scholarly journals Exome-wide analysis of copy number variation shows association of the human leukocyte antigen region with asthma in UK Biobank

2021 ◽  
Author(s):  
Katherine A Fawcett ◽  
German Demidov ◽  
Nick Shrine ◽  
Megan L Paynton ◽  
Stephan Ossowski ◽  
...  
Keyword(s):  
Amino Acid ◽  
Fine Mapping ◽  
Copy Number ◽  
Amino Acid Change ◽  
Human Leukocyte ◽  
Uk Biobank ◽  
Sequencing Data ◽  
Leukocyte Antigen ◽  
Hla Dqa1

Background: The role of copy number variants (CNVs) in susceptibility to asthma is not well understood. This is, in part, due to the difficulty of accurately measuring CNVs in large enough sample sizes to detect associations. The recent availability of whole-exome sequencing (WES) in large biobank studies provides an unprecedented opportunity to study the role of CNVs in asthma. Methods: We called common CNVs in 49,953 individuals in the first release of UK Biobank WES using ClinCNV software. CNVs were tested for association with asthma in a stage 1 analysis comprising 7,098 asthma cases and 36,578 controls from the first release of sequencing data. Nominally-associated CNVs were then meta-analysed in stage 2 with an additional 17,280 asthma cases and 115,562 controls from the second release of UK Biobank exome sequencing, followed by validation and fine-mapping. Results: Five of 189 CNVs were associated with asthma in stage 2, including a deletion overlapping the HLA-DQA1 and HLA-DQB1 genes, a duplication of CHROMR/PRKRA, deletions within MUC22 and TAP2, and a duplication in FBRSL1. The HLA-DQA1, HLA-DQB1, MUC22 and TAP2 genes all reside within the human leukocyte antigen (HLA) region on chromosome 6. In silico analyses demonstrated that the deletion overlapping HLA-DQA1 and HLA-DQB1 is likely to be an artefact arising from under-mapping of reads from non-reference HLA haplotypes, and that the CHROMR/PRKRA and FBRSL1 duplications represent presence/absence of pseudogenes within the HLA region. Bayesian fine-mapping of the HLA region suggested that there are two independent asthma association signals. The variants with the largest posterior inclusion probability in the two credible sets were an amino acid change in HLA-DQB1 (glutamine to histidine at residue 253) and a multi-allelic amino acid change in HLA-DRB1 (presence/absence of serine, glycine or leucine at residue 11). Conclusions: At least two independent loci characterised by amino acid changes in the HLA-DQA1, HLA-DQB1 and HLA-DRB1 genes are likely to account for association of SNPs and CNVs in this region with asthma. The high divergence of haplotypes in the HLA can give rise to spurious CNVs, providing an important, cautionary tale for future large-scale analyses of sequencing data.

scholarly journals HATK: HLA analysis toolkit

2020 ◽  
Author(s):  
Wanson Choi ◽  
Yang Luo ◽  
Soumya Raychaudhuri ◽  
Buhm Han
Keyword(s):  
Amino Acid ◽  
Fine Mapping ◽  
Disease Susceptibility ◽  
Human Leukocyte ◽  
Amino Acid Sequences ◽  
Hla Typing ◽  
Amino Acid Residues ◽  
Leukocyte Antigen ◽  
Mapping Analysis ◽  
Visualization Tools

Abstract Summary Fine-mapping human leukocyte antigen (HLA) genes involved in disease susceptibility to individual alleles or amino acid residues has been challenging. Using information regarding HLA alleles obtained from HLA typing, HLA imputation or HLA inference, our software expands the alleles to amino acid sequences using the most recent IMGT/HLA database and prepares a dataset suitable for fine-mapping analysis. Our software also provides useful functionalities, such as various association tests, visualization tools and nomenclature conversion. Availability and implementation https://github.com/WansonChoi/HATK.

scholarly journals SweHLA: the high confidence HLA typing bio-resource drawn from 1000 Swedish genomes

2019 ◽  
Vol 28 (5) ◽  
pp. 627-635 ◽  
Author(s):  
Jessika Nordin ◽  
Adam Ameur ◽  
Kerstin Lindblad-Toh ◽  
Ulf Gyllensten ◽  
Jennifer R. S. Meadows
Keyword(s):  
Human Leukocyte ◽  
Class Ii ◽  
Hla Typing ◽  
Class I ◽  
Sequencing Data ◽  
High Confidence ◽  
Leukocyte Antigen ◽  
Hla Dqa1 ◽  
Inference Methods ◽  
Ngs Data

