Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 11.910
Filtrar
1.
Int J Mol Sci ; 22(9)2021 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-34066804

RESUMO

The elderly and patients with several comorbidities experience more severe cases of coronavirus disease 2019 (COVID-19) than healthy patients without underlying medical conditions. However, it is unclear why these people are prone to developing alveolar pneumonia, rapid exacerbations, and death. Therefore, we hypothesized that people with comorbidities may have a genetic predisposition that makes them more vulnerable to various factors; for example, they are likely to become more severely ill when infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To test this hypothesis, we searched the literature extensively. Polymorphisms of genes, such as those that encode angiotensin-converting enzyme 1 (ACE1), have been associated with numerous comorbidities, such as cardiovascular disease, hypertension, diabetes, chronic kidney disease, and obesity, and there are potential mechanisms to explain these associations (e.g., DD-type carriers have greater ACE1 activity, and patients with a genetic alpha-1 anti-trypsin (AAT) deficiency lack control over inflammatory mediators). Since comorbidities are associated with chronic inflammation and are closely related to the renin-angiotensin-aldosterone system (RAAS), these individuals may already have a mild ACE1/ACE2 imbalance before viral infection, which increases their risk for developing severe cases of COVID-19. However, there is still much debate about the association between ACE1 D/I polymorphism and comorbidities. The best explanation for this discrepancy could be that the D allele and DD subtypes are associated with comorbidities, but the DD genotype alone does not have an exceptionally large effect. This is also expected since the ACE1 D/I polymorphism is only an intron marker. We also discuss how polymorphisms of AAT and other genes are involved in comorbidities and the severity of SARS-CoV-2 infection. Presumably, a combination of multiple genes and non-genetic factors is involved in the establishment of comorbidities and aggravation of COVID-19.


Assuntos
COVID-19/genética , Predisposição Genética para Doença , Peptidil Dipeptidase A/genética , Idoso , Alelos , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , COVID-19/metabolismo , COVID-19/fisiopatologia , COVID-19/virologia , Comorbidade , Antígenos HLA/genética , Antígenos HLA/metabolismo , Haplótipos , Humanos , Inflamação/genética , Inflamação/metabolismo , Homem de Neandertal/genética , Peptidil Dipeptidase A/metabolismo , Polimorfismo Genético , Fatores de Risco , Índice de Gravidade de Doença
2.
BMC Bioinformatics ; 22(1): 231, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33952199

RESUMO

BACKGROUND: Epitope prediction is a useful approach in cancer immunology and immunotherapy. Many computational methods, including machine learning and network analysis, have been developed quickly for such purposes. However, regarding clinical applications, the existing tools are insufficient because few of the predicted binding molecules are immunogenic. Hence, to develop more potent and effective vaccines, it is important to understand binding and immunogenic potential. Here, we observed that the interactive association constituted by human leukocyte antigen (HLA)-peptide pairs can be regarded as a network in which each HLA and peptide is taken as a node. We speculated whether this network could detect the essential interactive propensities embedded in HLA-peptide pairs. Thus, we developed a network-based deep learning method called DeepNetBim by harnessing binding and immunogenic information to predict HLA-peptide interactions. RESULTS: Quantitative class I HLA-peptide binding data and qualitative immunogenic data (including data generated from T cell activation assays, major histocompatibility complex (MHC) binding assays and MHC ligand elution assays) were retrieved from the Immune Epitope Database database. The weighted HLA-peptide binding network and immunogenic network were integrated into a network-based deep learning algorithm constituted by a convolutional neural network and an attention mechanism. The results showed that the integration of network centrality metrics increased the power of both binding and immunogenicity predictions, while the new model significantly outperformed those that did not include network features and those with shuffled networks. Applied on benchmark and independent datasets, DeepNetBim achieved an AUC score of 93.74% in HLA-peptide binding prediction, outperforming 11 state-of-the-art relevant models. Furthermore, the performance enhancement of the combined model, which filtered out negative immunogenic predictions, was confirmed on neoantigen identification by an increase in both positive predictive value (PPV) and the proportion of neoantigen recognition. CONCLUSIONS: We developed a network-based deep learning method called DeepNetBim as a pan-specific epitope prediction tool. It extracted the attributes of the network as new features from HLA-peptide binding and immunogenic models. We observed that not only did DeepNetBim binding model outperform other updated methods but the combination of our two models showed better performance. This indicates further applications in clinical practice.


