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1.
Nat Genet ; 52(10): 1122-1131, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32895551

RESUMO

The human proteome is a major source of therapeutic targets. Recent genetic association analyses of the plasma proteome enable systematic evaluation of the causal consequences of variation in plasma protein levels. Here we estimated the effects of 1,002 proteins on 225 phenotypes using two-sample Mendelian randomization (MR) and colocalization. Of 413 associations supported by evidence from MR, 130 (31.5%) were not supported by results of colocalization analyses, suggesting that genetic confounding due to linkage disequilibrium is widespread in naïve phenome-wide association studies of proteins. Combining MR and colocalization evidence in cis-only analyses, we identified 111 putatively causal effects between 65 proteins and 52 disease-related phenotypes ( https://www.epigraphdb.org/pqtl/ ). Evaluation of data from historic drug development programs showed that target-indication pairs with MR and colocalization support were more likely to be approved, evidencing the value of this approach in identifying and prioritizing potential therapeutic targets.


Assuntos
Proteínas Sanguíneas/genética , Predisposição Genética para Doença , Análise da Randomização Mendeliana , Proteoma/genética , Estudo de Associação Genômica Ampla , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
2.
Mol Cell Proteomics ; 19(11): 1749-1759, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32788344

RESUMO

Coronavirus disease 2019 (COVID-19) is a highly contagious infection and threating the human lives in the world. The elevation of cytokines in blood is crucial to induce cytokine storm and immunosuppression in the transition of severity in COVID-19 patients. However, the comprehensive changes of serum proteins in COVID-19 patients throughout the SARS-CoV-2 infection is unknown. In this work, we developed a high-density antibody microarray and performed an in-depth proteomics analysis of serum samples collected from early COVID-19 (n = 15) and influenza (n = 13) patients. We identified a large set of differentially expressed proteins (n = 132) that participate in a landscape of inflammation and immune signaling related to the SARS-CoV-2 infection. Furthermore, the significant correlations of neutrophil and lymphocyte with the CCL2 and CXCL10 mediated cytokine signaling pathways was identified. These information are valuable for the understanding of COVID-19 pathogenesis, identification of biomarkers and development of the optimal anti-inflammation therapy.


Assuntos
Proteínas Sanguíneas/imunologia , Infecções por Coronavirus/imunologia , Tosse/imunologia , Síndrome da Liberação de Citocina/imunologia , Febre/imunologia , Cefaleia/imunologia , Influenza Humana/imunologia , Mialgia/imunologia , Pneumonia Viral/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/patogenicidade , Proteínas Sanguíneas/genética , Criança , Infecções por Coronavirus/genética , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/virologia , Tosse/genética , Tosse/fisiopatologia , Tosse/virologia , Síndrome da Liberação de Citocina/genética , Síndrome da Liberação de Citocina/fisiopatologia , Síndrome da Liberação de Citocina/virologia , Citocinas/genética , Citocinas/imunologia , Feminino , Febre/genética , Febre/fisiopatologia , Febre/virologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Cefaleia/genética , Cefaleia/fisiopatologia , Cefaleia/virologia , Humanos , Influenza Humana/genética , Influenza Humana/fisiopatologia , Influenza Humana/virologia , Masculino , Pessoa de Meia-Idade , Mialgia/genética , Mialgia/fisiopatologia , Mialgia/virologia , Orthomyxoviridae/patogenicidade , Pandemias , Pneumonia Viral/genética , Pneumonia Viral/fisiopatologia , Pneumonia Viral/virologia , Análise Serial de Proteínas , Proteoma/genética , Proteoma/imunologia , Receptores de Citocinas/genética , Receptores de Citocinas/imunologia , Transdução de Sinais/imunologia
3.
PLoS One ; 15(8): e0236754, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32756590

RESUMO

The antimalarial agent mefloquine is currently being investigated for its potential to inhibit feline coronavirus and feline calicivirus infections. A simple, high pressure liquid chromatography assay was developed to detect mefloquine plasma concentrations in feline plasma. The assay's lower limit of quantification was 250 ng/mL. The mean ± standard deviation intra- and inter-day precision expressed as coefficients of variation were 6.83 ± 1.75 and 5.33 ± 1.37%, respectively, whereas intra- and inter-day accuracy expressed as a percentage of the bias were 11.40 ± 3.73 and 10.59 ± 3.88%, respectively. Accordingly, this validated assay should prove valuable for future in vivo clinical trials of mefloquine as an antiviral agent against feline coronavirus and feline calicivirus. However, the proportion of mefloquine binding to feline plasma proteins has not been reported. The proportion of drug bound to plasma protein binding is an important concept when developing drug dosing regimens. As cats with feline infectious peritonitis (FIP) demonstrate altered concentrations of plasma proteins, the proportion of mefloquine binding to plasma proteins in both clinically normal cats and FIP-affected cats was also investigated. An in vitro method using rapid equilibrium dialysis demonstrated that mefloquine was highly plasma protein bound in both populations (on average > 99%).


