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1.
BMC Biol ; 19(1): 5, 2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33441133

RESUMO

BACKGROUND: Viruses are ubiquitous biological entities, estimated to be the largest reservoirs of unexplored genetic diversity on Earth. Full functional characterization and annotation of newly discovered viruses requires tools to enable taxonomic assignment, the range of hosts, and biological properties of the virus. Here we focus on prokaryotic viruses, which include phages and archaeal viruses, and for which identifying the viral host is an essential step in characterizing the virus, as the virus relies on the host for survival. Currently, the method for determining the viral host is either to culture the virus, which is low-throughput, time-consuming, and expensive, or to computationally predict the viral hosts, which needs improvements at both accuracy and usability. Here we develop a Gaussian model to predict hosts for prokaryotic viruses with better performances than previous computational methods. RESULTS: We present here Prokaryotic virus Host Predictor (PHP), a software tool using a Gaussian model, to predict hosts for prokaryotic viruses using the differences of k-mer frequencies between viral and host genomic sequences as features. PHP gave a host prediction accuracy of 34% (genus level) on the VirHostMatcher benchmark dataset and a host prediction accuracy of 35% (genus level) on a new dataset containing 671 viruses and 60,105 prokaryotic genomes. The prediction accuracy exceeded that of two alignment-free methods (VirHostMatcher and WIsH, 28-34%, genus level). PHP also outperformed these two alignment-free methods much (24-38% vs 18-20%, genus level) when predicting hosts for prokaryotic viruses which cannot be predicted by the BLAST-based or the CRISPR-spacer-based methods alone. Requiring a minimal score for making predictions (thresholding) and taking the consensus of the top 30 predictions further improved the host prediction accuracy of PHP. CONCLUSIONS: The Prokaryotic virus Host Predictor software tool provides an intuitive and user-friendly API for the Gaussian model described herein. This work will facilitate the rapid identification of hosts for newly identified prokaryotic viruses in metagenomic studies.

2.
Epigenetics ; : 1-12, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33319642

RESUMO

IgA nephropathy (IgAN) is the most common primary glomerular disease in China and worldwide. The proliferation of B cells is known to be associated with both risk and prognosis of IgAN, but the epigenetic mechanism underlying this association is unknown. In this study we carried out the first Epigenome-wide Association Study (EWAS) by using the latest Infinium Methylation EPIC BeadChip on 184 B cell-specific samples (92 case/control pairs) for Chinese IgAN population. After rigorous data normalization and residual batch effect correction, linear mixed effect model was used to detect methylation CpG sites associated with IgAN adjusting for age, gender and smoking. False discovery rate (FDR) less than 10% was used to account for multiple testing. Weighted gene co-methylation networks were generated to identify gene modules highly correlated with IgAN. A permutation test was performed to account for the potential effect of overfitting. After adjusting clinical covariates and potential technical batch effects, three CpGs corresponding to PCDH17, TERT, WDR82 genes and three in the intergenic regions passed the genome-wide significant threshold. Methylation network analysis identified an additional IgAN associated gene module, containing 72 significant CpGs including GALNT6, IQSEC1, CDC16 and SYS1, involved in the pathway related to tubular atrophy/interstitial fibrosis of IgAN. These results suggested important DNA methylation and gene targets in CD19+ B cells for the pathogenesis of IgAN.

3.
Brief Bioinform ; 2020 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-33333556

RESUMO

African swine fever virus (ASFV) poses serious threats to the pig industry. The multigene family (MGF) proteins are extensively distributed in ASFVs and are generally classified into five families, including MGF-100, MGF-110, MGF-300, MGF-360 and MGF-505. Most MGF proteins, however, have not been well characterized and classified within each family. To bridge this gap, this study first classified MGF proteins into 31 groups based on protein sequence homology and network clustering. A web server for classifying MGF proteins was established and kept available for free at http://www.computationalbiology.cn/MGF/home.html. Results showed that MGF groups of the same family were most similar to each other and had conserved sequence motifs; the genetic diversity of MGF groups varied widely, mainly due to the occurrence of indels. In addition, the MGF proteins were predicted to have large structural and functional diversity, and MGF proteins of the same MGF family tended to have similar structure, location and function. Reconstruction of the ancestral states of MGF groups along the ASFV phylogeny showed that most MGF groups experienced either the copy number variations or the gain-or-loss changes, and most of these changes happened within strains of the same genotype. It is found that the copy number decrease and the loss of MGF groups were much larger than the copy number increase and the gain of MGF groups, respectively, suggesting the ASFV tended to lose MGF proteins in the evolution. Overall, the work provides a detailed classification for MGF proteins and would facilitate further research on MGF proteins.