Assuntos
Aprendizado Profundo , Algoritmos , Epitopos , Antígenos HLA/genética , Antígenos HLA/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Classe II , Humanos , Ligação Proteica
3.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 46(4): 404-413, 2021 Apr 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-33967088

RESUMO

The human leukocyte antigen (HLA) molecules encoded within the human major histocompatibility complex are a group of highly conserved cell surface proteins, which are related to antigen recognition. HLA genes display a high degree of genetic polymorphism, which is the basis of individual differences in immunity. Specific HLA genotypes have been highly associated with typical adverse drug reactions. HLA-A*31:01 and HLA-B*15:02 are associated with carbamazepine-induced severe cutaneous adverse reactions, HLA-B*57:01 is related to abacavir-induced drug-induced hypersensitivity syndrome and flucloxacillin/pazopanib-induced drug-induced liver injury, while HLA-B*35:01 is a potential biomarker for predicting polygonum multiflorum-induced liver injury. It is not clear how small drug molecules to interact with HLA molecules and T cell receptors (TCR). There are four mechanistic hypotheses, including the hapten/prohapten theory, the pharmacological interaction concept, the altered peptide repertoire model, and the altered TCR repertoire model.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Genótipo , Antígenos HLA/genética , Humanos , Polimorfismo Genético
5.
Lancet Oncol ; 22(4): 548-557, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33794208

RESUMO

BACKGROUND: Most uterine cervical high-risk human papillomavirus (HPV) infections are transient, with only a small fraction developing into cervical cancer. Family aggregation studies and heritability estimates suggest a significant inherited genetic component. Candidate gene studies and previous genome-wide association studies (GWASs) report associations between the HLA region and cervical cancer. Adopting a genome-wide approach, we aimed to compare genetic variation in women with invasive cervical cancer and cervical intraepithelial neoplasia (CIN) grade 3 with that in healthy controls. METHODS: We did a GWAS in a cohort of unrelated European individuals using data from UK Biobank, a population-based cohort including 273 377 women aged 40-69 years at recruitment between March 13, 2006, and Oct 1, 2010. We used an additive univariate logistic regression model to analyse genetic variants associated with invasive cervical cancer or CIN3. We sought replication of candidate associations in FinnGen, a large independent dataset of 128 123 individuals. We also did a two-sample mendelian randomisation approach to explore the role of risk factors in the genetic risk of cervical cancer. FINDINGS: We included 4769 CIN3 and invasive cervical cancer case samples and 145 545 control samples in the GWAS. Of 9 600 464 assayed and imputed single-nucleotide polymorphisms (SNPs), six independent variants were associated with CIN3 and invasive cervical cancer. These included novel loci rs10175462 (PAX8; odds ratio [OR] 0·87, 95% CI 0·84-0·91; p=1·07 × 10-9) and rs27069 (CLPTM1L; 0·88, 0·84-0·92; p=2·51 × 10-9), and previously reported signals at rs9272050 (HLA-DQA1; 1·27, 1·21-1·32; p=2·51 × 10-28), rs6938453 (MICA; 0·79, 0·75-0·83; p=1·97 × 10-17), rs55986091 (HLA-DQB1; 0·66, 0·60-0·72; p=6·42 × 10-28), and rs9266183 (HLA-B; 0·73, 0·64-0·83; p=1·53 × 10-6). Three SNPs were replicated in the independent Finnish dataset of 1648 invasive cervical cancer cases: PAX8 (rs10175462; p=0·015), CLPTM1L (rs27069; p=2·54 × 10-7), and HLA-DQA1 (rs9272050; p=7·90 × 10-8). Mendelian randomisation further supported the complementary role of smoking (OR 2·46, 95% CI 1·64-3·69), older age at first pregnancy (0·80, 0·68-0·95), and number of sexual partners (1·95, 1·44-2·63) in the risk of developing cervical cancer. INTERPRETATION: Our results provide new evidence for the genetic susceptibility to cervical cancer, specifically the PAX8, CLPTM1L, and HLA genes, suggesting disruption in apoptotic and immune function pathways. Future studies integrating host and viral, genetic, and epigenetic variation, could further elucidate complex host-viral interactions. FUNDING: NIHR Imperial BRC Wellcome 4i Clinician Scientist Training Programme.


