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1.
EClinicalMedicine ; 40: 101099, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34490415

RESUMO

Background: Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, there has been increasing urgency to identify pathophysiological characteristics leading to severe clinical course in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human leukocyte antigen alleles (HLA) have been suggested as potential genetic host factors that affect individual immune response to SARS-CoV-2. We sought to evaluate this hypothesis by conducting a multicenter study using HLA sequencing. Methods: We analyzed the association between COVID-19 severity and HLAs in 435 individuals from Germany (n = 135), Spain (n = 133), Switzerland (n = 20) and the United States (n = 147), who had been enrolled from March 2020 to August 2020. This study included patients older than 18 years, diagnosed with COVID-19 and representing the full spectrum of the disease. Finally, we tested our results by meta-analysing data from prior genome-wide association studies (GWAS). Findings: We describe a potential association of HLA-C*04:01 with severe clinical course of COVID-19. Carriers of HLA-C*04:01 had twice the risk of intubation when infected with SARS-CoV-2 (risk ratio 1.5 [95% CI 1.1-2.1], odds ratio 3.5 [95% CI 1.9-6.6], adjusted p-value = 0.0074). These findings are based on data from four countries and corroborated by independent results from GWAS. Our findings are biologically plausible, as HLA-C*04:01 has fewer predicted bindings sites for relevant SARS-CoV-2 peptides compared to other HLA alleles. Interpretation: HLA-C*04:01 carrier state is associated with severe clinical course in SARS-CoV-2. Our findings suggest that HLA class I alleles have a relevant role in immune defense against SARS-CoV-2. Funding: Funded by Roche Sequencing Solutions, Inc.

2.
Transbound Emerg Dis ; 2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34405560

RESUMO

Whether people living with HIV (PLWH) are at greater risk of acquiring SARS-CoV-2 infection is currently unknown. Prospective serologic studies may allow seroincidence analyses, where all infections are accurately identified. Because of this, we evaluated the incidence of associated factors with and the clinical outcome of SARS-CoV-2 infection in PLWH in Southern Spain. This prospective cohort study included PLWH from a Tertiary University Hospital in Southern Spain. Patients were enrolled in the study if (1) they had attended as outpatients our Unit from 1 August 2019 to 8 February 2020 and (2) had two subsequent evaluations from 9 February 2020 to 4 March 2021. SARS-CoV-2 infections were diagnosed by PCR, antigen detection or serology. Seven hundred and nine PLWH were included in the study. Of them, 55 [7.8%, 95% confidence interval (95% CI) 5.9%-9.9%] patients developed SARS-CoV-2 infection. Between 18 May and 29 November 2020, the rate of seroconversion was 5.3% (95% CI: 3.1%-9.0%) for the general population in the area of Seville and 2.3% (95% CI: 1.3%-2.6%) for PLWH in this study (p = .001). After multivariable analysis, adjusted by age, sex, and risk factors for HIV infection, active tobacco use and CDC stage, active tobacco smoking was the only factor independently associated with lower risk of SARS-Cov-2 infection [Incidence rate ratio: 0.29 (95% CI 0.16-0.55) p < .001]. In conclusion, the incidence of SARS-CoV-2 infection among PLWH in Southern Spain during the ongoing pandemic was lower than that reported for the general population in the same area.

3.
Diagnostics (Basel) ; 11(8)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34441435

RESUMO

Liver stiffness (LS) at sustained virological response (SVR) after direct-acting antivirals (DAA)-based therapy is a predictor of liver events in hepatitis C virus (HCV)-infected patients. The study aim was to identify genetic factors associated with LS changes from the moment of starting anti-HCV therapy to SVR. This prospective study included HCV-infected patients from the GEHEP-011 cohort who achieved SVR with DAA-based therapy, with LS pre-treatment ≥ 9.5 kPa and LS measurement available at SVR. Plink and Magma software were used to carry out genome-wide single-nucleotide polymorphism (SNP)-based and gene-based association analyses, respectively. The ShinyGO application was used for exploring enrichment in Gene Ontology (GO) categories for biological processes. Overall, 242 patients were included. Median (quartile 1, quartile 3) LS values at pre-treatment and at SVR were 16.8 (12, 28) kPa and 12.0 (8.5, 19.3) kPa, respectively. Thirty-five SNPs and three genes reached suggestive association with LS changes from the moment of starting anti-HCV therapy to SVR. GO categories related to DNA packaging complex, DNA conformation change, chromosome organization and chromatin organization were significantly enriched. Our study reports possible genetic factors associated with LS changes during HCV-infection cure. In addition, our results suggest that processes related to DNA conformation are also involved in these changes.