Assuntos
Calicivirus Felino/efeitos dos fármacos , Coronavirus Felino/efeitos dos fármacos , Peritonite Infecciosa Felina/tratamento farmacológico , Mefloquina/farmacologia , Animais , Proteínas Sanguíneas/genética , Infecções por Caliciviridae/tratamento farmacológico , Infecções por Caliciviridae/veterinária , Infecções por Caliciviridae/virologia , Calicivirus Felino/patogenicidade , Gatos , Coronavirus Felino/patogenicidade , Peritonite Infecciosa Felina/sangue , Peritonite Infecciosa Felina/virologia , Ligação Proteica/efeitos dos fármacos
4.
PLoS One ; 15(8): e0236439, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32813744

RESUMO

Extracellular vesicles (EVs) in human blood are a potential source of biomarkers. To which extent anticoagulation affects their concentration, cellular origin and protein composition is largely unexplored. To study this, blood from 23 healthy subjects was collected in acid citrate dextrose (ACD), citrate or EDTA, or without anticoagulation to obtain serum. EVs were isolated by ultracentrifugation or by size-exclusion chromatography (SEC) for fluorescence-SEC. EVs were analyzed by micro flow cytometry, NTA, TEM, Western blot, and protein mass spectrometry. The plasma EV concentration was unaffected by anticoagulants, but serum contained more platelet EVs. The protein composition of plasma EVs differed between anticoagulants, and between plasma and serum. Comparison to other studies further revealed that the shared EV protein composition resembles the "protein corona" of synthetic nanoparticles incubated in plasma or serum. In conclusion, we have validated a higher concentration of platelet EVs in serum than plasma by contemporary EV methods. Anticoagulation should be carefully described (i) to enable study comparison, (ii) to utilize available sample cohorts, and (iii) when preparing/selecting biobank samples. Further, the similarity of the EV protein corona and that of nanoparticles implicates that EVs carry both intravesicular and extravesicular cargo, which will expand their applicability for biomarker discovery.


Assuntos
Biomarcadores/sangue , Proteínas Sanguíneas/isolamento & purificação , Vesículas Extracelulares/genética , Proteoma/genética , Adulto , Plaquetas/química , Proteínas Sanguíneas/genética , Feminino , Citometria de Fluxo/métodos , Voluntários Saudáveis , Humanos , Masculino , Espectrometria de Massas/métodos , Pessoa de Meia-Idade
5.
Nature ; 583(7817): 596-602, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32669715

RESUMO

Ageing is the single greatest cause of disease and death worldwide, and understanding the associated processes could vastly improve quality of life. Although major categories of ageing damage have been identified-such as altered intercellular communication, loss of proteostasis and eroded mitochondrial function1-these deleterious processes interact with extraordinary complexity within and between organs, and a comprehensive, whole-organism analysis of ageing dynamics has been lacking. Here we performed bulk RNA sequencing of 17 organs and plasma proteomics at 10 ages across the lifespan of Mus musculus, and integrated these findings with data from the accompanying Tabula Muris Senis2-or 'Mouse Ageing Cell Atlas'-which follows on from the original Tabula Muris3. We reveal linear and nonlinear shifts in gene expression during ageing, with the associated genes clustered in consistent trajectory groups with coherent biological functions-including extracellular matrix regulation, unfolded protein binding, mitochondrial function, and inflammatory and immune response. Notably, these gene sets show similar expression across tissues, differing only in the amplitude and the age of onset of expression. Widespread activation of immune cells is especially pronounced, and is first detectable in white adipose depots during middle age. Single-cell RNA sequencing confirms the accumulation of T cells and B cells in adipose tissue-including plasma cells that express immunoglobulin J-which also accrue concurrently across diverse organs. Finally, we show how gene expression shifts in distinct tissues are highly correlated with corresponding protein levels in plasma, thus potentially contributing to the ageing of the systemic circulation. Together, these data demonstrate a similar yet asynchronous inter- and intra-organ progression of ageing, providing a foundation from which to track systemic sources of declining health at old age.


Assuntos
Envelhecimento/genética , Envelhecimento/fisiologia , Regulação da Expressão Gênica , Especificidade de Órgãos/genética , Animais , Proteínas Sanguíneas/análise , Proteínas Sanguíneas/genética , Feminino , Cadeias J de Imunoglobulina/genética , Cadeias J de Imunoglobulina/metabolismo , Masculino , Camundongos , Plasmócitos/citologia , Plasmócitos/metabolismo , RNA Mensageiro/análise , RNA Mensageiro/genética , RNA-Seq , Análise de Célula Única , Linfócitos T/citologia , Linfócitos T/metabolismo , Fatores de Tempo , Transcriptoma
6.
Clin Appl Thromb Hemost ; 26: 1076029620943671, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32702995

RESUMO

Severe acute respiratory syndrome coronavirus 2 infection (COVID-19) is known to induce severe inflammation and activation of the coagulation system, resulting in a prothrombotic state. Although inflammatory conditions and organ-specific diseases have been shown to be strong determinants of morbidity and mortality in patients with COVID-19, it is unclear whether preexisting differences in coagulation impact the severity of COVID-19. African Americans have higher rates of COVID-19 infection and disease-related morbidity and mortality. Moreover, African Americans are known to be at a higher risk for thrombotic events due to both biological and socioeconomic factors. In this review, we explore whether differences in baseline coagulation status and medical management of coagulation play an important role in COVID-19 disease severity and contribute to racial disparity trends within COVID-19.