Assuntos
Neoplasia Intraepitelial Cervical/genética , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , Fator de Transcrição PAX8/genética , Neoplasias do Colo do Útero/genética , Adulto , Idoso , Neoplasia Intraepitelial Cervical/patologia , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Antígenos HLA/genética , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Neoplasias do Colo do Útero/patologia
6.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807854

RESUMO

We observed substantial differences in predicted Major Histocompatibility Complex II (MHCII) epitope presentation of SARS-CoV-2 proteins for different populations but only minor differences in predicted MHCI epitope presentation. A comparison of this predicted epitope MHC-coverage revealed for the early phase of infection spread (till day 15 after reaching 128 observed infection cases) highly significant negative correlations with the case fatality rate. Specifically, this was observed in different populations for MHC class II presentation of the viral spike protein (p-value: 0.0733 for linear regression), the envelope protein (p-value: 0.023), and the membrane protein (p-value: 0.00053), indicating that the high case fatality rates of COVID-19 observed in some countries seem to be related with poor MHC class II presentation and hence weak adaptive immune response against these viral envelope proteins. Our results highlight the general importance of the SARS-CoV-2 structural proteins in immunological control in early infection spread looking at a global census in various countries and taking case fatality rate into account. Other factors such as health system and control measures become more important after the early spread. Our study should encourage further studies on MHCII alleles as potential risk factors in COVID-19 including assessment of local populations and specific allele distributions.


Assuntos
COVID-19/mortalidade , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , SARS-CoV-2/química , Proteínas Estruturais Virais/química , Imunidade Adaptativa , Alelos , COVID-19/imunologia , COVID-19/transmissão , Biologia Computacional/métodos , Correlação de Dados , Epitopos de Linfócito B/genética , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Antígenos HLA/genética , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Mortalidade , SARS-CoV-2/imunologia , Proteínas Estruturais Virais/imunologia
7.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807915

RESUMO

Coronavirus disease 2019 (COVID-19) is induced by SARS-CoV-2 and may arise as a variety of clinical manifestations, ranging from an asymptomatic condition to a life-threatening disease associated with cytokine storm, multiorgan and respiratory failure. The molecular mechanism behind such variability is still under investigation. Several pieces of experimental evidence suggest that genetic variants influencing the onset, maintenance and resolution of the immune response may be fundamental in predicting the evolution of the disease. The identification of genetic variants behind immune system reactivity and function in COVID-19 may help in the elaboration of personalized therapeutic strategies. In the frenetic look for universally shared treatment plans, those genetic variants that are common to other diseases/models may also help in addressing future research in terms of drug repurposing. In this paper, we discuss the most recent updates about the role of immunogenetics in determining the susceptibility to and the history of SARS-CoV-2 infection. We propose a narrative review of available data, speculating about lessons that we have learnt from other viral infections and immunosenescence, and discussing what kind of aspects of research should be deepened in order to improve our knowledge of how host genetic variability impacts the outcome for COVID-19 patients.


Assuntos
COVID-19/imunologia , Imunogenética , Sistema ABO de Grupos Sanguíneos/imunologia , COVID-19/sangue , COVID-19/epidemiologia , COVID-19/genética , Suscetibilidade a Doenças/imunologia , Predisposição Genética para Doença , Antígenos HLA/sangue , Antígenos HLA/genética , Antígenos HLA/imunologia , Humanos , Imunidade/genética , Índice de Gravidade de Doença
8.
Nat Commun ; 12(1): 1639, 2021 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-33712626

RESUMO

Conventional human leukocyte antigen (HLA) imputation methods drop their performance for infrequent alleles, which is one of the factors that reduce the reliability of trans-ethnic major histocompatibility complex (MHC) fine-mapping due to inter-ethnic heterogeneity in allele frequency spectra. We develop DEEP*HLA, a deep learning method for imputing HLA genotypes. Through validation using the Japanese and European HLA reference panels (n = 1,118 and 5,122), DEEP*HLA achieves the highest accuracies with significant superiority for low-frequency and rare alleles. DEEP*HLA is less dependent on distance-dependent linkage disequilibrium decay of the target alleles and might capture the complicated region-wide information. We apply DEEP*HLA to type 1 diabetes GWAS data from BioBank Japan (n = 62,387) and UK Biobank (n = 354,459), and successfully disentangle independently associated class I and II HLA variants with shared risk among diverse populations (the top signal at amino acid position 71 of HLA-DRß1; P = 7.5 × 10-120). Our study illustrates the value of deep learning in genotype imputation and trans-ethnic MHC fine-mapping.


Assuntos
Aprendizado Profundo , Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença/genética , Antígenos HLA/genética , Complexo Principal de Histocompatibilidade/genética , Alelos , Grupos de Populações Continentais , Grupos Étnicos/genética , Estudo de Associação Genômica Ampla , Genótipo , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Desequilíbrio de Ligação
9.
Vet J ; 270: 105612, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33641811

RESUMO

Part 1 of this 2-part review outlined the importance of disease classification in diabetes genetic studies, as well as the ways in which genetic variants may contribute to risk of a complex disease within an individual, or within a particular group of individuals. Part 2, presented here, describes in more detail our current understanding of the genetics of canine diabetes mellitus compared to our knowledge of the human disease. Ongoing work to improve our knowledge, using new technologies, is also introduced.


