HLA alleles and haplotypes observed in 263 US families

Osoegawa, Kazutoyo; Mallempati, Kalyan C.; Gangavarapu, Sridevi; Oki, Aqsa Sjuhada; Gendzekhadze, Ketevan; Marino, Susana R.; Brown, Nicholas K.; Bettinotti, María P.; Weimer, Eric T.; Montero‐Martin, Gonzalo; Creary, Lisa E.; Vayntrub, Tamara; Chang, Chia Jung; Askar, Medhat; Mack, Steven J.; Fernández-Viña, Marcelo

doi:10.1016/j.humimm.2019.05.018

Cited by 18 publications

(21 citation statements)

References 55 publications

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“…HLA genotypes were extracted in Histoimmunogenetics Markup Language (HML) format ( 21 ) and imported into 17 th International HLA and Immunogenetics Workshop (17 th IHIW) database ( 22 ). Some individuals in the extended families had no DNA, and missing HLA genotypes were manually imputed previously described ( 23 ). The allelic and genotypic (or “phase”) ambiguities were present in HLA genotypes due to the technical and methodological limitations, and reported previously ( 24 ).…”

Section: Methodsmentioning

confidence: 99%

High Resolution Haplotype Analyses of Classical HLA Genes in Families With Multiple Sclerosis Highlights the Role of HLA-DP Alleles in Disease Susceptibility

et al. 2021

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Multiple sclerosis (MS) susceptibility shows strong genetic associations with HLA alleles and haplotypes. We genotyped 11 HLA genes in 477 non-Hispanic European MS patients and their 954 unaffected parents using a validated next-generation sequencing (NGS) methodology. HLA haplotypes were assigned unequivocally by tracing HLA allele transmissions. We explored HLA haplotype/allele associations with MS using the genotypic transmission disequilibrium test (gTDT) and multiallelic TDT (mTDT). We also conducted a case-control (CC) study with all patients and 2029 healthy unrelated ethnically matched controls. We performed separate analyses of 54 extended multi-case families by reviewing transmission of haplotype blocks. The haplotype fragment including DRB5*01:01:01~DRB1*15:01:01:01 was significantly associated with predisposition (gTDT: p < 2.20e-16; mTDT: p =1.61e-07; CC: p < 2.22e-16) as reported previously. A second risk allele, DPB1*104:01 (gTDT: p = 3.69e-03; mTDT: p = 2.99e-03; CC: p = 1.00e-02), independent from the haplotype bearing DRB1*15:01 was newly identified. The allele DRB1*01:01:01 showed significant protection (gTDT: p = 8.68e-06; mTDT: p = 4.50e-03; CC: p = 1.96e-06). Two DQB1 alleles, DQB1*03:01 (gTDT: p = 2.86e-03; mTDT: p = 5.56e-02; CC: p = 4.08e-05) and DQB1*03:03 (gTDT: p = 1.17e-02; mTDT: p = 1.16e-02; CC: p = 1.21e-02), defined at two-field level also showed protective effects. The HLA class I block, A*02:01:01:01~C*03:04:01:01~B*40:01:02 (gTDT: p = 5.86e-03; mTDT: p = 3.65e-02; CC: p = 9.69e-03) and the alleles B*27:05 (gTDT: p = 6.28e-04; mTDT: p = 2.15e-03; CC: p = 1.47e-02) and B*38:01 (gTDT: p = 3.20e-03; mTDT: p = 6.14e-03; CC: p = 1.70e-02) showed moderately protective effects independently from each other and from the class II associated factors. By comparing statistical significance of 11 HLA loci and 19 haplotype segments with both untruncated and two-field allele names, we precisely mapped MS candidate alleles/haplotypes while eliminating false signals resulting from ‘hitchhiking’ alleles. We assessed genetic burden for the HLA allele/haplotype identified in this study. This family-based study including the highest-resolution of HLA alleles proved to be powerful and efficient for precise identification of HLA genotypes associated with both, susceptibility and protection to development of MS.