Assuntos
Afro-Americanos , Betacoronavirus , Infecções por Coronavirus/etnologia , Pandemias , Pneumonia Viral/etnologia , Trombofilia/etnologia , Tromboembolia Venosa/etnologia , Afro-Americanos/genética , Anemia Falciforme/sangue , Anemia Falciforme/etnologia , Anticoagulantes/uso terapêutico , Proteínas Sanguíneas/análise , Proteínas Sanguíneas/genética , Ensaios Clínicos como Assunto , Comorbidade , Infecções por Coronavirus/sangue , Infecções por Coronavirus/complicações , Fator VIII/análise , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Estudos de Associação Genética , Predisposição Genética para Doença , Disparidades em Assistência à Saúde , Humanos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/etnologia , Masculino , Seleção de Pacientes , Pneumonia Viral/sangue , Pneumonia Viral/complicações , Polimorfismo de Nucleotídeo Único , Prevalência , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/etnologia , Fatores de Risco , Determinantes Sociais da Saúde , Fatores Socioeconômicos , Trombofilia/sangue , Trombofilia/tratamento farmacológico , Trombofilia/etiologia , Tromboembolia Venosa/sangue , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/prevenção & controle
7.
Biochim Biophys Acta Proteins Proteom ; 1868(9): 140458, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32474106

RESUMO

Type 2 Diabetes (T2D) is characterized by alteration in the circulatory levels of key inflammatory proteins, where our body strives to eliminate the perturbing factor through inflammation as a final resort to restore homeostasis. Plasma proteins play a crucial role to orchestrate this immune response. Over the past two decades, rigorous genetic efforts taken to comprehend T2D physiology have been partially successful and have left behind a dearth of knowledge of its causality. Here, we have investigated how the reported genetic variants of T2D are associated with circulatory levels of key plasma proteins. We identified 99 T2D genetic variants that serve as strong pQTL (protein Quantitative Trait Loci) for 72 plasma proteins, of which 4 proteins namely Small nuclear ribonucleoprotein F [SNRPF] (p = 2.99 × 10-14), Platelet endothelial cell adhesion molecule [PECAM1] (p = 1.9 × 10-45), Trypsin-2 [PRSS2] (p = 7.6 × 10-43) and Trypsin-3 [PRSS3] (p = 5.7 × 10-8) were previously not reported for association to T2D. The genes that encode these 72 proteins were observed to be highly expressed in at least one of the four T2D relevant tissues - liver, pancreas, adipose and whole blood. Comparative analysis of interactions of the studied proteins amongst these four tissues revealed distinct molecular connectivity. Assessment of biological function by gene-set enrichment highlighted innate immune system as the lead process enacted by the identified proteins (FDR q = 3.7 × 10-16). To validate the findings, we analyzed Coronary Artery Disease (CAD) and Rheumatoid Arthritis (RA) individually and as expected, we observed innate immune system as a top enriched pathway for RA but not for CAD. Our study illuminates strong regulation of plasma proteome by the established genetic variants of T2D.


Assuntos
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/imunologia , Variação Genética , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Tecido Adiposo/metabolismo , Sangue , Proteínas Sanguíneas/genética , Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Fígado/metabolismo , Pâncreas/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Mapas de Interação de Proteínas , Tripsina/genética , Tripsinogênio/genética , Proteínas Centrais de snRNP/genética
8.
PLoS Comput Biol ; 16(6): e1007882, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32492067

RESUMO

Molecular quantitative trait locus (QTL) analyses are increasingly popular to explore the genetic architecture of complex traits, but existing studies do not leverage shared regulatory patterns and suffer from a large multiplicity burden, which hampers the detection of weak signals such as trans associations. Here, we present a fully multivariate proteomic QTL (pQTL) analysis performed with our recently proposed Bayesian method LOCUS on data from two clinical cohorts, with plasma protein levels quantified by mass-spectrometry and aptamer-based assays. Our two-stage study identifies 136 pQTL associations in the first cohort, of which >80% replicate in the second independent cohort and have significant enrichment with functional genomic elements and disease risk loci. Moreover, 78% of the pQTLs whose protein abundance was quantified by both proteomic techniques are confirmed across assays. Our thorough comparisons with standard univariate QTL mapping on (1) these data and (2) synthetic data emulating the real data show how LOCUS borrows strength across correlated protein levels and markers on a genome-wide scale to effectively increase statistical power. Notably, 15% of the pQTLs uncovered by LOCUS would be missed by the univariate approach, including several trans and pleiotropic hits with successful independent validation. Finally, the analysis of extensive clinical data from the two cohorts indicates that the genetically-driven proteins identified by LOCUS are enriched in associations with low-grade inflammation, insulin resistance and dyslipidemia and might therefore act as endophenotypes for metabolic diseases. While considerations on the clinical role of the pQTLs are beyond the scope of our work, these findings generate useful hypotheses to be explored in future research; all results are accessible online from our searchable database. Thanks to its efficient variational Bayes implementation, LOCUS can analyze jointly thousands of traits and millions of markers. Its applicability goes beyond pQTL studies, opening new perspectives for large-scale genome-wide association and QTL analyses. Diet, Obesity and Genes (DiOGenes) trial registration number: NCT00390637.