Assuntos
Diabetes Mellitus/veterinária , Doenças do Cão/genética , Predisposição Genética para Doença/genética , Animais , Diabetes Mellitus/classificação , Diabetes Mellitus/genética , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Doenças do Cão/classificação , Doenças do Cão/imunologia , Cães , Antígenos HLA/genética , Antígenos HLA/imunologia , Sequenciamento de Nucleotídeos em Larga Escala/veterinária , Humanos , Imunidade/genética , Células Secretoras de Insulina/imunologia , Complexo Principal de Histocompatibilidade/genética , Mutação
10.
Front Immunol ; 12: 598778, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33717077

RESUMO

Emerging infectious diseases (EIDs) caused by viruses are increasing in frequency, causing a high disease burden and mortality world-wide. The COVID-19 pandemic caused by the novel SARS-like coronavirus (SARS-CoV-2) underscores the need to innovate and accelerate the development of effective vaccination strategies against EIDs. Human leukocyte antigen (HLA) molecules play a central role in the immune system by determining the peptide repertoire displayed to the T-cell compartment. Genetic polymorphisms of the HLA system thus confer a strong variability in vaccine-induced immune responses and may complicate the selection of vaccine candidates, because the distribution and frequencies of HLA alleles are highly variable among different ethnic groups. Herein, we build on the emerging paradigm of rational epitope-based vaccine design, by describing an immunoinformatics tool (Predivac-3.0) for proteome-wide T-cell epitope discovery that accounts for ethnic-level variations in immune responsiveness. Predivac-3.0 implements both CD8+ and CD4+ T-cell epitope predictions based on HLA allele frequencies retrieved from the Allele Frequency Net Database. The tool was thoroughly assessed, proving comparable performances (AUC ~0.9) against four state-of-the-art pan-specific immunoinformatics methods capable of population-level analysis (NetMHCPan-4.0, Pickpocket, PSSMHCPan and SMM), as well as a strong accuracy on proteome-wide T-cell epitope predictions for HIV-specific immune responses in the Japanese population. The utility of the method was investigated for the COVID-19 pandemic, by performing in silico T-cell epitope mapping of the SARS-CoV-2 spike glycoprotein according to the ethnic context of the countries where the ChAdOx1 vaccine is currently initiating phase III clinical trials. Potentially immunodominant CD8+ and CD4+ T-cell epitopes and population coverages were predicted for each population (the Epitope Discovery mode), along with optimized sets of broadly recognized (promiscuous) T-cell epitopes maximizing coverage in the target populations (the Epitope Optimization mode). Population-specific epitope-rich regions (T-cell epitope clusters) were further predicted in protein antigens based on combined criteria of epitope density and population coverage. Overall, we conclude that Predivac-3.0 holds potential to contribute in the understanding of ethnic-level variations of vaccine-induced immune responsiveness and to guide the development of epitope-based next-generation vaccines against emerging pathogens, whose geographic distributions and populations in need of vaccinations are often well-defined for regional epidemics.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , Epitopos de Linfócito T/metabolismo , Grupos Étnicos , Antígenos HLA/metabolismo , Proteômica/métodos , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/metabolismo , COVID-19/epidemiologia , Vacinas contra COVID-19 , Doenças Transmissíveis Emergentes , Epitopos de Linfócito T/genética , Antígenos HLA/genética , Humanos , Imunogenicidade da Vacina , Aplicações da Informática Médica , Pandemias/prevenção & controle , Polimorfismo Genético , Ligação Proteica , Software , Glicoproteína da Espícula de Coronavírus/genética
11.
Methods Mol Biol ; 2212: 225-243, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33733359

RESUMO

Unraveling the complex biological mechanisms underlying human health and disease is a great challenge. With genomic data, many aspects can be investigated in great detail, such as interactions between different genetic variants as well as their effects on one or multiple traits. Modeling epistasis and pleiotropy jointly necessitates appropriate statistical methods. A suitable tool for this is C-JAMP, which is a recently proposed method based on copula functions. In this chapter, we outline C-JAMP and how it can be applied to investigate epistatic effects on multiple traits to advance our understanding of biological processes. We further discuss important aspects of this area of research, such as polygenic risk scores and ancestry-specific modeling, which we propose to include in future extensions of the software.


