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1.
Am J Hum Genet ; 105(4): 763-772, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31564439

RESUMO

Large-scale multi-ethnic cohorts offer unprecedented opportunities to elucidate the genetic factors influencing complex traits related to health and disease among minority populations. At the same time, the genetic diversity in these cohorts presents new challenges for analysis and interpretation. We consider the utility of race and/or ethnicity categories in genome-wide association studies (GWASs) of multi-ethnic cohorts. We demonstrate that race/ethnicity information enhances the ability to understand population-specific genetic architecture. To address the practical issue that self-identified racial/ethnic information may be incomplete, we propose a machine learning algorithm that produces a surrogate variable, termed HARE. We use height as a model trait to demonstrate the utility of HARE and ethnicity-specific GWASs.

2.
Nat Med ; 25(8): 1274-1279, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31285632

RESUMO

Peripheral artery disease (PAD) is a leading cause of cardiovascular morbidity and mortality; however, the extent to which genetic factors increase risk for PAD is largely unknown. Using electronic health record data, we performed a genome-wide association study in the Million Veteran Program testing ~32 million DNA sequence variants with PAD (31,307 cases and 211,753 controls) across veterans of European, African and Hispanic ancestry. The results were replicated in an independent sample of 5,117 PAD cases and 389,291 controls from the UK Biobank. We identified 19 PAD loci, 18 of which have not been previously reported. Eleven of the 19 loci were associated with disease in three vascular beds (coronary, cerebral, peripheral), including LDLR, LPL and LPA, suggesting that therapeutic modulation of low-density lipoprotein cholesterol, the lipoprotein lipase pathway or circulating lipoprotein(a) may be efficacious for multiple atherosclerotic disease phenotypes. Conversely, four of the variants appeared to be specific for PAD, including F5 p.R506Q, highlighting the pathogenic role of thrombosis in the peripheral vascular bed and providing genetic support for Factor Xa inhibition as a therapeutic strategy for PAD. Our results highlight mechanistic similarities and differences among coronary, cerebral and peripheral atherosclerosis and provide therapeutic insights.

3.
Circulation ; 140(12): 1031-1040, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31337231

RESUMO

BACKGROUND: Approximately 13% of black individuals carry 2 copies of the apolipoprotein L1 (APOL1) risk alleles G1 or G2, which are associated with 1.5- to 2.5-fold increased risk of chronic kidney disease. There have been conflicting reports as to whether an association exists between APOL1 risk alleles and cardiovascular disease (CVD) that is independent of the effects of APOL1 on kidney disease. We sought to test the association of APOL1 G1/G2 alleles with coronary artery disease, peripheral artery disease, and stroke among black individuals in the Million Veteran Program. METHODS: We performed a time-to-event analysis of retrospective electronic health record data using Cox proportional hazard and competing-risks Fine and Gray subdistribution hazard models. The primary exposure was APOL1 risk allele status. The primary outcome was incident coronary artery disease among individuals without chronic kidney disease during the 12.5-year follow-up period. We separately analyzed the cross-sectional association of APOL1 risk allele status with lipid traits and 115 cardiovascular diseases using phenome-wide association. RESULTS: Among 30 903 black Million Veteran Program participants, 3941 (13%) carried the 2 APOL1 risk allele high-risk genotype. Individuals with normal kidney function at baseline with 2 risk alleles had slightly higher risk of developing coronary artery disease compared with those with no risk alleles (hazard ratio, 1.11 [95% CI, 1.01-1.21]; P=0.039). Similarly, modest associations were identified with incident stroke (hazard ratio, 1.20 [95% CI, 1.05-1.36; P=0.007) and peripheral artery disease (hazard ratio, 1.15 [95% CI, 1.01-1.29l; P=0.031). When both cardiovascular and renal outcomes were modeled, APOL1 was strongly associated with incident renal disease, whereas no significant association with the CVD end points could be detected. Cardiovascular phenome-wide association analyses did not identify additional significant associations with CVD subsets. CONCLUSIONS: APOL1 risk variants display a modest association with CVD, and this association is likely mediated by the known APOL1 association with chronic kidney disease.