Assuntos
Teorema de Bayes , Proteínas Sanguíneas/genética , Locos de Características Quantitativas , Biomarcadores/sangue , Estudo de Associação Genômica Ampla , Humanos
9.
Eur J Endocrinol ; 183(3): 285-295, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32567559

RESUMO

Objective: Determining the factors associated with new-onset pre-diabetes and type 2 diabetes mellitus (T2D) is important for improving the current prevention strategies and for a better understanding of the disease. Design: To study the factors (clinical, circulating protein and genetic) associated with new onset pre-diabetes and T2D in an initially healthy (without diabetes) populational familial cohort with a long follow-up (STANISLAS cohort). Methods: A total of 1506 participants attended both the visit 1 and visit 4, separated by ≈20 years. Over 400 proteins, GWAS and genetic associations were studied using models adjusted for potential confounders. Both prospective (V1 to V4) and cross-sectional (V4) analyses were performed. Results: People who developed pre-diabetes (n = 555) and/or T2D (n = 73) were older, had higher BMI, blood pressure, glucose, LDL cholesterol, and lower eGFR. After multivariable selection, PAPP-A (pappalysin-1) was the only circulating protein associated with the onset of both pre-diabetes and T2D with associations persisting at visit 4 (i.e. ≈20 years later). FGF-21 (fibroblast growth factor 21) was a strong prognosticator for incident T2D in the longitudinal analysis, but not in the cross-sectional analysis. The heritability of the circulating PAPP-A was estimated at 44%. In GWAS analysis, the SNP rs634737 was associated with PAPP-A both at V1 and V4. External replication also showed lower levels of PAPP-A in patients with T2D. Conclusions: The risk of developing pre-diabetes and T2D increases with age and with features of the metabolic syndrome. Circulating PAPP-A, which has an important genetic component, was associated with both the development and presence of pre-diabetes and T2D.


Assuntos
Proteínas Sanguíneas/genética , Proteínas Sanguíneas/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Genômica/métodos , Proteômica/métodos , Adulto , Estudos de Coortes , Estudos Transversais , Diabetes Mellitus Tipo 2/sangue , Feminino , Humanos , Masculino , Estado Pré-Diabético/sangue , Estado Pré-Diabético/genética , Estado Pré-Diabético/metabolismo , Estudos Prospectivos , Fatores de Risco , Adulto Jovem
10.
PLoS Genet ; 16(6): e1008863, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32559195

RESUMO

Inactivation of the Rb tumor suppressor causes context-dependent increases in cell proliferation or cell death. In a genetic screen for factors that promoted Rb mutant cell death in Drosophila, we identified Psid, a regulatory subunit of N-terminal acetyltransferase B (NatB). We showed that NatB subunits were required for elevated EGFR/MAPK signaling and Rb mutant cell survival. We showed that NatB regulates the posttranscriptional levels of the highly conserved pathway components Grb2/Drk, MAPK, and PP2AC but not that of the less conserved Sprouty. Interestingly, NatB increased the levels of positive pathway components Grb2/Drk and MAPK while decreased the levels of negative pathway component PP2AC, which were mediated by the distinct N-end rule branch E3 ubiquitin ligases Ubr4 and Cnot4, respectively. These results suggest a novel mechanism by which NatB and N-end rule pathways modulate EGFR/MAPK signaling by inversely regulating the levels of multiple conserved positive and negative pathway components. As inactivation of Psid blocked EGFR signaling-dependent tumor growth, this study raises the possibility that NatB is potentially a novel therapeutic target for cancers dependent on deregulated EGFR/Ras signaling.


