Deriving HLA genotyping from whole genome sequencing data using Omixon HLA twin(tm) in G3’s global clinical study

Juhos, Szilveszter; Vago, Tunde; Ferriola, Deborah; Duke, Jamie L.; Vörös, Szilárd; Brown, Bradley O.; Marvasty, Idean; Hague, Tim; Monos, Dimitri

doi:10.1016/j.humimm.2015.07.183

Cited by 4 publications

(3 citation statements)

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“…Notably, most of the tools they studied achieved much higher accuracies than previously reported by Bauer et al, 2016, which emphasizes a drastic improvement in read coverage and processing in the MHC region ( Bauer et al, 2016 ). Finally, researchers successfully implemented these tools in association studies, promoting their importance for HLA-centric epidemiological studies ( Juhos et al, 2015 ; Xie et al, 2017 ; Mimori et al, 2019 ; Vince et al, 2020a ).…”

Section: Inferring and Imputing Hla Alleles: From Complex Read-mapping To The Study Of Linkage Disequilibriummentioning

confidence: 99%

Approaching Genetics Through the MHC Lens: Tools and Methods for HLA Research

et al. 2021

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The current SARS-CoV-2 pandemic era launched an immediate and broad response of the research community with studies both about the virus and host genetics. Research in genetics investigated HLA association with COVID-19 based on in silico, population, and individual data. However, they were conducted with variable scale and success; convincing results were mostly obtained with broader whole-genome association studies. Here, we propose a technical review of HLA analysis, including basic HLA knowledge as well as available tools and advice. We notably describe recent algorithms to infer and call HLA genotypes from GWAS SNPs and NGS data, respectively, which opens the possibility to investigate HLA from large datasets without a specific initial focus on this region. We thus hope this overview will empower geneticists who were unfamiliar with HLA to run MHC-focused analyses following the footsteps of the Covid-19|HLA & Immunogenetics Consortium.

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Section: Inferring and Imputing Hla Alleles: From Complex Read-mapping To The Study Of Linkage Disequilibriummentioning

confidence: 99%

Approaching Genetics Through the MHC Lens: Tools and Methods for HLA Research

et al. 2021

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“…However, there is no protocol for specific detection of the HLA-C*03:02 allele. HLA-C*03:02 genotyping methods for research purposes include saturated tiling capture sequencing, 10 next-generation sequencing, 11 whole-genome sequencing, 12 multiplex sequencing-based typing (SBT), 13,14 sequence-specific oligonucleotides (SSO), 9 and multiplex real-time PCR 15 which uses series of primer sets for analysis of multiple HLA loci. All of those methods are very costly and would be difficult to be applied in clinical settings for allopurinol personalized medicine.…”

Section: Introductionmentioning

confidence: 99%

A Novel Allele-Specific PCR Protocol for the Detection of the HLA-C*03:02 Allele, a Pharmacogenetic Marker, in Vietnamese Kinh People

Pham¹,

Tran²,

Sukasem³

et al. 2021

TACG

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Background: Allopurinol, a common anti-hyperuricemia drug, is well known as an inducer of severe cutaneous adverse drug reactions (SCARs). One of the most well-defined risk factors of allopurinol-induced SCARs is the presence of polymorphic alleles of human leukocyte antigen (HLA) genes, such as HLA-B*58:01 and HLA-C*03:02 alleles. There is no commercial test or published in-house protocol for the specific detection of the HLA-C*03 :02 allele. In this article, we established for the first time a simple allele-specific (AS) PCR method to identify HLA-C*03:02 allele carriers, and at the same time, determine their zygosities. Methods: A two-step AS-PCR protocol, using four primer sets, was designed to specifically amplify and differentiate the HLA-C*03:02 allele from 17 other HLA-C alleles found in Vietnamese people. The protocol was validated with PCR-sequencing-based typing (SBT) of 100 samples of unknown genotypes. Results: The PCR protocol can detect the HLA-C*03:02 allele and determine the zygosity. The results of this protocol were highly consistent with those of the SBT (ĸ = 0.98, p < 0.001). Regarding the specific detection of the HLA-C*03:02 allele, the PCR protocol had a sensitivity of 100% (95% CI: 91.61-100%) and specificity of 98.3% (95% CI: 90.9-99.7%). The protocol was used to determine the distribution of the HLA-C*03:02 allele in 810 unrelated Vietnamese Kinh people, 14.2% of which were HLA-C*03:02 carriers, the allele frequency was 7.5%. Conclusion: A novel AS-PCR protocol with a sensitivity of 100% for the detection of the HLA-C*03:02 allele was established. The protocol can be used for personalized treatment with allopurinol in order to minimize the risk of SCARs in Vietnamese people as well as in other Asian populations with similar genetic characteristics.