4.
Chest ; 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33189655

RESUMO

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a devastating syndrome with heterogeneous subtypes, but few causal biomarkers have been identified. RESEARCH QUESTION: Would multi-stage Mendelian randomization identify new causal protein biomarkers for ARDS 28-day mortality? STUDY DESIGN AND METHODS: Three hundred moderate to severe ARDS patients were randomly selected from the Molecular Epidemiology of ARDS (MEARDS) cohort for proteomics analysis. Orthogonal projections to latent structures discriminant analysis (OPLS-DA) was applied to detect the association between proteins and ARDS 28-day mortality. Candidate proteins were analyzed using generalized summary data-based Mendelian randomization (GSMR). Protein quantitative trait summary statistics were retrieved from the INTERVAL study (n=2,504), and a genome-wide association study for ARDS was conducted from the Identification of SNPs Predisposing to Altered Acute Lung Injury Risk (iSPAAR) consortium study (n=534). Causal mediation analysis detected the role of platelet count in mediating the effect of protein on ARDS prognosis. RESULTS: Plasma IGFBP7 moderately increased ARDS 28-day mortality [Odd Ratio (OR)=1·11, 95%CI=1·04-1·19, P=1·80×10-3] per log2-increase. GSMR analysis coupled with four other Mendelian randomization methods revealed IGFBP7 as a causal biomarker for ARDS 28-day mortality (OR=2·61, 95%CI=1·33-5·13, P=5·31×10-3). Causal mediation analysis indicated that the association between IGFBP7 and ARDS 28-day mortality is mediated by platelet count (OR=1·03, 95%CI=1·02-1·04, P=0·01). INTERPRETATION: We identified plasma IGFBP7 as a novel causal protein involved in the pathogenesis of ARDS 28-day mortality and platelet function in ARDS, a topic for further experimental and clinical investigation.

5.
Hum Genet ; 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33170346

RESUMO

Page 4: In the "Results-Genetic correlation between AD and metabolic traits" section, the sentence "We also observed that HDL had a significant genetic correlation with AD (Rg = -0.137, P = 0.0436)" should be "We also observed that HDL had a significant genetic correlation with AD (Rg = 0.322, P = 0.017)".

6.
Crit Care Explor ; 2(10): e0241, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33134939

RESUMO

Objectives: Acute respiratory distress syndrome is characterized by an overly exuberant inflammatory state in the lung. Specialized proresolving mediators are endogenous agonists for the resolution of lung inflammation and injury in health, yet their association with acute respiratory distress syndrome severity and outcomes remains to be defined. In the current study, we investigate associations between plasma levels of specialized proresolving mediators and acute respiratory distress syndrome severity and mortality. Design: Translational pilot study nested within a large prospective cohort of patients with risk factors for acute respiratory distress syndrome. Setting: ICU from a large medical center. Patients: Twenty-six Caucasian patients with acute respiratory distress syndrome and available plasma from early in critical illness. Interventions: None. Measurements and Main Results: Here, in samples from 26 acute respiratory distress syndrome patients, we examined plasma levels of select specialized proresolving mediators that promote lung injury resolution in preclinical systems, namely lipoxin A4 and maresin 1, and select prophlogistic lipid mediators linked to acute respiratory distress syndrome pathogenesis, namely cysteinyl leukotrienes and thromboxane B2. These mediators were detected by sensitive enzyme-linked immunosorbent assay: lipoxin A4 (assay range) (8.2-5,000 pg/mL), maresin 1 (7.8-1,000 pg/mL), cysteinyl leukotrienes (7.8-1,000 pg/mL), and thromboxane B2 (15.6-2,000 pg/mL). Lower plasma levels of specialized proresolving mediators were associated with increased duration of ventilatory support and ICU length of stay. Even in this small sample size, trends were evident for increased cysteinyl leukotrienes to specialized proresolving mediator ratios (cysteinyl leukotrienes/maresin 1 and cysteinyl leukotrienes/lipoxin A4) in acute respiratory distress syndrome nonsurvivors. Conclusions: Lower specialized proresolving mediator levels in acute respiratory distress syndrome patients may disrupt timely resolution of lung inflammation and/or injury and contribute to clinical severity and mortality.