AbstractThere is a need to accurately call human leukocyte antigen (HLA) genes from existing short-read sequencing data, however there is no single solution that matches the gold standard of Sanger sequenced lab typing. Here we aimed to combine results from available software programs, minimizing the biases of applied algorithm and HLA reference. The result is a robust HLA population resource for the published 1000 Swedish genomes, and a framework for future HLA interrogation. HLA 2nd-field alleles were called using four imputation and inference methods for the classical eight genes (class I: HLA-A, HLA-B, HLA-C; class II: HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRB1). A high confidence population set (SweHLA) was determined using an n−1 concordance rule for class I (four software) and class II (three software) alleles. Results were compared across populations and individual programs benchmarked to SweHLA. Per gene, 875 to 988 of the 1000 samples were genotyped in SweHLA; 920 samples had at least seven loci called. While a small fraction of reference alleles were common to all software (class I = 1.9% and class II = 4.1%), this did not affect the overall call rate. Gene-level concordance was high compared to European populations (>0.83%), with COX and PGF the dominant SweHLA haplotypes. We noted that 15/18 discordant alleles (delta allele frequency >2) were previously reported as disease-associated. These differences could in part explain across-study genetic replication failures, reinforcing the need to use multiple software solutions. SweHLA demonstrates a way to use existing NGS data to generate a population resource agnostic to individual HLA software biases.

scholarly journals Fine mapping of the HLA locus in Parkinson’s disease in Europeans

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Eric Yu ◽  
Aditya Ambati ◽  
Maren Stolp Andersen ◽  
Lynne Krohn ◽  
Mehrdad A. Estiar ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Amino Acid ◽  
Multiple Comparisons ◽  
Diagnostic Significance ◽  
Specific Amino Acid ◽  
European Origin ◽  
Leukocyte Antigen ◽  
Hla Dqa1

AbstractWe fine mapped the leukocyte antigen (HLA) region in 13,770 Parkinson’s disease (PD) patients, 20,214 proxy-cases, and 490,861 controls of European origin. Four HLA types were associated with PD after correction for multiple comparisons, HLA-DQA1*03:01, HLA-DQB1*03:02, HLA-DRB1*04:01, and HLA-DRB1*04:04. Haplotype analyses followed by amino acid analysis and conditional analyses suggested that the association is protective and primarily driven by three specific amino acid polymorphisms present in most HLA-DRB1*04 subtypes—11V, 13H, and 33H (OR = 0.87, 95% CI: 0.83–0.90, p < 8.23 × 10−9 for all three variants). No other effects were present after adjustment for these amino acids. Our results suggest that specific HLA-DRB1 variants are associated with reduced risk of PD, providing additional evidence for the role of the immune system in PD. Although effect size is small and has no diagnostic significance, understanding the mechanism underlying this association may lead to the identification of new targets for therapeutics development.

scholarly journals CD8 T cells and antibodies drive SARS-CoV-2 evolution in chronic infection

2021 ◽  
Author(s):  
Elham Khatamzas ◽  
Maximilian Muenchhoff ◽  
Alexandra Rehn ◽  
Alexander Graf ◽  
Johannes Hellmuth ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Human Leukocyte ◽  
Sequencing Data ◽  
Plasma Therapy ◽  
Leukocyte Antigen ◽  
T Cell Recognition ◽  
First Time

Abstract ​​Since its recent zoonotic spill-over severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is constantly adapting to the human host as illustrated by the emergence of variants of concern with increased transmissibility and immune evasion. Prolonged replication in immunosuppressed individuals and evasion from spike-specific antibodies is known to drive intra-host SARS-CoV-2 evolution. Here we show for the first time the major role of CD8 T cells in SARS-CoV-2 evolution. In a patient with chronic, ultimately fatal infection, we observed three spike mutations that prevented neutralisation by convalescent plasma therapy. Moreover, at least four mutations in non-spike proteins emerged that hampered CD8 T-cell recognition of mutant epitopes, two of these occurred before spike mutations. A comparison with worldwide sequencing data showed that several of these T-cell escape mutations had emerged independently as homoplasies in multiple circulating lineages. We propose that human leukocyte antigen class I contributes to shaping the evolutionary landscape of SARS-CoV-2.

scholarly journals HLA alleles associated with asparaginase hypersensitivity in childhood ALL: a report from the DFCI Consortium

2020 ◽  
Vol 21 (8) ◽  
pp. 541-547 ◽  
Author(s):  
Vincent Gagné ◽  
Pascal St-Onge ◽  
Patrick Beaulieu ◽  
Caroline Laverdière ◽  
Jean-Marie Leclerc ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Human Leukocyte ◽  
Sequencing Data ◽  
Treatment Protocols ◽  
Childhood All ◽  
Hla Alleles ◽  
Leukocyte Antigen ◽  
Whole Exome ◽  
Whole Exome Sequencing Data ◽  
Hla Dqa1