4.
PLoS Pathog ; 15(4): e1007715, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30998783

RESUMO

Hepatitis B virus (HBV) persists with global and virus-specific T-cell dysfunction, without T-cell based correlates of outcomes. To determine if γδT-cells are altered in HBV infection relative to clinical status, we examined the frequency, phenotype and function of peripheral blood Vδ1+ and Vδ2+γδT-cells by multi-parameter cytometry in a clinically diverse North American cohort of chronic hepatitis B (CHB), acute hepatitis B (AHB) and uninfected control subjects. We show that circulating γδT-cells were comprised predominantly of CD3hiCD4- Vδ2+γδT-cells with frequencies that were 2-3 fold higher among Asian than non-Asian Americans and inversely correlated with age, but without differences between CHB, AHB and control subjects. However, compared to control subjects, CHB was associated with increased TbethiEomesdim phenotype in Vδ2+γδT-cells whereas AHB was associated with increased TbethiEomesdim phenotype in Vδ1+γδT-cells, with significant correlations between Tbet/Eomes expression in γδT-cells with their expression of NK and T-cell activation and regulatory markers. As for effector functions, IFNγ/TNF responses to phosphoantigens or PMA/Ionomycin in Vδ2+γδT-cells were weaker in AHB but preserved in CHB, without significant differences for Vδ1+γδT-cells. Furthermore, early IFNγ/TNF responses in Vδ2+ γδT-cells to brief PMA/Ionomycin stimulation correlated inversely with serum ALT but not HBV DNA. Accordingly, IFNγ/TNF responses in Vδ2+γδT-cells were weaker in patients with CHB with hepatitis flare compared to those without hepatitis flares, and this functional deficit persisted beyond clinical resolution of CHB flare. We conclude that circulating γδT-cells show distinct activation and differentiatiation in acute and chronic HBV infection as part of lymphoid stress surveillance with potential role in clinical outcomes.

5.
Cell Metab ; 29(3): 769-783.e4, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30713110

RESUMO

The interaction between the immune system and endocrine cells in the pancreas is crucial for the initiation and progression of type 1 diabetes (T1D). Imaging mass cytometry (IMC) enables multiplexed assessment of the abundance and localization of more than 30 proteins on the same tissue section at 1-µm resolution. Herein, we have developed a panel of 33 antibodies that allows for the quantification of key cell types including pancreatic exocrine cells, islet cells, immune cells, and stromal components. We employed this panel to analyze 12 pancreata obtained from donors with clinically diagnosed T1D and 6 pancreata from non-diabetic controls. In the pancreata from donors with T1D, we simultaneously visualized significant alterations in islet architecture, endocrine cell composition, and immune cell presentation. Indeed, we demonstrate the utility of IMC to investigate complex events on the cellular level that will provide new insights on the pathophysiology of T1D.

6.
Nat Genet ; 50(11): 1514-1523, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30275531

RESUMO

The Million Veteran Program (MVP) was established in 2011 as a national research initiative to determine how genetic variation influences the health of US military veterans. Here we genotyped 312,571 MVP participants using a custom biobank array and linked the genetic data to laboratory and clinical phenotypes extracted from electronic health records covering a median of 10.0 years of follow-up. Among 297,626 veterans with at least one blood lipid measurement, including 57,332 black and 24,743 Hispanic participants, we tested up to around 32 million variants for association with lipid levels and identified 118 novel genome-wide significant loci after meta-analysis with data from the Global Lipids Genetics Consortium (total n > 600,000). Through a focus on mutations predicted to result in a loss of gene function and a phenome-wide association study, we propose novel indications for pharmaceutical inhibitors targeting PCSK9 (abdominal aortic aneurysm), ANGPTL4 (type 2 diabetes) and PDE3B (triglycerides and coronary disease).

8.
Immunity ; 48(5): 1029-1045.e5, 2018 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-29768164

RESUMO

Exhausted CD8 T (Tex) cells are immunotherapy targets in chronic infection and cancer, but a comprehensive assessment of Tex cell diversity in human disease is lacking. Here, we developed a transcriptomic- and epigenetic-guided mass cytometry approach to define core exhaustion-specific genes and disease-induced changes in Tex cells in HIV and human cancer. Single-cell proteomic profiling identified 9 distinct Tex cell clusters using phenotypic, functional, transcription factor, and inhibitory receptor co-expression patterns. An exhaustion severity metric was developed and integrated with high-dimensional phenotypes to define Tex cell clusters that were present in healthy subjects, common across chronic infection and cancer or enriched in either disease, linked to disease severity, and changed with HIV therapy. Combinatorial patterns of immunotherapy targets on different Tex cell clusters were also defined. This approach and associated datasets present a resource for investigating human Tex cell biology, with implications for immune monitoring and immunomodulation in chronic infections, autoimmunity, and cancer.