Assuntos
Proteínas Sanguíneas/metabolismo , Proteínas de Drosophila/metabolismo , Receptores ErbB/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Acetiltransferase N-Terminal B/metabolismo , Neoplasias/genética , Receptores de Peptídeos de Invertebrados/metabolismo , Acetilcoenzima A/metabolismo , Acetilação , Alelos , Animais , Animais Geneticamente Modificados , Apoptose/genética , Proteínas Sanguíneas/genética , Proliferação de Células/genética , Sobrevivência Celular/genética , Modelos Animais de Doenças , Proteínas de Drosophila/genética , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Masculino , Acetiltransferase N-Terminal B/genética , Neoplasias/patologia , Proteína do Retinoblastoma/genética , Mutações Sintéticas Letais , Fatores de Transcrição/genética
11.
PLoS Negl Trop Dis ; 14(6): e0008379, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32479494

RESUMO

Few studies have addressed gene expression of hemostasis-related factors during acute thrombo-hemorrhagic diseases. Bites by the lanced-headed viper Bothrops jaracaca induce rapid hemostatic disturbances in victims, leading to systemic bleedings, thrombocytopenia and consumption coagulopathy. Although circulating levels of coagulation factors recover rapidly after administration of specific antivenom therapy, it is unclear if B. jararaca venom (BjV) upregulates the mRNA synthesis of hepatic hemostasis-related factors, or if the recovery occurs under basal conditions after the neutralization of venom components by antivenom. Thus, we aimed to investigate if BjV regulates gene expression of important hemostasis-related factors synthetized by the liver. On that account, Swiss mice were injected with saline or BjV (1.6 mg/kg b.w, s.c.), and after 3, 6 and 24 h blood samples and liver fragments were collected to analyze mRNA expression by real-time qPCR. Increased gene expression of fibrinogen chains, haptoglobin and STAT3 was observed during envenomation, particularly at 3 and 6 h. At 24h, mRNA levels of F10 were raised, while those of Serpinc1, Proc and Adamts13 were diminished. Surprisingly, F3 mRNA levels were steadily decreased at 3 h. Gene expression of Thpo, F7, F5 Tfpi, Mug1 was unaltered. mRNA levels of Vwf, P4hb, F8, F2, Plg, and Serpinf2 were minimally altered, but showed important associations with Nfkb1 gene expression. In conclusion, snakebite envenomation upregulates hepatic mRNA synthesis particularly of fibrinogen chains, and acute-phase markers. This response explains the fast recovery of fibrinogen levels after antivenom administration to patients bitten by B. jararaca snakes.


Assuntos
Proteínas Sanguíneas/genética , Regulação da Expressão Gênica , Hemostasia/genética , Fígado/metabolismo , Mordeduras de Serpentes/metabolismo , Animais , Antivenenos/uso terapêutico , Transtornos da Coagulação Sanguínea , Bothrops/metabolismo , Modelos Animais de Doenças , Fibrinogênio/química , Fibrinogênio/genética , Fibrinogênio/metabolismo , Haptoglobinas/metabolismo , Hemorragia , Hemostáticos , Masculino , Camundongos , RNA Mensageiro/metabolismo , Fator de Transcrição STAT3/metabolismo , Mordeduras de Serpentes/sangue , Trombocitopenia , Fatores de Tempo , Fatores de Transcrição/genética
12.
Circ Heart Fail ; 13(5): e006749, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32408813

RESUMO

BACKGROUND: We used a large-scale, high-throughput DNA aptamer-based discovery proteomic platform to identify circulating biomarkers of cardiac remodeling and incident heart failure (HF) in community-dwelling individuals. METHODS: We evaluated 1895 FHS (Framingham Heart Study) participants (age 55±10 years, 54% women) who underwent proteomic profiling and echocardiography. Plasma levels of 1305 proteins were related to echocardiographic traits and to incident HF using multivariable regression. Statistically significant protein-HF associations were replicated in the HUNT (Nord-Trøndelag Health) study (n=2497, age 63±10 years, 43% women), and results were meta-analyzed. Genetic variants associated with circulating protein levels (pQTLs) were related to echocardiographic traits in the EchoGen (n=30 201) and to incident HF in the CHARGE (n=20 926) consortia. RESULTS: Seventeen proteins associated with echocardiographic traits in cross-sectional analyses (false discovery rate <0.10), and 8 of these proteins had pQTLs associated with echocardiographic traits in EchoGen (P<0.0007). In Cox models adjusted for clinical risk factors, 29 proteins demonstrated associations with incident HF in FHS (174 HF events, mean follow-up 19 [limits, 0.2-23.7] years). In meta-analyses of FHS and HUNT, 6 of these proteins were associated with incident HF (P<3.8×10-5; 3 with higher risk: NT-proBNP [N-terminal proB-type natriuretic peptide], TSP2 [thrombospondin-2], MBL [mannose-binding lectin]; and 3 with lower risk: ErbB1 [epidermal growth factor receptor], GDF-11/8 [growth differentiation factor-11/8], and RGMC [hemojuvelin]). For 5 of the 6 proteins, pQTLs were associated with echocardiographic traits (P<0.0006) in EchoGen, and for RGMC, a protein quantitative trait loci was associated with incident HF (P=0.001). CONCLUSIONS: A large-scale proteomics approach identified new predictors of cardiac remodeling and incident HF. Future studies are warranted to elucidate how biological pathways represented by these proteins may mediate cardiac remodeling and HF risk and to assess if these proteins can improve HF risk prediction.