Assuntos
Epistasia Genética , Pleiotropia Genética , Antígenos HLA/genética , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Software , Bancos de Espécimes Biológicos , Índice de Massa Corporal , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Fenótipo , Estudos Prospectivos , Locos de Características Quantitativas , Característica Quantitativa Herdável , Reino Unido , Relação Cintura-Quadril
12.
Front Immunol ; 12: 632890, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33732254

RESUMO

Coronavirus disease-19 (COVID-19) in children is usually mild but some are susceptible to a Kawasaki disease (KD)-like multisystem inflammatory syndrome in children (MIS-C) in the convalescent stage, posing a need to differentiate the phenotype, susceptibility, autoimmunity, and immunotherapy between KD and MIS-C, particularly in the upcoming mass vaccination of COVID-19. Patients with MIS-C are prone to gastrointestinal symptoms, coagulopathy, and shock in addition to atypical KD syndrome with fever, mucocutaneous lesions, lymphadenopathy, and/or cardiovascular events. MIS-C manifests KD-like symptoms that alert physicians to early recognize and adopt the KD treatment regimen for patients with MIS-C. MIS-C linked to COVID-19 teaches us infection-associated autoimmune vasculitis and vice versa. Studies on genetic susceptibility have identified certain human leukocyte antigen (HLA) locus and toll-like receptor (TLR) associated with KD and/or COVID-19. Certain HLA subtypes, such as HLA-DRB1 and HLA-MICA A4 are associated with KD. HLA-B*46:01 is proposed to be the risk allele of severe COVID-19 infection, and blood group O type is a protective factor of COVID-19. The autoimmune vasculitis of KD, KD shock syndrome (KDSS), or MIS-C is mediated by a genetic variant of HLA, FcγR, and/or antibody-dependent enhancement (ADE) resulting in hyperinflammation with T helper 17 (Th17)/Treg imbalance with augmented Th17/Th1 mediators: interleukin-6 (IL-6), IL-10, inducible protein-10 (IP-10), Interferon (IFNγ), and IL-17A, and lower expression of Treg-signaling molecules, FoxP3, and transforming growth factor (TGF-ß). There are certain similarities and differences in phenotypes, susceptibility, and pathogenesis of KD, KDSS, and MIS-C, by which a physician can make early protection, prevention, and precision treatment of the diseases. The evolution of immunotherapies for the diseases has shown that intravenous immunoglobulin (IVIG) alone or combined with corticosteroids is the standard treatment for KD, KDSS, and MIS-C. However, a certain portion of patients who revealed a treatment resistance to IVIG or IVIG plus corticosteroids, posing a need to early identify the immunopathogenesis, to protect hosts with genetic susceptibility, and to combat Th17/Treg imbalance by anti-cytokine or pro-Treg for reversal of the hyperinflammation and IVIG resistance. Based on physiological and pathological immunity of the diseases under genetic susceptibility and host milieu conditions, a series of sequential regimens are provided to develop a so-called "Know thyself, enemy (pathogen), and ever-victorious" strategy for the prevention and immunotherapy of KD and/or MIS-C.


Assuntos
Autoimunidade , COVID-19/imunologia , COVID-19/terapia , Predisposição Genética para Doença/genética , Imunoterapia/métodos , Síndrome de Linfonodos Mucocutâneos/imunologia , Síndrome de Linfonodos Mucocutâneos/terapia , Fenótipo , SARS-CoV-2/imunologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Síndrome de Resposta Inflamatória Sistêmica/terapia , Adolescente , Corticosteroides/uso terapêutico , COVID-19/genética , COVID-19/virologia , Criança , Pré-Escolar , Citocinas/sangue , Feminino , Antígenos HLA/genética , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Lactente , Masculino , Síndrome de Linfonodos Mucocutâneos/genética , Síndrome de Resposta Inflamatória Sistêmica/genética , Síndrome de Resposta Inflamatória Sistêmica/virologia
13.
Nat Commun ; 12(1): 1660, 2021 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-33712587

RESUMO

In less than nine months, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) killed over a million people, including >25,000 in New York City (NYC) alone. The COVID-19 pandemic caused by SARS-CoV-2 highlights clinical needs to detect infection, track strain evolution, and identify biomarkers of disease course. To address these challenges, we designed a fast (30-minute) colorimetric test (LAMP) for SARS-CoV-2 infection from naso/oropharyngeal swabs and a large-scale shotgun metatranscriptomics platform (total-RNA-seq) for host, viral, and microbial profiling. We applied these methods to clinical specimens gathered from 669 patients in New York City during the first two months of the outbreak, yielding a broad molecular portrait of the emerging COVID-19 disease. We find significant enrichment of a NYC-distinctive clade of the virus (20C), as well as host responses in interferon, ACE, hematological, and olfaction pathways. In addition, we use 50,821 patient records to find that renin-angiotensin-aldosterone system inhibitors have a protective effect for severe COVID-19 outcomes, unlike similar drugs. Finally, spatial transcriptomic data from COVID-19 patient autopsy tissues reveal distinct ACE2 expression loci, with macrophage and neutrophil infiltration in the lungs. These findings can inform public health and may help develop and drive SARS-CoV-2 diagnostic, prevention, and treatment strategies.