4.
Sci Rep ; 10(1): 20958, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33262433

RESUMO

The impact of drug-drug interactions (DDI) between ritonavir-boosted lopinavir (LPV-r) to treat patients with coronavirus disease 2019 (COVID-19) and commonly used drugs in clinical practice is not well-known. Thus, we evaluated the rate and severity of DDI between LPV-r for COVID-19 treatment and concomitant medications. This was a cross-sectional study including all individuals diagnosed of SARS-CoV-2 infection treated with LPV-r and attended at a single center in Southern Spain (March 1st to April 30th, 2020). The frequency [95% confidence interval (95% CI)] of potential and major DDI were calculated. Overall, 469 patients were diagnosed of COVID-19, 125 (27%) of them were prescribed LPV-r. LPV-r had potential DDI with concomitant medications in 97 (78%, 95% CI 69-85%) patients, and in 33 (26%, 95% CI 19-35%) individuals showed major DDI. Twelve (36%) patients with major DDI and 14 (15%) individuals without major DDI died (p = 0.010). After adjustment, only the Charlson index was independently associated with death [adjusted OR (95% CI) for Charlson index ≥ 5: 85 (10-731), p < 0.001]. LPV-r was discontinued due to side effects in 31 (25%) patients. Management by the Infectious Diseases Unit was associated with a lower likelihood of major DDI [adjusted odds ratio (95% CI): 0.14 (0.04-0.53), p = 0.003). In conclusion, a high frequency of DDI between LPV-r for treating COVID-19 and concomitant medications was found, including major DDI. Patients with major DDI showed worse outcomes, but this association was explained by the older age and comorbidities. Patients managed by the Infectious Diseases Unit had lower risk of major DDI.


Assuntos
Antivirais/efeitos adversos , COVID-19/tratamento farmacológico , Lopinavir/efeitos adversos , Lopinavir/uso terapêutico , Inibidores de Proteases/efeitos adversos , Ritonavir/efeitos adversos , Ritonavir/uso terapêutico , Idoso , Antivirais/uso terapêutico , Estudos Transversais , Combinação de Medicamentos , Interações Medicamentosas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores de Proteases/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , Espanha
5.
J Infect Dis ; 222(12): 2007-2011, 2020 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-32516401

RESUMO

Toll-like receptor 2 (TLR2) plays a key role in innate immune response recognizing molecular patterns expressed by pathogens. rs111200466 is a TLR2 promoter insertion/deletion polymorphism with contradictory data about its role in human immunodeficiency virus type 1 (HIV-1) infection. We analyzed rs111200466 in HIV-1 disease progression and showed a correlation with a faster progression to the CD4+ < 200 cells/µL outcome for deletion allele carriers (Cox regression analysis: hazard ratio, 2.4 [95% confidence interval, 1.4-4]; P = .001). When naive patients with CD4+ < 200 cells/µL started antiretroviral treatment, rs111200466-deletion carriers showed a trend toward a slower, recovery rate (time required to reach CD4+ > 350 cells/µL; Cox P = .36). Our data suggest rs111200466 as a prognosis factor for HIV-1 disease progression.


Assuntos
Contagem de Linfócito CD4 , Infecções por HIV/genética , Polimorfismo Genético , Receptor 2 Toll-Like/genética , Estudos de Coortes , Progressão da Doença , Feminino , HIV-1 , Humanos , Masculino , Prognóstico , Regiões Promotoras Genéticas , Análise de Sobrevida
6.
Liver Int ; 39(10): 1918-1926, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31206233