Assuntos
Aptâmeros de Nucleotídeos , Proteínas Sanguíneas/análise , Ecocardiografia , Variação Genética , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/diagnóstico por imagem , Proteômica , Idoso , Biomarcadores/sangue , Proteínas Sanguíneas/genética , Estudos Transversais , Feminino , Predisposição Genética para Doença , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/genética , Ensaios de Triagem em Larga Escala , Humanos , Incidência , Masculino , Massachusetts/epidemiologia , Pessoa de Meia-Idade , Noruega/epidemiologia , Fenótipo , Valor Preditivo dos Testes , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Remodelação Ventricular/genética
13.
Proc Natl Acad Sci U S A ; 117(18): 9942-9951, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32321835

RESUMO

Genetic variants within complement factor H (CFH), a major alternative complement pathway regulator, are associated with the development of age-related macular degeneration (AMD) and other complementopathies. This is explained with the reduced binding of CFH or its splice variant factor H-like protein 1 (FHL-1) to self-ligands or altered self-ligands (e.g., malondialdehyde [MDA]-modified molecules) involved in homeostasis, thereby causing impaired complement regulation. Considering the critical role of CFH in inhibiting alternative pathway activation on MDA-modified surfaces, we performed an unbiased genome-wide search for genetic variants that modify the ability of plasma CFH to bind MDA in 1,830 individuals and characterized the mechanistic basis and the functional consequences of this. In a cohort of healthy individuals, we identified rs1061170 in CFH and the deletion of CFHR3 and CFHR1 as dominant genetic variants that modify CFH/FHL-1 binding to MDA. We further demonstrated that FHR1 and FHR3 compete with CFH for binding to MDA-epitopes and that FHR1 displays the highest affinity toward MDA-epitopes compared to CFH and FHR3. Moreover, FHR1 bound to MDA-rich areas on necrotic cells and prevented CFH from mediating its cofactor activity on MDA-modified surfaces, resulting in enhanced complement activation. These findings provide a mechanistic explanation as to why the deletion of CFHR3 and CFHR1 is protective in AMD and highlight the importance of genetic variants within the CFH/CFHR3/CFHR1 locus in the recognition of altered-self in tissue homeostasis.


Assuntos
Proteínas Sanguíneas/genética , Proteínas Inativadoras do Complemento C3b/genética , Degeneração Macular/genética , Idoso , Fator H do Complemento/genética , Epitopos/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Degeneração Macular/patologia , Masculino , Malondialdeído/metabolismo , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Ligação Proteica
14.
Sci Rep ; 10(1): 4528, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32161285

RESUMO

Dysregulated cholesterol homeostasis promotes the pathology of atherosclerosis, myocardial infarction and strokes. Cellular cholesterol is mainly regulated at the transcriptional level by SREBP2, but also through uptake of extracellular cholesterol from low density lipoproteins (LDL) via expression of LDL receptors (LDLR) at the cell surface. Identification of the mechanisms involved in regulation of these processes are thus key to understand the pathology of coronary artery disease. Here, we identify the large and poorly characterized BEACH domain protein Neurobeachin-like (NBEAL) 1 as a Golgi- associated protein required for regulation of cholesterol metabolism. NBEAL1 is most abundantly expressed in arteries. Genetic variants in NBEAL1 are associated with decreased expression of NBEAL1 in arteries and increased risk of coronary artery disease in humans. We show that NBEAL1 regulates cholesterol metabolism by modulating LDLR expression in a mechanism involving interaction with SCAP and PAQR3 and subsequent SREBP2-processing. Thus, low expression of NBEAL1 may lead to increased risk of coronary artery disease by downregulation of LDLR levels.


Assuntos
Proteínas Sanguíneas/genética , Proteínas Sanguíneas/metabolismo , Colesterol/metabolismo , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/metabolismo , Suscetibilidade a Doenças , Locos de Características Quantitativas , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Biomarcadores , Linhagem Celular , Regulação da Expressão Gênica , Humanos , Metabolismo dos Lipídeos
15.
Int J Radiat Biol ; 96(6): 748-758, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32149567

RESUMO

Purpose: Simple, rapid and high-throughput dose assessment is critical for clinical diagnosis, treatment and emergency intervention in a large-scale radiological accident. The goal of this study is to screen and identify new ionizing radiation-responsive protein biomarkers in rat plasma.Materials and methods: Sprague-Dawley rats were exposed to single doses of 0, 1, 3, 5 Gy of Cobalt-60 γ-rays total body irradiation at a dose rate of 1 Gy/min. The tandem mass tag labeling (TMT) combined with liquid chromatography mass spectrometry (LC-MS/MS) approach was used to screen the differentially expressed proteins in rat plasma collected at 1, 3, 5 and 7 days post-irradiation. Bioinformatics analysis was conducted to explore the biological functions of these proteins. The expression levels of candidate radiation-sensitive protein biomarkers were confirmed using enzyme-linked immune-sorbent assay (ELISA).Results: A total of 503 differentially expressed proteins were identified. Most of these proteins were implicated in immune response, phagocytosis and signal transduction following ionizing radiation. Five up-regulated proteins including alpha-2-macroglobulin (A2m), chromogranin-A (CHGA), glutathione pertidase 3 (GPX3), clusterin (Clu) and ceruloplasmin (Cp) were selected for ELISA analysis. It was found that the expression levels of A2m, CHGA and GPX3 protein were increased in a dose-dependent manner at 1, 3 and 5 days after irradiation.Conclusion: Proteomics analysis revealed radiation-induced differentially expressed proteins in rat plasma. Our results suggested that A2m, CHGA, GPX3 protein expressions alterations in rat plasma may have potential as biomarkers to evaluate radiation exposure.