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“…35 HLA genotyping from whole-genome sequencing is also challenging and not as accurate as the clinical-grade HLA genotyping used in our study. Low sequence coverage 36 and low accuracy of HLA-genotyping tools 37 limit applicability of the TCGA database or other large and well-annotated cohorts for the topic of our study. Our prospective analysis demonstrates an increased rate of germline homozygosity for HLA-I alleles in EGA patients.…”

Section: Discussionmentioning

confidence: 99%

Germline homozygosity and allelic imbalance of HLA-I are common in esophagogastric adenocarcinoma and impair the repertoire of immunogenic peptides

Garcia-Marquez,

Thelen,

Bauer

et al. 2024

J Immunother Cancer

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BackgroundThe individual HLA-I genotype is associated with cancer, autoimmune diseases and infections. This study elucidates the role of germline homozygosity or allelic imbalance of HLA-I loci in esophago-gastric adenocarcinoma (EGA) and determines the resulting repertoires of potentially immunogenic peptides.MethodsHLA genotypes and sequences of either (1) 10 relevant tumor-associated antigens (TAAs) or (2) patient-specific mutation-associated neoantigens (MANAs) were used to predict good-affinity binders using an in silico approach for MHC-binding (www.iedb.org). Imbalanced or lost expression of HLA-I-A/B/C alleles was analyzed by transcriptome sequencing. FluoroSpot assays and TCR sequencing were used to determine peptide-specific T-cell responses.ResultsWe show that germline homozygosity of HLA-I genes is significantly enriched in EGA patients (n=80) compared with an HLA-matched reference cohort (n=7605). Whereas the overall mutational burden is similar, the repertoire of potentially immunogenic peptides derived from TAAs and MANAs was lower in homozygous patients. Promiscuity of peptides binding to different HLA-I molecules was low for most TAAs and MANAs and in silico modeling of the homozygous to a heterozygous HLA genotype revealed normalized peptide repertoires. Transcriptome sequencing showed imbalanced expression of HLA-I alleles in 75% of heterozygous patients. Out of these, 33% showed complete loss of heterozygosity, whereas 66% had altered expression of only one or two HLA-I molecules. In a FluoroSpot assay, we determined that peptide-specific T-cell responses against NY-ESO-1 are derived from multiple peptides, which often exclusively bind only one HLA-I allele.ConclusionThe high frequency of germline homozygosity in EGA patients suggests reduced cancer immunosurveillance leading to an increased cancer risk. Therapeutic targeting of allelic imbalance of HLA-I molecules should be considered in EGA.

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Deriving HLA genotyping from whole genome sequencing data using Omixon HLA twin(tm) in G3’s global clinical study

Cited by 4 publications

References 0 publications

Approaching Genetics Through the MHC Lens: Tools and Methods for HLA Research

Approaching Genetics Through the MHC Lens: Tools and Methods for HLA Research

A Novel Allele-Specific PCR Protocol for the Detection of the HLA-C*03:02 Allele, a Pharmacogenetic Marker, in Vietnamese Kinh People

Germline homozygosity and allelic imbalance of HLA-I are common in esophagogastric adenocarcinoma and impair the repertoire of immunogenic peptides

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