9.
PLoS One ; 13(3): e0194713, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29566096

RESUMO

Antiretroviral therapy (ART) for HIV is vulnerable to unplanned treatment interruptions-consecutively missed doses over a series of days-which can result in virologic rebound. Yet clinicians lack a simple, valid method for estimating the risk of interruptions. If the likelihood of ART interruption could be derived from a convenient-to-gather summary measure of medication adherence, it might be a valuable tool for both clinical decision-making and research. We constructed an a priori probability model of ART interruption based on average adherence and tested its predictions using data collected on 185 HIV-infected, treatment-naïve individuals over the first 90 days of ART in a prospective cohort study in Mbarara, Uganda. The outcome of interest was the presence or absence of a treatment gap, defined as >72 hours without a dose. Using the pre-determined value of 0.50 probability as the cut point for predicting an interruption, the classification accuracy of the model was 73% (95% CI = 66%- 79%), the specificity was 87% (95% CI = 79%- 93%), and the sensitivity was 59% (95% CI = 48%- 69%). Overall model performance was satisfactory, with an area under the receiver operator characteristic curve (AUROC) of 0.85 (95% CI = 0.80-0.91) and Brier score of 0.20. The study serves as proof-of-concept that the probability model can accurately differentiate patients on the continuum of risk for short-term ART interruptions using a summary measure of adherence. The model may also aid in the design of targeted interventions.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Adesão à Medicação/estatística & dados numéricos , Suspensão de Tratamento/estatística & dados numéricos , Adulto , Fármacos Anti-HIV/administração & dosagem , Terapia Antirretroviral de Alta Atividade , Estudos de Coortes , Esquema de Medicação , Feminino , Infecções por HIV/epidemiologia , HIV-1 , Humanos , Masculino , Modelos Estatísticos , Probabilidade , Prognóstico , Fatores de Tempo , Uganda/epidemiologia
11.
Antiviral Res ; 150: 93-100, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29248746

RESUMO

In early 2017, the Hepatitis B Foundation invited 30 experts in the fields of hepatitis B and liver cancer research to identify projects they deemed important to the goal of finding a cure for chronic hepatitis B and D and the diseases with which these viral infections are associated. They were also asked to identify general categories of research and to prioritize sub-project topics within those areas. The experts generally agreed on broadly defined areas of research, but there was usually little difference between the highest and lowest scoring projects; for the most part, all programs described in this document were considered valuable and necessary. An executive summary of this discussion was recently published (Alter et al., Hepatology 2017). The present manuscript reports the areas of research identified by the workshop participants, provides a brief rationale for their selection, and attempts to express differences among the priorities assigned to each area of research, when such distinctions were expressed.


Assuntos
Antivirais/farmacologia , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Pesquisa , Humanos
12.
J Immunol Methods ; 453: 3-10, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28322863

RESUMO

The elimination of infected or tumor cells by direct lysis is a key T and NK cell effector function. T and NK cells can kill target cells by coordinated secretion of cytotoxic granules containing one or both pore-forming proteins, perforin and granulysin and combinations of granzyme (Gzm) family effector proteases (in humans: Gzm A, B, K, M and H). Understanding the pattern of expression of cytotoxic molecules and the relationship to different states of T and NK cells may have direct relevance for immune responses in autoimmunity, infectious disease and cancer. Approaches capable of simultaneously evaluating expression of multiple cytotoxic molecules with detailed information on T and NK differentiation state, however, remain limited. Here, we established a high dimensional mass cytometry approach to comprehensively interrogate single cell proteomic expression of cytotoxic programs and lymphocyte differentiation. This assay identified a coordinated expression pattern of cytotoxic molecules linked to CD8 T cell differentiation stages. Coordinated high expression of perforin, granulysin, Gzm A, Gzm B and Gzm M was associated with markers of late effector memory differentiation and expression of chemokine receptor CX3CR1. However, classical gating and dimensionality reduction approaches also identified other discordant patterns of cytotoxic molecule expression in CD8 T cells, including reduced perforin, but high Gzm A, Gzm K and Gzm M expression. When applied to non-CD8 T cells, this assay identified different patterns of cytotoxic molecule co-expression by CD56hi versus CD56dim defined NK cell developmental stages; in CD4 T cells, low expression of cytotoxic molecules was found mainly in TH1 phenotype cells, but not in Tregs or T follicular helper cells (TFH). Thus, this comprehensive, single cell, proteomic assessment of cytotoxic protein co-expression patterns demonstrates specialized cytotoxic programs in T cells and NK cells linked to their differentiation stages. Such comprehensive cytotoxic profiling may identify distinct patterns of cytotoxic potential relevant for specific infections, autoimmunity or tumor settings.