RESUMO

BACKGROUND: A low proportion of individuals repeatedly exposed to the hepatitis C virus (HCV) remain uninfected. This condition could have a genetic basis but it is not known whether or not it is mainly driven by a high-penetrance common allele. OBJECTIVE: To explore whether low susceptibility to HCV infection is mainly driven by a high-penetrance common allele. METHODS: In this genome-wide association study (GWAS), a total of 804 HCV-seropositive individuals and 27 high-risk HCV-seronegative (HRSN) subjects were included. Plink and Magma software were used to carry out single nucleotide polymorphism (SNP)-based and gene-based association analyses respectively. RESULTS: No SNP nor any gene was associated with low susceptibility to HCV infection after multiple testing correction. However, SNPs previously associated with this trait and allocated within the LDLR gene, rs5925 and rs688, were also associated with this condition in our study under a dominant model (24 out of 27 [88.9%] rs5925-C carriers in the HRSN group vs 560 of 804 [69.6%] rs5925-C carriers in the HCV-seropositive group, P = 0.031, odds ratio [OR] = 3.48; 95% confidence interval [CI] = 1.04-11.58; and 24 out of 27 [88.9%] rs688-T carriers in the HRSN group vs 556 of 804 [69.1%] rs688-T carriers in the HCV-seropositive group, P = 0.028, OR = 3.57, 95% CI = 1.65-11.96). CONCLUSIONS: Low susceptibility to HCV infection does not seem to be mainly driven by a high-penetrant common allele. By contrast, it seems a multifactorial trait where genes such as LDLR could be involved.


Assuntos
Hepatite C/genética , Polimorfismo de Nucleotídeo Único , Receptores de LDL/genética , Adulto , Alelos , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hepacivirus , Humanos , Masculino , Pessoa de Meia-Idade , Espanha
7.
JCI Insight ; 3(21)2018 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-30385722

RESUMO

Fibrosis is a major contributor to organ disease for which no specific therapy is available. MicroRNA-21 (miR-21) has been implicated in the fibrogenetic response, and inhibitors of miR-21 are currently undergoing clinical trials. Here, we explore how miR-21 inhibition may attenuate fibrosis using a proteomics approach. Transfection of miR-21 mimic or inhibitor in murine cardiac fibroblasts revealed limited effects on extracellular matrix (ECM) protein secretion. Similarly, miR-21-null mouse hearts showed an unaltered ECM composition. Thus, we searched for additional explanations as to how miR-21 might regulate fibrosis. In plasma samples from the community-based Bruneck Study, we found a marked correlation of miR-21 levels with several platelet-derived profibrotic factors, including TGF-ß1. Pharmacological miR-21 inhibition with an antagomiR reduced the platelet release of TGF-ß1 in mice. Mechanistically, Wiskott-Aldrich syndrome protein, a negative regulator of platelet TGF-ß1 secretion, was identified as a direct target of miR-21. miR-21-null mice had lower platelet and leukocyte counts compared with littermate controls but higher megakaryocyte numbers in the bone marrow. Thus, to our knowledge this study reports a previously unrecognized effect of miR-21 inhibition on platelets. The effect of antagomiR-21 treatment on platelet TGF-ß1 release, in particular, may contribute to the antifibrotic effects of miR-21 inhibitors.


Assuntos
Matriz Extracelular/efeitos dos fármacos , Fibrose/genética , MicroRNAs/antagonistas & inibidores , MicroRNAs/farmacologia , Idoso , Idoso de 80 Anos ou mais , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Ensaios Clínicos como Assunto , Matriz Extracelular/genética , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibrose/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL/genética , MicroRNAs/genética , Pessoa de Meia-Idade , Miocárdio/patologia , Estudos Prospectivos , Proteômica/métodos , RNA não Traduzido/genética , Fator de Crescimento Transformador beta1/genética , Proteína da Síndrome de Wiskott-Aldrich/efeitos dos fármacos , Proteína da Síndrome de Wiskott-Aldrich/genética
8.
EMBO Mol Med ; 9(9): 1244-1262, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28674080

RESUMO

Atherosclerosis, the major cause of cardiovascular disease, is a chronic inflammatory disease characterized by the accumulation of lipids and inflammatory cells in the artery wall. Aberrant expression of microRNAs has been implicated in the pathophysiological processes underlying the progression of atherosclerosis. Here, we define the contribution of miR-21 in hematopoietic cells during atherogenesis. Interestingly, we found that miR-21 is the most abundant miRNA in macrophages and its absence results in accelerated atherosclerosis, plaque necrosis, and vascular inflammation. miR-21 expression influences foam cell formation, sensitivity to ER-stress-induced apoptosis, and phagocytic clearance capacity. Mechanistically, we discovered that the absence of miR-21 in macrophages increases the expression of the miR-21 target gene, MKK3, promoting the induction of p38-CHOP and JNK signaling. Both pathways enhance macrophage apoptosis and promote the post-translational degradation of ABCG1, a transporter that regulates cholesterol efflux in macrophages. Altogether, these findings reveal a major role for hematopoietic miR-21 in atherogenesis.