Assuntos
Proteínas Sanguíneas/metabolismo , Raios gama/efeitos adversos , Regulação da Expressão Gênica/efeitos da radiação , Animais , Biomarcadores/sangue , Proteínas Sanguíneas/genética , Ontologia Genética , Mapas de Interação de Proteínas/efeitos da radiação , Ratos , Ratos Sprague-Dawley
16.
Mol Immunol ; 120: 113-121, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32113131

RESUMO

Litopenaeus vannamei, as an important marine aquaculture species, has attracted more and more attentions in past several years. More recently people got its genome fine mapping, which unveiled a gene treasure. In this study, we have identified a novel trypsin-like protein which came from previous WSSV-infected shrimp plasma iTRAQ data. This protein is a 39 kDa protein with 363 amino acids. It contains a conserved trypsin-domain and could be strongly induced with WSSV infection. Interestingly, knockdown of this protein made shrimps vulnerable to WSSV infection. Further exploration unveiled that this fragility was probably due to the fact that knockdown of this protein could cause shrimp hemocytes apoptosis, which indicated that this protein played key roles in preventing shrimp hemocytes from apoptosis. To further explore how LvTLAP protected shrimp hemocytes from apoptosis, GST pull down assay was applied to screen LvTLAP interacting protein in shrimp plasma. L. vannamei growth and transformation-dependent-like protein (LvGTD-like protein) was identified as a LvTLAP interacting protein, which played proapoptotic roles in cells. Thus, a possible explanation for LvTLAP anti-apoptosis activity was that this protein could block LvGTD-like protein proapoptotic activity to protect shrimp hemocytes from death. In general, our study has uncovered a novel WSSV responsive shrimp plasma protein, which played key roles in shrimp hemocytes anti-apoptosis and shrimp against WSSV infection.


Assuntos
Proteínas Sanguíneas/imunologia , Penaeidae/imunologia , Penaeidae/virologia , Vírus da Síndrome da Mancha Branca 1/patogenicidade , Sequência de Aminoácidos , Animais , Apoptose/genética , Apoptose/imunologia , Apoptose/fisiologia , Sequência de Bases , Proteínas Sanguíneas/química , Proteínas Sanguíneas/genética , DNA/genética , Técnicas de Silenciamento de Genes , Hemócitos/metabolismo , Hemócitos/patologia , Hemócitos/virologia , Penaeidae/genética
17.
Benef Microbes ; 11(2): 183-189, 2020 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-32028777

RESUMO

Related to previous reports on correlations between an animal's genotype, its commensal microbiota, and the ability to resist infections, the aim of the current study was to investigate the associations between sheep genotype and 5-methylcytosine (5-mC) DNA methylation patterns, sheep genotype and cell surface hydrophobicity of sheep gut commensal bacteria. In addition, the effect of the probiotic Lactobacillus acidophilus strain INMIA 9602 Er 317/402 (probiotic formulation Narine) on Salmonella carriage in sheep at Armenian farms was also investigated. Allelotypes and genotypes of different pathogen-sensitive sheep breeds from Armenian farms were studied based on genetic markers of blood transferrin, albumin, and ceruloplasmin. Additionally, the differences between the breeds of Mazekh, Balbas, and Mazekh/Balbas hybrids were reported. The relationship between host sheep blood transferrin and albumin polymorphisms and cell surface hydrophobicity/5-mC DNA methylation patterns from the predominant gut commensal bacteria was shown. The Narine probiotic eliminates Salmonella from the sheep gut microbiota. At the same time, no significant changes in the percentage of 5-mC DNA methylation of predominant gut bacteria after probiotic administration were observed. The evaluation of bacterial cell surface hydrophobicity, the most significant factor affecting bacterial adhesion, as well as 5-mC DNA methylation, might be used for specific sheep husbandry/breeding programs. This study suggests that the commercial probiotic Narine could potentially be used to reduce Salmonella carriage in sheep.