Assuntos
COVID-19/genética , COVID-19/virologia , SARS-CoV-2/genética , Adulto , Idoso , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Antivirais/farmacologia , COVID-19/tratamento farmacológico , COVID-19/epidemiologia , Teste de Ácido Nucleico para COVID-19 , Interações Medicamentosas , Feminino , Perfilação da Expressão Gênica , Genoma Viral , Antígenos HLA/genética , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Interações entre Hospedeiro e Microrganismos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Cidade de Nova Iorque/epidemiologia , Técnicas de Amplificação de Ácido Nucleico , Pandemias , RNA-Seq , SARS-CoV-2/classificação , SARS-CoV-2/efeitos dos fármacos
14.
Am J Hematol ; 96(5): 571-579, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33606297

RESUMO

Allogeneic hematopoietic cell transplantation (HCT) is the only curative option for bone marrow failure or hematopoietic malignant diseases for Fanconi anemia (FA) patients. Although results have improved over the last decades, reaching more than 90% survival when a human leukocyte antigen (HLA)-identical donor is available, alternative HCT donors are still less reported. We compared HCT outcomes using HLA-mismatched unrelated donors (MMUD; n = 123) or haplo-identical donors (HDs), either using only in vivo T cell depletion (n = 33) or T cells depleted in vivo with some type of graft manipulation ex vivo (n = 59) performed for FA between 2000 and 2018. Overall survival (OS) by 24 months was 62% (53-71%) for MMUD, versus 80% (66-95%) for HDs with only in vivo T cell depletion and 60% (47-73%) for HDs with in vivo and ex vivo T cell depletion (p = .22). Event-free survival (EFS) was better for HD-transplanted FA patients with only in vivo T cell depletion 86% (73-99%) than for those transplanted from a MMUD 58% (48-68%) or those with graft manipulation 56% (42-69%) (p = .046). Grade II-IV acute graft-versus-host disease (GVHD) was 41% (MMUD) versus 40% (HDs with no graft manipulation) versus 17% (HDs with T cell depleted graft), (p = .005). No differences were found for the other transplant related outcomes. These data suggest that HDs might be considered as an alternative option for FA patients with better EFS using unmanipulated grafts.


Assuntos
Transplante de Medula Óssea , Anemia de Fanconi/terapia , Antígenos HLA/imunologia , Histocompatibilidade , Transplante de Células-Tronco de Sangue Periférico , Adolescente , Aloenxertos , Transplante de Medula Óssea/estatística & dados numéricos , Criança , Anemia de Fanconi/genética , Anemia de Fanconi/mortalidade , Feminino , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Antígenos HLA/genética , Haplótipos , Histocompatibilidade/genética , Histocompatibilidade/imunologia , Teste de Histocompatibilidade , Humanos , Estimativa de Kaplan-Meier , Doadores Vivos , Depleção Linfocítica , Masculino , Transplante de Células-Tronco de Sangue Periférico/estatística & dados numéricos , Disfunção Primária do Enxerto/epidemiologia , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Estudos Prospectivos , Irmãos , Subpopulações de Linfócitos T/imunologia , Resultado do Tratamento
15.
AIDS ; 35(5): 783-789, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33587436

RESUMO

OBJECTIVES: The Strategic Timing of AntiRetroviral Treatment (START) and Strategies for Management of Antiretroviral Therapy (SMART) trials demonstrated that ART can partly reverse clinically defined immune dysfunction induced by HIV replication. As control of HIV replication is influenced by the HLA region, we explored whether HLA alleles independently influence the risk of clinical events in HIV+ individuals. DESIGN: Cohort study. METHODS: In START and SMART participants, associations between imputed HLA alleles and AIDS, infection-related cancer, herpes virus-related AIDS events, chronic inflammation-related conditions, and bacterial pneumonia were assessed. Cox regression was used to estimate hazard ratios for the risk of events among allele carriers versus noncarriers. Models were adjusted for sex, age, geography, race, time-updated CD4+ T-cell counts and HIV viral load and stratified by treatment group within trials. HLA class I and II alleles were analyzed separately. The Benjamini--Hochberg procedure was used to limit the false discovery rate to less than 5% (i.e. q value <0.05). RESULTS: Among 4829 participants, there were 132 AIDS events, 136 chronic inflammation-related conditions, 167 bacterial pneumonias, 45 infection-related cancers, and 49 herpes virus-related AIDS events. Several associations with q value less than 0.05 were found: HLA-DQB1∗06:04 and HLA-DRB1∗13:02 with AIDS (adjusted HR [95% CI] 2.63 [1.5-4.6] and 2.25 [1.4-3.7], respectively), HLA-B∗15:17 and HLA-DPB1∗15:01 with bacterial pneumonia (4.93 [2.3-10.7] and 4.33 [2.0-9.3], respectively), and HLA-A∗69:01 with infection-related cancer (15.26 [3.5-66.7]). The carriage frequencies of these alleles were 10% or less. CONCLUSION: This hypothesis-generating study suggests that certain HLA alleles may influence the risk of immune dysfunction-related events irrespective of viral load and CD4+ T-cell count.


