Complete nucleotide sequence characterization of DRB5 alleles reveals a homogeneous allele group that is distinct from other DRB genes

Barsakis, Konstantinos; Babrzadeh, Farbod; Chi, Anjo; Mallempati, Kalyan C.; Pickle, William; Mindrinos, Michael; Fernández-Viña, Marcelo

doi:10.1016/j.humimm.2019.04.001

Cited by 6 publications

(2 citation statements)

References 69 publications

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“…The allelic and genotypic (or “phase”) ambiguities were present in HLA genotypes due to the technical and methodological limitations, and reported previously ( 24 ). We included the ambiguities for the haplotype analyses ( 24 , 25 ), but reported only the lowest-digit allele name in this manuscript, e.g. HLA-DRB1*15:01:01:01 .…”

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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“…This typing was a DRB5 *01:08:01N where no transcripts were identified by RNA-Seq, even after repeat testing was performed. While mRNA transcripts of this null allele are likely produced, transcript levels were likely extremely low, possibly due to intracellular degradation as a result of its early transcript termination ( Voorter et al, 1997 ; Barsakis et al, 2019 ). This is a limitation for any RNA-based HLA typing method compared to a genomic DNA NGS typing method.…”

Section: Discussionmentioning

confidence: 99%

Unique Molecular Identifier-Based High-Resolution HLA Typing and Transcript Quantitation Using Long-Read Sequencing

et al. 2022

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HLA typing provides essential results for stem cell and solid organ transplants, as well as providing diagnostic benefits for various rheumatology, gastroenterology, neurology, and infectious diseases. It is becoming increasingly clear that understanding the expression of patient HLA transcripts can provide additional benefits for many of these same patient groups. Our study cohort was evaluated using a long-read RNA sequencing methodology to provide rapid HLA genotyping results and normalized HLA transcript expression. Our assay used NGSEngine to determine the HLA genotyping result and normalized mRNA transcript expression using Athlon2. The assay demonstrated an excellent concordance rate of 99.7%. Similar to previous studies, for the class I loci, patients demonstrated significantly lower expression of HLA-C than HLA-A and -B (Mann–Whitney U, p value = 0.0065 and p value = 0.0154, respectively). In general, the expression of class II transcripts was lower than that of class I transcripts. This study demonstrates a rapid high-resolution HLA typing assay using RNA-Seq that can provide accurate HLA genotyping and HLA allele-specific transcript expression in 7–8 h, a timeline short enough to perform the assay for deceased donors.

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Preface: 17th International HLA and Immunogenetics Workshop

Vayntrub

Mack²,

Fernández-Viña

2020

Human Immunology

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Complete nucleotide sequence characterization of DRB5 alleles reveals a homogeneous allele group that is distinct from other DRB genes

Cited by 6 publications

References 69 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

Unique Molecular Identifier-Based High-Resolution HLA Typing and Transcript Quantitation Using Long-Read Sequencing

Preface: 17th International HLA and Immunogenetics Workshop

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