Assuntos
Apoptose , Aterosclerose/fisiopatologia , Macrófagos/imunologia , MicroRNAs/imunologia , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/imunologia , Animais , Aterosclerose/genética , Aterosclerose/imunologia , Aterosclerose/patologia , Vasos Sanguíneos/imunologia , Feminino , Humanos , MAP Quinase Quinase 3/genética , MAP Quinase Quinase 3/imunologia , Macrófagos/citologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética , Necrose/genética , Necrose/imunologia , Necrose/patologia , Necrose/fisiopatologia
9.
Cell Rep ; 19(13): 2743-2755, 2017 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-28658622

RESUMO

Macrophages perform critical functions in both innate immunity and cholesterol metabolism. Here, we report that activation of Toll-like receptor 4 (TLR4) in macrophages causes lanosterol, the first sterol intermediate in the cholesterol biosynthetic pathway, to accumulate. This effect is due to type I interferon (IFN)-dependent histone deacetylase 1 (HDAC1) transcriptional repression of lanosterol-14α-demethylase, the gene product of Cyp51A1. Lanosterol accumulation in macrophages, because of either treatment with ketoconazole or induced conditional disruption of Cyp51A1 in mouse macrophages in vitro, decreases IFNß-mediated signal transducer and activator of transcription (STAT)1-STAT2 activation and IFNß-stimulated gene expression. These effects translate into increased survival to endotoxemic shock by reducing cytokine secretion. In addition, lanosterol accumulation increases membrane fluidity and ROS production, thus potentiating phagocytosis and the ability to kill bacteria. This improves resistance of mice to Listeria monocytogenes infection by increasing bacterial clearance in the spleen and liver. Overall, our data indicate that lanosterol is an endogenous selective regulator of macrophage immunity.


Assuntos
Lanosterol/imunologia , Macrófagos/imunologia , Receptor 4 Toll-Like/imunologia , Animais , Regulação para Baixo , Feminino , Técnicas de Inativação de Genes , Humanos , Imunidade Inata/efeitos dos fármacos , Lanosterol/metabolismo , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Esterol 14-Desmetilase/imunologia
10.
Circ Res ; 118(1): 38-47, 2016 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-26472816

RESUMO

RATIONALE: Several lines of evidence indicate that the regulation of microRNA (miRNA) levels by different stimuli may contribute to the modulation of stimulus-induced responses. The miR-17-92 cluster has been linked to tumor development and angiogenesis, but its role in vascular endothelial growth factor-induced endothelial cell (EC) functions is unclear and its regulation is unknown. OBJECTIVE: The purpose of this study was to elucidate the mechanism by which VEGF regulates the expression of miR-17-92 cluster in ECs and determine its contribution to the regulation of endothelial angiogenic functions, both in vitro and in vivo. This was done by analyzing the effect of postnatal inactivation of miR-17-92 cluster in the endothelium (miR-17-92 iEC-KO mice) on developmental retinal angiogenesis, VEGF-induced ear angiogenesis, and tumor angiogenesis. METHODS AND RESULTS: Here, we show that Erk/Elk1 activation on VEGF stimulation of ECs is responsible for Elk-1-mediated transcription activation (chromatin immunoprecipitation analysis) of the miR-17-92 cluster. Furthermore, we demonstrate that VEGF-mediated upregulation of the miR-17-92 cluster in vitro is necessary for EC proliferation and angiogenic sprouting. Finally, we provide genetic evidence that miR-17-92 iEC-KO mice have blunted physiological retinal angiogenesis during development and diminished VEGF-induced ear angiogenesis and tumor angiogenesis. Computational analysis and rescue experiments show that PTEN (phosphatase and tensin homolog) is a target of the miR-17-92 cluster and is a crucial mediator of miR-17-92-induced EC proliferation. However, the angiogenic transcriptional program is reduced when miR-17-92 is inhibited. CONCLUSIONS: Taken together, our results indicate that VEGF-induced miR-17-92 cluster expression contributes to the angiogenic switch of ECs and participates in the regulation of angiogenesis.


Assuntos
Endotélio Vascular/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , MicroRNAs/biossíntese , Neovascularização Fisiológica/fisiologia , Fator A de Crescimento do Endotélio Vascular/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Endotélio Vascular/efeitos dos fármacos , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Knockout , MicroRNAs/genética , Neovascularização Fisiológica/efeitos dos fármacos
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