Assuntos
Infecções por HIV , Antígenos HLA/genética , Alelos , Estudos de Coortes , Progressão da Doença , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , HIV-1 , Humanos
16.
J Clin Exp Hematop ; 61(1): 1-9, 2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33551435

RESUMO

As HLA haploidentical related donors are quickly available, HLA haploidentical hematopoietic stem cell transplantation (haploHSCT) using high-dose post-transplant cyclophosphamide (PTCy) is now widely used. Recent basic and clinical studies revealed the details of immune reconstitution after T-cell replete haploHSCT using PTCy. T cells and NK cells in the graft proliferate abundantly at day 3 post-haploHSCT, and the PTCy eliminates these proliferating cells. After ablation of proliferating mature cells, donor-derived NK cell reconstitution occurs after the second week; however, recovering NK cells remain functionally impaired for at least several months after haploHSCT. PTCy depletes proliferating cells, resulting in the preferential accumulation of Treg and CD4+ T cells, especially the memory stem T cell (TSCM) phenotype. TSCM capable of both self-renewal and differentiation into effector T cells may play an important role in the first month of immune reconstitution. Subsequently, de novo T cells progressively recover but their levels remain well below those of donor CD4+ T cells at the first year after haploHSCT. The phenotype of recovering T cells after HSCT is predominantly effector memory, whereas B cells are predominantly phenotypically naive throughout the first year after haploHSCT. B cell recovery depends on de novo generation and they are not detected until week 4 after haploHSCT. At week 5, recovering B cells mostly exhibit an unconventional transitional cell phenotype and the cell subset undergoes maturation. Recent advances in immune reconstitution have improved our understanding of the relationship between haploHSCT with PTCy and the clinical outcome.


Assuntos
Ciclofosfamida/administração & dosagem , Antígenos HLA/genética , Transplante de Células-Tronco Hematopoéticas , Reconstituição Imune , Cuidados Pós-Operatórios , Linfócitos T/imunologia , Transplante Haploidêntico , Linfócitos B/imunologia , Linfócitos B/metabolismo , Biomarcadores , Terapia Combinada , Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Imunofenotipagem , Contagem de Leucócitos , Leucócitos/imunologia , Leucócitos/metabolismo , Depleção Linfocítica , Subpopulações de Linfócitos T , Linfócitos T/citologia , Linfócitos T/metabolismo , Fatores de Tempo , Resultado do Tratamento
17.
Nat Commun ; 12(1): 1264, 2021 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-33627654

RESUMO

The recent development of imputation methods enabled the prediction of human leukocyte antigen (HLA) alleles from intergenic SNP data, allowing studies to fine-map HLA for immune phenotypes. Here we report an accurate HLA imputation method, CookHLA, which has superior imputation accuracy compared to previous methods. CookHLA differs from other approaches in that it locally embeds prediction markers into highly polymorphic exons to account for exonic variability, and in that it adaptively learns the genetic map within MHC from the data to facilitate imputation. Our benchmarking with real datasets shows that our method achieves high imputation accuracy in a wide range of scenarios, including situations where the reference panel is small or ethnically unmatched.


Assuntos
Antígenos HLA/metabolismo , Alelos , Grupo com Ancestrais do Continente Asiático , Diabetes Mellitus Tipo 1/genética , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Genótipo , Antígenos HLA/genética , Humanos , Modelos Teóricos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
18.
Molecules ; 26(2)2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33430125