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Section: Methodsmentioning

confidence: 99%

High Resolution Haplotype Analyses of Classical HLA Genes in Families With Multiple Sclerosis Highlights the Role of HLA-DP Alleles in Disease Susceptibility

et al. 2021

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“…15 HLA-DRB1*14:54:01:01 was similarly included, due to its frequent occurrence in the population and use as a DR14 reference. 16,17 Alleles that were selected due to availability of extended UTR sequence include HLA- genotype data can be submitted for the 18th IHIW. Successive IPD-IMGT/HLA Database releases provide additional full-length sequences, which is reflected in the catalog of corresponding standard IHIW reference sequences.…”

Section: Selection Of Standard Reference Sequencesmentioning

confidence: 99%

“…For instance, HLA‐B*15:10:01:01 is included in addition to HLA‐B*15:01:01:01 group reference, due to the historical use of HLA‐B*15:10 as a B70 serotype reference 15 . HLA‐DRB1*14:54:01:01 was similarly included, due to its frequent occurrence in the population and use as a DR14 reference 16,17 . Alleles that were selected due to availability of extended UTR sequence include HLA‐B*27:05:02:01, HLA‐B*56:01:01:02, HLA‐C*03:03:01:01, HLA‐DRB1*08:02:01:01, HLA‐DRB1*15:01:01:02.…”

Section: International Hla and Immunogenetics Workhopmentioning

confidence: 99%

Standard reference sequences for submission of HLA genotyping for the 18th International HLA and Immunogenetics Workshop

Matern

Mack²,

Osoegawa

et al. 2021

HLA

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human leukocyte antigen (HLA) and Immunogenetics Workshops (IHIWs) have fostered international collaborations of researchers and experts in the fields of HLA, histocompatibility and immunology. These IHIW collaborations have comprised many projects focused on achieving a variety of specific goals. The international and collaborative nature of these projects necessitates the collection and analysis of complex data generated in multiple laboratories, often using multiple methods of acquisition. Collection and storage of these data in a consistent way adds value to IHIW projects, which can be extended to future work. DNA-based genotyping data, especially HLA genotyping data, can be transmitted in the form of a Histoimmunogenetics Markup Language (HML) document. HML facilitates clear communication of a genotype and supporting metadata, such as, sequencing platform, laboratory assays, consensus sequence, and interpretation. Sequence information can be reported relative to known reference sequences, which add meaning and context to genotypes. Selecting the correct reference sequence for a given allele sequence is nuanced, and guidelines have emerged through collaborative community efforts such as Data Standards Hackathons. Here, we describe the guidelines established for the selection of reference sequences to be used in transmission of HLA (and MICA/MICB) genotyping data for the 18th IHIW.

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“…The classical MHC-I genes are the human leukocyte antigen class I (HLA-I) genes HLA-A, HLA-B, and HLA-C. Each gene is polymorphic with multiple allelic variations, and more than 19,000 alleles were listed for classical HLA-I genes on the IPD-IMGT/HLA Database as of May 2020 11 . Allelic variants of individual genes frequently occur as groups of co-inherited alleles called haplotypes 12 , which are jointly implicated in various disease susceptibilities 13 . The non-classical MHC-I genes encode HLA-E, HLA-F, HLA-G, cluster of differentiation 1 (CD1), and MHC-related protein 1 (MR1).…”

Section: Introductionmentioning

confidence: 99%

Variations in MHC class I antigen presentation and immunopeptidome selection pathways

2020

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Major histocompatibility class I (MHC-I) proteins mediate immunosurveillance against pathogens and cancers by presenting antigenic or mutated peptides to antigen receptors of CD8+ T cells and by engaging receptors of natural killer (NK) cells. In humans, MHC-I molecules are highly polymorphic. MHC-I variations permit the display of thousands of distinct peptides at the cell surface. Recent mass spectrometric studies have revealed unique and shared characteristics of the peptidomes of individual MHC-I variants. The cell surface expression of MHC-I–peptide complexes requires the functions of many intracellular assembly factors, including the transporter associated with antigen presentation (TAP), tapasin, calreticulin, ERp57, TAP-binding protein related (TAPBPR), endoplasmic reticulum aminopeptidases (ERAPs), and the proteasomes. Recent studies provide important insights into the structural features of these factors that govern MHC-I assembly as well as the mechanisms underlying peptide exchange. Conformational sensing of MHC-I molecules mediates the quality control of intracellular MHC-I assembly and contributes to immune recognition by CD8 at the cell surface. Recent studies also show that several MHC-I variants can follow unconventional assembly routes to the cell surface, conferring selective immune advantages that can be exploited for immunotherapy.

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HLA alleles and haplotypes observed in 263 US families

Cited by 18 publications

References 55 publications

High Resolution Haplotype Analyses of Classical HLA Genes in Families With Multiple Sclerosis Highlights the Role of HLA-DP Alleles in Disease Susceptibility

High Resolution Haplotype Analyses of Classical HLA Genes in Families With Multiple Sclerosis Highlights the Role of HLA-DP Alleles in Disease Susceptibility

Standard reference sequences for submission of HLA genotyping for the 18th International HLA and Immunogenetics Workshop

Variations in MHC class I antigen presentation and immunopeptidome selection pathways

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