7.
Genet Med ; 2020 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-32873934

RESUMO

PURPOSE: Erythropoietic protoporphyria (EPP), characterized by painful cutaneous photosensitivity, results from pathogenic variants in ferrochelatase (FECH). For 96% of patients, EPP results from coinheriting a rare pathogenic variant in trans of a common hypomorphic variant c.315-48T>C (minor allele frequency 0.05). The estimated prevalence of EPP derived from the number of diagnosed individuals in Europe is 0.00092%, but this may be conservative due to underdiagnosis. No study has estimated EPP prevalence using large genetic data sets. METHODS: Disease-associated FECH variants were identified in the UK Biobank, a data set of 500,953 individuals including 49,960 exome sequences. EPP prevalence was then estimated. The association of FECH variants with EPP-related traits was assessed. RESULTS: Analysis of pathogenic FECH variants in the UK Biobank provides evidence that EPP prevalence is 0.0059% (95% confidence interval [CI]: 0.0042-0.0076%), 1.7-3.0 times more common than previously thought in the UK. In homozygotes for the common c.315-48T>C FECH variant, there was a novel decrement in both erythrocyte mean corpuscular volume (MCV) and hemoglobin. CONCLUSION: The prevalence of EPP has been underestimated secondary to underdiagnosis. The common c.315-48T>C allele is associated with both MCV and hemoglobin, an association that could be important both for those with and without EPP.

8.
Mol Plant ; 13(10): 1434-1454, 2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-32896643

RESUMO

The molecular mechanism by which plants defend against plant root-knot nematodes (RKNs) is largely unknown. The plant receptor kinase FERONIA and its peptide ligands, rapid alkalinization factors (RALFs), regulate plant immune responses and cell expansion, which are two important factors for successful RKN parasitism. In this study, we found that mutation of FERONIA in Arabidopsis thaliana resulted in plants showing low susceptibility to the RKN Meloidogyne incognita. To identify the underlying mechanisms associated with this phenomenon, we identified 18 novel RALF-likes from multiple species of RKNs and showed that two RALF-likes (i.e., MiRALF1 and MiRALF3) from M. incognita were expressed in the esophageal gland with high expression during the parasitic stages of nematode development. These nematode RALF-likes also possess the typical activities of plant RALFs and can directly bind to the extracellular domain of FERONIA to modulate specific steps of nematode parasitism-related immune responses and cell expansion. Genetically, both MiRALF1/3 and FERONIA are required for RKN parasitism in Arabidopsis and rice. Collectively, our study suggests that nematode-encoded RALFs facilitate parasitism via plant-encoded FERONIA and provides a novel paradigm for studying host-pathogen interactions.

9.
Metabolism ; 112: 154345, 2020 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-32835759

RESUMO

OBJECTIVE: We aimed to examine the associations of obesity-related traits (body mass index [BMI], central obesity) and their genetic predisposition with the risk of developing severe COVID-19 in a population-based data. RESEARCH DESIGN AND METHODS: We analyzed data from 489,769 adults enrolled in the UK Biobank-a population-based cohort study. The exposures of interest are BMI categories and central obesity (e.g., larger waist circumference). Using genome-wide genotyping data, we also computed polygenic risk scores (PRSs) that represent an individual's overall genetic risk for each obesity trait. The outcome was severe COVID-19, defined by hospitalization for laboratory-confirmed COVID-19. RESULTS: Of 489,769 individuals, 33% were normal weight (BMI, 18.5-24.9 kg/m2), 43% overweight (25.0-29.9 kg/m2), and 24% obese (≥30.0 kg/m2). The UK Biobank identified 641 patients with severe COVID-19. Compared to adults with normal weight, those with a higher BMI had a dose-response increases in the risk of severe COVID-19, with the following adjusted ORs: for 25.0-29.9 kg/m2, 1.40 (95%CI 1.14-1.73; P = 0.002); for 30.0-34.9 kg/m2, 1.73 (95%CI 1.36-2.20; P < 0.001); for 35.0-39.9 kg/m2, 2.82 (95%CI 2.08-3.83; P < 0.001); and for ≥40.0 kg/m2, 3.30 (95%CI 2.17-5.03; P < 0.001). Likewise, central obesity was associated with significantly higher risk of severe COVID-19 (P < 0.001). Furthermore, larger PRS for BMI was associated with higher risk of outcome (adjusted OR per BMI PRS Z-score 1.14, 95%CI 1.05-1.24; P = 0.004). CONCLUSIONS: In this large population-based cohort, individuals with more-severe obesity, central obesity, or genetic predisposition for obesity are at higher risk of developing severe-COVID-19.

10.
Artigo em Inglês | MEDLINE | ID: mdl-32693092

RESUMO

Asthma is a heterogeneous respiratory disease reflecting distinct pathobiologic mechanisms. These mechanisms are based, at least partly, on different genetic factors shared by many other conditions, such as allergic diseases and obesity. Investigating the shared genetic effects enables better understanding of the mechanisms of phenotypic correlations and is less subject to confounding by environmental factors. The increasing availability of large-scale genome-wide association study (GWAS) for asthma has enabled researchers to examine the genetic contributions to the epidemiologic associations between asthma subtypes and those between coexisting diseases and/or traits and asthma. Studies have found not only shared but also distinct genetic components between asthma subtypes, indicating that the heterogeneity is related to distinct genetics. This review summarizes a recently compiled analytic approach-genome-wide cross-trait analysis-to determine shared and distinct genetic architecture. The genome-wide cross-trait analysis features in several analytic aspects: genetic correlation, cross-trait meta-analysis, Mendelian randomization, polygenic risk score, and functional analysis. In this article, we discuss in detail the scientific goals that can be achieved by these analyses, their advantages, and their limitations. We also make recommendations for future directions: (1) ethnicity-specific asthma GWASs and (2) application of cross-trait methods to multiomics data to dissect the heritability found in GWASs. Finally, these analytic approaches are also applicable to complex and heterogeneous traits beyond asthma.

