HLA-E typing of more than 2.5 million potential hematopoietic stem cell donors: Methods and population-specific allele frequencies

Sauter, Jürgen; Putke, Kathrin; Schefzyk, Daniel; Pruschke, Jens; Solloch, Ute V.; Bernas, Stefanie N.; Massalski, Carolin; Daniel, Keller; Klußmeier, Anja; Hofmann, Jan A.; Lange, Vinzenz; Schmidt, Alexander H.

doi:10.1016/j.humimm.2020.12.008

Cited by 20 publications

(12 citation statements)

References 36 publications

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“…We found the combined frequency in this cohort of HLA‐E * 01:01 and HLA‐E * 01:03 alleles was 97.5%, which is in line with the previously published data 7,8,16 . It should be noted however, that as this cohort is not a random population sample we acknowledge that allele frequencies presented from this cohort do not necessarily represent the true frequencies in populations.…”

Section: Assigned Allele Name Closest Allele Genomic Dna Mismatch Gen...supporting

confidence: 91%

“…11 We found the combined frequency in this cohort of HLA-E*01:01 and HLA-E*01:03 alleles was 97.5%, which is in line with the previously published data. 7,8,16 It should be noted however, that as this cohort is not a random population sample we acknowledge that allele frequencies presented from this cohort do not necessarily represent the true frequencies in populations. Across all samples in this cohort, we observed 19 unique protein variants and aside from HLA-E*01:01 and HLA-E*01:03, the next most frequently observed allele was HLA-E*01:06 at 2.0% (Figure 1).…”

mentioning

confidence: 98%

“…Previous research consistently showed the presence of two high frequency protein variants, HLA-E*01:01 and HLA-E*01:03, which accounted for 95%-100% of alleles sequenced across cohorts of individuals from a range of ethnicities, depending on the genotyping strategy used. 7,8 The difference between these proteins is an amino acid substitution in codon 107, arginine in HLA-E*01:01 and glycine in HLA-E*01:03, which is caused by a single nucleotide polymorphism (SNP) of A>G at genomic position 756 in exon 3. This amino acid change has little impact on the overall structure of the molecule, yet studies show the HLA-E*01:03 molecule has higher thermal stability and expression on the cell surface compared to HLA-E*01:01.…”

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confidence: 99%

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86 novel HLA‐E alleles discovered through full‐gene sequencing of 6227 hematopoietic cell transplant patients and unrelated donors

Lucas

Georgiou

Cooper

et al. 2022

HLA

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Until recently the number of alleles of the nonclassical HLA class I gene HLA‐E documented in the IPD‐IMGT/HLA Database was small and as a result, the gene was often not considered to be notably polymorphic. Here, we describe our work in identifying and submitting 86 novel HLA‐E alleles after full‐gene single‐molecule real‐time (SMRT) DNA sequencing of 6227 DNA samples. These samples were comprised of 2468 patients undergoing hematopoietic cell transplantation and 3759 unrelated potential donors. A total of 111 unique HLA‐E alleles were detected in this cohort. The majority of novel alleles (79.1%) contained polymorphisms in intronic regions, highlighting the significant undiscovered variation present in the noncoding regions of the HLA‐E gene.

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Section: Assigned Allele Name Closest Allele Genomic Dna Mismatch Gen...supporting

confidence: 91%

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confidence: 98%

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confidence: 99%

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86 novel HLA‐E alleles discovered through full‐gene sequencing of 6227 hematopoietic cell transplant patients and unrelated donors

Lucas

Georgiou

Cooper

et al. 2022

HLA

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“…47 Indeed, a recent paper using data from the 100K genomes project and confirmatory sequencing identified intronic polymorphism in HLA-DRA and a plethora of DRB1 associations. 48 While only two different DRA proteins were known to exist, identification of intronic polymorphisms shows that the gene is more diverse than previously thought, continuing a trend in the field recently observed for HLA-E. 49,50 Recently, DP haplotypes (spanning DPA1, DPB1 and their intergenic region) were shown to contain previously unknown polymorphism around the promotor, with potentially functional consequences. 51 We observed in some additional cell lines (not included in this study) that despite successful amplification of most loci, we were unable to obtain PCR products for some.…”

Section: Discussionmentioning

confidence: 97%

Widespread non‐coding polymorphism in HLA class II genes of International HLA and Immunogenetics Workshop cell lines

