource studies: NBR89 and NBR179). Samples and data from Finnish subjects were obtained from the Blood Service Biobank of the FRCBS. Permission to execute the multicentre study was approved by the IRB from Thermo Fisher Scientific. The exchange of samples and study data between Members participating in the study is regulated by the Consortium and Members' Agreement for the BGC. The data used in our study were at the individual level. However, all data were properly de-identified before their use in this study. The blood service organisations that provided the samples were responsible for anonymising the data, and these organisations held all link tables connecting samples to personally identifiable information securely. Our research team at the BGC did not collect or have access to any personally identifiable data at any point during the study.

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