Aim: To evaluate the association between human leukocyte antigen (HLA) alleles and native Escherichia coli asparaginase hypersensitivity (AH) in children with acute lymphoblastic leukemia (ALL) who received Dana-Farber Cancer Institute treatment protocols. Patients & methods: HLA-DQA1, HLA-DRB1 and HLA-DQB1 alleles were retrieved from available whole exome sequencing data of a subset of childhood ALL patients from Quebec ALL cohort and analyzed for an association with AH. PCR assay was developed to analyze associated alleles in the entire discovery and replication cohorts. Results: Two alleles in linkage disequilibrium ( HLA-DRB1*07:01 and DQA1*02:01) were associated with AH. Additional analyses, performed to distinguish between HLA-DRB1*07:01 haplotypes with and without DQB1*02:02 allele, showed that the association was dependent on the presence of DQB1*02:02. Conclusion: This study confirms the implication of HLA-DRB1*07:01, DQA1*02:01 and DQB1*02:02 alleles in developing AH in childhood ALL.

scholarly journals Transplantation for bone marrow failure: current issues

Hematology ◽  
2016 ◽  
Vol 2016 (1) ◽  
pp. 90-98 ◽  
Author(s):  
Régis Peffault de Latour
Keyword(s):  
Bone Marrow Failure ◽  
Clonal Evolution ◽  
Human Leukocyte ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Leukocyte Antigen ◽  
Sibling Donor ◽  
Alternative Donor

Abstract The preferred treatment of idiopathic aplastic anemia (AA) is allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen (HLA)–identical sibling donor. Transplantation from a well-matched unrelated donor (MUD) may be considered for patients without a sibling donor after failure of immunosuppressive therapy, as may alternative transplantation (mismatched, cord blood or haplo-identical HSCT) for patients without a MUD. HSCT may also be contemplated for congenital disorders in cases of pancytopenia or severe isolated cytopenia. Currently, HSCT aims are not only to cure patients but also to avoid long-term complications, notably chronic graft-versus-host disease (GVHD), essential for a good quality of life long term. This paper summarizes recent advances in HSCT for idiopathic and inherited AA disorders. The effect of age on current transplantation outcomes, the role of transplantation in paroxysmal nocturnal hemoglobinuria, and the prevention of GVHD are also discussed. Emerging strategies regarding the role of up-front unrelated donor and alternative donor HSCT in idiopathic AA, along with advances in the treatment of clonal evolution in Fanconi anemia, are also examined.

Narcolepsy: Differential Diagnosis or Etiology in Some Cases of Bipolar Disorder and Schizophrenia?

CNS Spectrums ◽  
2003 ◽  
Vol 8 (2) ◽  
pp. 120-126 ◽  
Author(s):  
Alan B. Douglass
Keyword(s):  
Bipolar Disorder ◽  
Differential Diagnosis ◽  
Psychiatric Patients ◽  
Human Leukocyte ◽  
Sleep Paralysis ◽  
Leukocyte Antigen ◽  
Psychotic Features ◽  
Hypnagogic Hallucinations ◽  
Rule Out

AbstractDoes narcolepsy, a neurological disease, need to be considered when diagnosing major mental illness? Clinicians have reported cases of narcolepsy with prominent hypnagogic hallucinations that were mistakenly diagnosed as schizophrenia. In some bipolar disorder patients with narcolepsy, the HH resulted in their receiving a more severe diagnosis (ie, bipolar disorder with psychotic features or schizoaffective disorder). The role of narcolepsy in psychiatric patients has remained obscure and problematic, and it may be more prevalent than commonly believed. Classical narcolepsy patients display the clinical “tetrad”—cataplexy, hypnagogic hallucinations, daytime sleep attacks, and sleep paralysis. Over 85% also display the human leukocyte antigen marker DQB10602 (subset of DQ6). Since 1998, discoveries in neuroanatomy and neurophysiology have greatly advanced the understanding of narcolepsy, which involves a nearly total loss of the recently discovered orexin/hypocretin (hypocretin) neurons of the hypothalamus, likely by an autoimmune mechanism. Hypocretin neurons normally supply excitatory signals to brainstem nuclei producing norepinephrine, serotonin, histamine, and dopamine, with resultant suppression of sleep. They also project to basal forebrain areas and cortex. A literature review regarding the differential diagnosis of narcolepsy, affective disorder, and schizophrenia is presented. Furthermore, it is now possible to rule out classical narcolepsy in difficult psychiatric cases. Surprisingly, psychotic patients with narcolepsy will likely require stimulants to fully recover. Many conventional antipsychotic drugs would worsen their symptoms and make them appear to become a “chronic psychotic,” while in fact they can now be properly diagnosed and treated.

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