RESUMO

To prevent accumulation of misfolded proteins in the endoplasmic reticulum, chaperones perform quality control on newly translated proteins and redirect misfolded proteins to the cytosol for degradation by the ubiquitin-proteasome system. This pathway is called ER-associated protein degradation (ERAD). The human cytomegalovirus protein US2 induces accelerated ERAD of HLA class I molecules to prevent immune recognition of infected cells by CD8+ T cells. Using US2-mediated HLA-I degradation as a model for ERAD, we performed a genome-wide CRISPR/Cas9 library screen to identify novel cellular factors associated with ERAD. Besides the identification of known players such as TRC8, p97, and UBE2G2, the ubiquitin-fold modifier1 (UFM1) pathway was found to affect degradation of HLA-I. UFMylation is a post-translational modification resembling ubiquitination. Whereas we observe ubiquitination of HLA-I, no UFMylation was detected on HLA-I or several other proteins involved in degradation of HLA-I, suggesting that the UFM1 pathway impacts ERAD in a different manner than ubiquitin. Interference with the UFM1 pathway seems to specifically inhibit the ER-to-cytosol dislocation of HLA-I. In the absence of detectable UFMylation of HLA-I, UFM1 may contribute to US2-mediated HLA-I degradation by misdirecting protein sorting indirectly. Mass spectrometry analysis of US2-expressing cells showed that ribosomal proteins are a major class of proteins undergoing extensive UFMylation; the role of these changes in protein degradation may be indirect and remains to be established.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Citomegalovirus/metabolismo , Degradação Associada com o Retículo Endoplasmático , Antígenos HLA/metabolismo , Proteínas/metabolismo , Proteólise , Proteínas do Envelope Viral/metabolismo , Linfócitos T CD8-Positivos/virologia , Citomegalovirus/genética , Antígenos HLA/genética , Humanos , Proteínas/genética , Células U937
19.
Hum Immunol ; 82(3): 147-154, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33478842

RESUMO

The ability to identify specific HLA molecules against which a patient has alloantibodies has revolutionized assessment of immunologic compatibility. Anti-HLA antibodies are typically evaluated as reactive against well-defined serologic antigen groups. Thus, donor HLA genotyping is aimed at defining HLA at the serologic split-antigen level to avoid incompatible antigen-antibody combinations. However, anti-HLA antibodies can have reactivities not accurately described by well-defined serologic antigens. While existence of these antibodies is acknowledged, their precise impact on clinical practice is not clear. We performed a single-center review of 2 years of pre-and post-transplant anti-HLA antibody testing data combined with high-resolution HLA genotyping data for living and deceased organ donors to evaluate the clinical impact of anti-HLA antibodies with reactivities outside of commonly defined serologic antigen groups. We find approximately 15% of patients awaiting transplantation have alloantibodies with differential reactivity for HLA proteins encoded by specific alleles within a serologic antigen group. Allele-specific antibodies are associated with positive cellular crossmatches not accurately predicted by standard donor HLA genotyping and can manifest as post-transplant donor-specific antibodies. Our data highlights the importance of evaluating anti-HLA antibodies at the allele-level and provides evidence supporting utility for high-resolution HLA genotyping in solid organ transplantation.


Assuntos
Tipagem e Reações Cruzadas Sanguíneas/métodos , Genótipo , Antígenos HLA/genética , Isoanticorpos/sangue , Transplante de Órgãos , Adulto , Alelos , Feminino , Histocompatibilidade , Humanos , Incidência , Masculino , Polimorfismo Genético , Análise de Sequência de DNA , Estados Unidos/epidemiologia
20.
Nat Genet ; 53(2): 185-194, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33462484

RESUMO

Clinical laboratory tests are a critical component of the continuum of care. We evaluate the genetic basis of 35 blood and urine laboratory measurements in the UK Biobank (n = 363,228 individuals). We identify 1,857 loci associated with at least one trait, containing 3,374 fine-mapped associations and additional sets of large-effect (>0.1 s.d.) protein-altering, human leukocyte antigen (HLA) and copy number variant (CNV) associations. Through Mendelian randomization (MR) analysis, we discover 51 causal relationships, including previously known agonistic effects of urate on gout and cystatin C on stroke. Finally, we develop polygenic risk scores (PRSs) for each biomarker and build 'multi-PRS' models for diseases using 35 PRSs simultaneously, which improved chronic kidney disease, type 2 diabetes, gout and alcoholic cirrhosis genetic risk stratification in an independent dataset (FinnGen; n = 135,500) relative to single-disease PRSs. Together, our results delineate the genetic basis of biomarkers and their causal influences on diseases and improve genetic risk stratification for common diseases.


Assuntos
Biomarcadores/sangue , Biomarcadores/urina , Antígenos HLA/genética , Proteínas/genética , Bancos de Espécimes Biológicos , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Variações do Número de Cópias de DNA , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Pleiotropia Genética , Humanos , Desequilíbrio de Ligação , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica , Serina Endopeptidases/genética , Reino Unido
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...