Turner

Hayward

Gymer

et al. 2022

HLA

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As the primary genetic determinant of immune recognition of self and non‐self, the hyperpolymorphic HLA genes play key roles in disease association and transplantation. The large, variably sized HLA class II genes have historically been less well characterized than the shorter HLA class I genes. Here, we have used Pacific Biosciences Single Molecule Real‐Time (SMRT®) DNA sequencing to perform four‐field resolution HLA typing of HLA‐DRB1/3/4/5, ‐DQA1, ‐DQB1, ‐DPA1 and ‐DPB1 from a panel of 181 B‐lymphoblastoid cell lines from the International HLA and Immunogenetics Workshops. By interrogating all exons, introns, and the untranslated regions of these important reference cells, we have improved their HLA typing resolution on the IPD‐IMGT/HLA database. We observed widespread non‐coding polymorphism, with over twice as many unique genomic sequences identified compared with coding sequences (CDS). We submitted 263 unique sequences to the IPD‐IMGT/HLA Database, often from multiple cell lines, including 114 confirmations of existing alleles, of which 30 were also extensions to full‐length genomic sequences where only CDS was available previously. A total of 149 novel alleles were identified, largely differing from their closest reference allele sequences by a single nucleotide polymorphism (SNP). However, some highly divergent alleles were deemed to be recombinants, only detectable by full‐length sequencing with long, phased reads. The fourth‐field variation we observed allowed fine mapping of linkage disequilibrium patterns and haplotypes to particular ancestries. This study has highlighted the under‐appreciated non‐coding diversity in HLA class II genes, with potential implications for population genetic and clinical studies.

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“…For HLA-E, the typing method has long been limited to resolve the dimorphic amino acid at position 107 (R or G) by either PCR-SSP (PCR with Sequence-Specific Primers (194)(195)(196)(197), PCR-SSO (PCR-Sequence Specific Oligo Probes (198), PCR-RFLP (PCR Restriction Fragment Length Polymorphism) alone (199) or in combination with ARMS (Amplification Refractory Mutation System) (200), PCR-SSCP (PCR-single strand conformation polymorphism) (201), Taqman assay (202) or sequence based typing of a limited part of the HLA-E gene either by Sanger sequencing (203)(204)(205)(206)(207) or recently also by NGS with Illumina (208). In this latter study HLA-E was typed for over 2.5 million potential stem cell donors worldwide and although only a limited 535 bp amplicon (including last part of exon 2, intron 2 and first part of exon 3) was sequenced, it has caused an explosion of new HLA-E alleles (209).…”

Section: Non-classical Hla Class I Determinationmentioning

confidence: 99%

HLA Class I Molecules as Immune Checkpoints for NK Cell Alloreactivity and Anti-Viral Immunity in Kidney Transplantation

et al. 2021

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Natural killer (NK) cells are innate lymphocytes that can kill diseased- or virally-infected cells, mediate antibody dependent cytotoxicity and produce type I immune-associated cytokines upon activation. NK cells also contribute to the allo-immune response upon kidney transplantation either by promoting allograft rejection through lysis of cells of the transplanted organ or by promoting alloreactive T cells. In addition, they protect against viral infections upon transplantation which may be especially relevant in patients receiving high dose immune suppression. NK cell activation is tightly regulated through the integrated balance of signaling via inhibitory- and activating receptors. HLA class I molecules are critical regulators of NK cell activation through the interaction with inhibitory- as well as activating NK cell receptors, hence, HLA molecules act as critical immune checkpoints for NK cells. In the current review, we evaluate how NK cell alloreactivity and anti-viral immunity are regulated by NK cell receptors belonging to the KIR family and interacting with classical HLA class I molecules, or by NKG2A/C and LILRB1/KIR2DL4 engaging non-classical HLA-E or -G. In addition, we provide an overview of the methods to determine genetic variation in these receptors and their HLA ligands.

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HLA-E typing of more than 2.5 million potential hematopoietic stem cell donors: Methods and population-specific allele frequencies

Cited by 20 publications

References 36 publications

86 novel HLA‐E alleles discovered through full‐gene sequencing of 6227 hematopoietic cell transplant patients and unrelated donors

86 novel HLA‐E alleles discovered through full‐gene sequencing of 6227 hematopoietic cell transplant patients and unrelated donors

Widespread non‐coding polymorphism in HLA class II genes of International HLA and Immunogenetics Workshop cell lines

HLA Class I Molecules as Immune Checkpoints for NK Cell Alloreactivity and Anti-Viral Immunity in Kidney Transplantation

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