Assuntos
Linfócitos T CD8-Positivos/fisiologia , Células Matadoras Naturais/fisiologia , Espectrometria de Massas/métodos , Proteínas Citotóxicas Formadoras de Poros/isolamento & purificação , Células Th1/imunologia , Antígeno CD56/metabolismo , Receptor 1 de Quimiocina CX3C/metabolismo , Diferenciação Celular , Células Cultivadas , Citotoxicidade Imunológica , Voluntários Saudáveis , Humanos , Memória Imunológica , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Proteômica , Análise de Célula Única
14.
J Virol ; 91(10)2017 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-28275182

RESUMO

The antiviral effects of hepatitis C virus (HCV)-specific CD8 T cells have been shown in an HCV replicon system but not in an authentic infectious HCV cell culture (HCVcc) system. Here, we developed tools to examine the antigenicity of HCV-infected HLA-A2-positive Huh7.5 hepatoma cells (Huh7.5A2 cells) in activating HCV-specific CD8 T cells and the downstream antiviral effects. Infectious HCV epitope mutants encoding the well-defined genotype 1a-derived HLA-A2-restricted HCV NS3-1073 or NS5-2594 epitope were generated from a genotype 2a-derived HCV clone (Jc1Gluc2A) by site-directed mutagenesis. CD8 T-cell lines specific for NS3-1073 and NS5-2594 were expanded from HCV-seropositive persons by peptide stimulation in vitro or engineered from HCV-seronegative donor T cells by transduction of a lentiviral vector expressing HCV-specific T-cell receptors. HCV-specific CD8 T cells were cocultured with Huh7.5 cells that were pulsed with titrating doses of HCV epitope peptides or infected with HCV epitope mutants. HCV-specific CD8 T-cell activation (CD107a, gamma interferon, macrophage inflammatory protein 1ß, tumor necrosis factor alpha) was dependent on the peptide concentrations and the relative percentages of HCV-infected Huh7.5A2 cells. HCV-infected Huh7.5A2 cells activated HCV-specific CD8 T cells at levels comparable to those achieved with 0.1 to 2 µM pulsed peptides, providing a novel estimate of the level at which endogenously processed HCV epitopes are presented on HCV-infected cells. While HCV-specific CD8 T-cell activation with cytolytic and antiviral effects was blunted by PD-L1 expression on HCV-infected Huh7.5A2 cells, resulting in the improved viability of Huh7.5A2 cells, PD-1 blockade reversed this effect, producing enhanced cytolytic elimination of HCV-infected Huh7.5A2 cells. Our findings, obtained using an infectious HCVcc system, show that the HCV-specific CD8 T-cell function is modulated by antigen expression levels, the percentage of HCV-infected cells, and the PD-1/PD-L1 pathways and has antiviral and cytotoxic effects.IMPORTANCE We developed several novel molecular and immunological tools to study the interactions among HCV, HCV-infected hepatocytes, and HCV-specific CD8 T cells. Using these tools, we show the level at which HCV-infected hepatoma cells present endogenously processed HCV epitopes to HCV-specific CD8 T cells with antiviral and cytotoxic effects. We also show the marked protective effect of PD-L1 expression on HCV-infected hepatoma cells against HCV-specific CD8 T cells.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Hepacivirus/imunologia , Hepatócitos/virologia , Antígeno B7-H1/genética , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linhagem Celular Tumoral , Quimiocina CCL4/genética , Técnicas de Cocultura , Testes Imunológicos de Citotoxicidade , Antígeno HLA-A2/imunologia , Hepacivirus/genética , Hepatócitos/imunologia , Humanos , Interferon gama/genética , Ativação Linfocitária , Proteína 1 de Membrana Associada ao Lisossomo/genética , Mutagênese Sítio-Dirigida , Peptídeos/farmacologia , Receptores de Antígenos de Linfócitos T/genética , Transdução Genética , Fator de Necrose Tumoral alfa/genética
15.
Clin Liver Dis ; 20(4): 629-644, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27742004

RESUMO

Hepatitis B virus (HBV) infection is a major global health challenge. HBV can cause significant morbidity and mortality by establishing acute and chronic hepatitis. Approximately 250 million people worldwide are chronically infected, and more than 2 billion people have been exposed to HBV. Since the discovery of HBV, the advances in our understanding of HBV virology and immunology have translated into effective vaccines and therapies for HBV infection. Although current therapies successfully suppress viral replication but rarely succeed in viral eradication, recent discoveries in HBV virology and immunology provide exciting rationales for novel treatment strategies aiming at HBV cure.