Assuntos
Proteínas Sanguíneas/genética , Portador Sadio/veterinária , Microbioma Gastrointestinal , Lactobacillus acidophilus/fisiologia , Probióticos/administração & dosagem , Salmonella , 5-Metilcitosina/metabolismo , Animais , Armênia , Aderência Bacteriana , Portador Sadio/microbiologia , Portador Sadio/prevenção & controle , Metilação de DNA , Fazendas/estatística & dados numéricos , Genoma Bacteriano , Genótipo , Interações Hidrofóbicas e Hidrofílicas , Polimorfismo Genético , Ovinos/genética , Ovinos/microbiologia , Doenças dos Ovinos/microbiologia , Doenças dos Ovinos/prevenção & controle
18.
Am J Hum Genet ; 106(3): 303-314, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32059761

RESUMO

Disease risk varies significantly between ethnic groups, however, the clinical significance and implications of these observations are poorly understood. Investigating ethnic differences within the human proteome may shed light on the impact of ancestry on disease risk. We used admixture mapping to explore the impact of genetic ancestry on 237 cardiometabolic biomarkers in 2,216 Latin Americans within the Outcomes Reduction with an Initial Glargine Intervention (ORIGIN) study. We developed a variance component model in order to determine the proportion of variance explained by inter-ancestry differences, and we applied it to the biomarker panel. Multivariable linear regression was used to identify and localize genetic loci affecting biomarker variability between ethnicities. Variance component analysis revealed that 5% of biomarkers were significantly impacted by genetic admixture (p < 0.05/237), including C-peptide, apolipoprotein-E, and intercellular adhesion molecule 1. We also identified 46 regional associations across 40 different biomarkers (p < 1.13 × 10-6). An independent analysis revealed that 34 of these 46 regions were associated at genome-wide significance (p < 5 × 10-8) with their respective biomarker in either Europeans or Latin populations. Additional analyses revealed that an admixture mapping signal associated with increased C-peptide levels was also associated with an increase in diabetes risk (odds ratio [OR] = 6.07 per SD, 95% confidence interval [CI] 1.44 to 25.56, p = 0.01) and surrogate measures of insulin resistance. Our results demonstrate the impact of ancestry on biomarker levels, suggesting that some of the observed differences in disease prevalence have a biological basis, and that reference intervals for those biomarkers should be tailored to ancestry. Specifically, our results point to a strong role of ancestry in insulin resistance and diabetes risk.


Assuntos
Proteínas Sanguíneas/genética , Grupos Populacionais/genética , Proteoma , Biomarcadores/metabolismo , Humanos
19.
Int J Hematol ; 111(3): 352-359, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31894534

RESUMO

Hemoglobin (Hb) is an iron-containing metalloprotein that transports oxygen molecules from the lungs to the rest of the human body. Among the different variants of Hb, HbA1 is the most common and is composed of two alpha (αHb) and two beta globin chains (ßHb) constructing a heterotetrameric protein complex (α2ß2). Due to the higher number of AHSP genes, there is a tendency to produce approximately twice as much of α subunit as ß subunit. Therefore, there is a chance of presenting excess α subunit leftover in human blood plasma; excess subunits subsequently bind with each other and aggregates ß-thalassemia occurs due to lack of or reduced numbers of ßHb subunit. Alpha-hemoglobin-stabilizing protein (AHSP) is a scavenger protein which acts as a molecular chaperon by reversibly binding with free αHb forming a complex (AHSP-αHb) that prevents aggregation and precipitation preventing deleterious effects towards developing serious human diseases including ß-thalassemia. Clinical severity worsens if mutations in AHSP gene co-occur in patients with ß-thalassemia. Considering the mechanism of action of AHSP and its contribution to ameliorating ß-thalassemia severity, it could potentially be used as a modulatory agent in the treatment of ß-thalassemia.


Assuntos
Proteínas Sanguíneas/genética , Proteínas Sanguíneas/fisiologia , Chaperonas Moleculares/genética , Chaperonas Moleculares/fisiologia , Talassemia beta/genética , Humanos
20.
Nat Commun ; 11(1): 15, 2020 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-31900413

RESUMO

DNA methylation and blood circulating proteins have been associated with many complex disorders, but the underlying disease-causing mechanisms often remain unclear. Here, we report an epigenome-wide association study of 1123 proteins from 944 participants of the KORA population study and replication in a multi-ethnic cohort of 344 individuals. We identify 98 CpG-protein associations (pQTMs) at a stringent Bonferroni level of significance. Overlapping associations with transcriptomics, metabolomics, and clinical endpoints suggest implication of processes related to chronic low-grade inflammation, including a network involving methylation of NLRC5, a regulator of the inflammasome, and associated pQTMs implicating key proteins of the immune system, such as CD48, CD163, CXCL10, CXCL11, LAG3, FCGR3B, and B2M. Our study links DNA methylation to disease endpoints via intermediate proteomics phenotypes and identifies correlative networks that may eventually be targeted in a personalized approach of chronic low-grade inflammation.


Assuntos
Proteínas Sanguíneas/genética , Inflamação/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimiocina CXCL10/genética , Estudos de Coortes , Ilhas de CpG , Metilação de DNA , Epigenoma , Epigenômica , Feminino , Proteínas Ligadas por GPI/genética , Alemanha , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Pessoa de Meia-Idade , Proteômica , Receptores de IgG/genética
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