Assuntos
Anticorpos Anti-Hepatite B/imunologia , Antígenos da Hepatite B/imunologia , Vacinas contra Hepatite B/farmacologia , Vírus da Hepatite B/fisiologia , Hepatite B , Vacinação/métodos , Replicação Viral/imunologia , Hepatite B/imunologia , Hepatite B/prevenção & controle , Hepatite B/virologia , Humanos
16.
Cell Metab ; 24(4): 616-626, 2016 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-27732837

RESUMO

The human endocrine pancreas consists of multiple cell types and plays a critical role in glucose homeostasis. Here, we apply mass cytometry technology to measure all major islet hormones, proliferative markers, and readouts of signaling pathways involved in proliferation at single-cell resolution. Using this innovative technology, we simultaneously examined baseline proliferation levels of all endocrine cell types from birth through adulthood, as well as in response to the mitogen harmine. High-dimensional analysis of our marker protein expression revealed three major clusters of beta cells within individuals. Proliferating beta cells are confined to two of the clusters.


Assuntos
Citometria de Fluxo/métodos , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/metabolismo , Análise de Célula Única/métodos , Agregação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Harmina/farmacologia , Humanos , Ilhotas Pancreáticas/efeitos dos fármacos
18.
Curr Opin Pharmacol ; 30: 93-105, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27570126

RESUMO

Hepatitis B virus (HBV) evades, subverts, activates and regulates host immune components, thereby impacting its natural history and disease pathogenesis. Recent advances in our understanding of immune interactions in chronic viral infection and tumor therapy are applicable to chronic hepatitis B (CHB). With recent successes of tumor immunotherapy, there is a renewed interest in exploring immunotherapeutics in achieving sustained and functional cure of chronic hepatitis B. In this review, we discuss aspects of host innate and adaptive immune regulatory and pathogenic responses relevant for HBV infection. We also highlight several immune modulatory approaches in clinical development to treat CHB.


Assuntos
Vírus da Hepatite B/imunologia , Hepatite B Crônica/terapia , Imunoterapia/métodos , Imunidade Adaptativa , Animais , Antivirais/farmacologia , Hepatite B Crônica/imunologia , Humanos , Imunidade Inata
19.
Dig Dis Sci ; 61(6): 1744-56, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27059981

RESUMO

BACKGROUND: As the era of interferon-alpha (IFN)-based therapy for hepatitis C ends, long-term treatment outcomes are now being evaluated. AIM: To more fully understand the natural history of hepatitis C infection by following a multisite cohort of patients. METHODS: Patients with chronic HCV were prospectively enrolled in 1999-2000 from 11 VA medical centers and followed through retrospective medical record review. RESULTS: A total of 2211 patients were followed for an average of 8.5 years after enrollment. Thirty-one percent of patients received HCV antiviral therapy, 15 % with standard IFN/ribavirin only, 16 % with pegylated IFN/ribavirin, and 26.7 % of treated patients achieved sustained virologic response (SVR). Cirrhosis developed in 25.8 % of patients. Treatment nonresponders had a greater than twofold increase in the hazard of cirrhosis and hepatocellular carcinoma, compared to untreated patients, whereas SVR patients were only marginally protected from cirrhosis. Nearly 6 % developed hepatocellular carcinoma, and 27.1 % died during the follow-up period. Treated patients, regardless of response, had a significant survival benefit compared to untreated patients (HR 0.58, CI 0.46-0.72). Improved survival was also associated with college education, younger age, lower levels of alcohol consumption, and longer duration of medical service follow-up-factors typically associated with treatment eligibility. CONCLUSIONS: As more hepatitis C patients are now being assessed for all-oral combination therapy, these results highlight that patient compliance and limiting harmful behaviors contribute a significant proportion of the survival benefit in treated patients and that the long-term clinical benefits of SVR may be less profound than previously reported.


Assuntos
Hepatite C/tratamento farmacológico , Interferon-alfa/uso terapêutico , Cirrose Hepática/etiologia , Adulto , Estudos de Coortes , Feminino , Hepatite C/epidemiologia , Humanos , Interferon-alfa/administração & dosagem , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Ribavirina/administração & dosagem , Ribavirina/uso terapêutico , Estados Unidos/epidemiologia , United States Department of Veterans Affairs
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