12.
Brief Bioinform ; 2020 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-32349124

RESUMO

Circular RNAs (circRNAs) are covalently closed long noncoding RNAs critical in diverse cellular activities and multiple human diseases. Several cancer-related viral circRNAs have been identified in double-stranded DNA viruses (dsDNA), yet no systematic study about the viral circRNAs has been reported. Herein, we have performed a systematic survey of 11 924 circRNAs from 23 viral species by computational prediction of viral circRNAs from viral-infection-related RNA sequencing data. Besides the dsDNA viruses, our study has also revealed lots of circRNAs in single-stranded RNA viruses and retro-transcribing viruses, such as the Zika virus, the Influenza A virus, the Zaire ebolavirus, and the Human immunodeficiency virus 1. Most viral circRNAs had reverse complementary sequences or repeated sequences at the flanking sequences of the back-splice sites. Most viral circRNAs only expressed in a specific cell line or tissue in a specific species. Functional enrichment analysis indicated that the viral circRNAs from dsDNA viruses were involved in KEGG pathways associated with cancer. All viral circRNAs presented in the current study were stored and organized in VirusCircBase, which is freely available at http://www.computationalbiology.cn/ViruscircBase/home.html and is the first virus circRNA database. VirusCircBase forms the fundamental atlas for the further exploration and investigation of viral circRNAs in the context of public health.

13.
PeerJ ; 8: e8855, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32274268

RESUMO

The African swine fever virus (ASFV) has severely influenced the swine industry of the world. Unfortunately, there is currently no effective antiviral drug or vaccine against the virus. Identification of new anti-ASFV drugs is urgently needed. Here, an up-to-date set of protein-protein interactions between ASFV and swine were curated by integration of protein-protein interactions from multiple sources. Thirty-eight swine proteins were observed to interact with ASFVs and were defined as ASFV-interacting swine proteins. The ASFV-interacting swine proteins were found to play a central role in the swine protein-protein interaction network, with significant larger degree, betweenness and smaller shortest path length than other swine proteins. Some of ASFV-interacting swine proteins also interacted with several other viruses and could be taken as potential targets of drugs for broad-spectrum effect, such as HSP90AB1. Finally, the antiviral drugs which targeted ASFV-interacting swine proteins and ASFV proteins were predicted. Several drugs with either broad-spectrum effect or high specificity on ASFV-interacting swine proteins were identified, such as Polaprezinc and Geldanamycin. Structural modeling and molecular dynamics simulation showed that Geldanamycin could bind with swine HSP90AB1 stably. This work could not only deepen our understanding towards the ASFV-swine interactions, but also help for the development of effective antiviral drugs against the ASFVs.

14.
Cell Host Microbe ; 27(3): 325-328, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32035028

RESUMO

An in-depth annotation of the newly discovered coronavirus (2019-nCoV) genome has revealed differences between 2019-nCoV and severe acute respiratory syndrome (SARS) or SARS-like coronaviruses. A systematic comparison identified 380 amino acid substitutions between these coronaviruses, which may have caused functional and pathogenic divergence of 2019-nCoV.


Assuntos
Betacoronavirus/classificação , Infecções por Coronavirus/virologia , Genoma Viral , Filogenia , Pneumonia Viral/virologia , Substituição de Aminoácidos , China , Coronavírus da Síndrome Respiratória do Oriente Médio , Pandemias , Vírus da SARS
15.
Cancer Causes Control ; 31(3): 273-282, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32006205

RESUMO

PURPOSE: The relationship of allergic diseases, such as asthma, hay fever, and eczema, with cancer is under debate. Observational studies have reported conflicting findings, but such studies are susceptible to confounding and reverse causation. Understanding the potential role of allergy in carcinogenesis may shed new light on the biological mechanisms underpinning intrinsic immunity and cancer. METHODS: We conducted a Mendelian randomization study, using germline genetic variants as instrumental variables, to determine the causal relevance of allergic disease and on two most common malignancies: breast cancer and prostate cancer. We used the summary statistics from the largest ever genome-wide association studies conducted on allergic disease (ncase = 180,129), asthma (ncase = 14,085), breast (ncase = 122,977), and prostate cancer (ncase = 79,148) and calculated odds ratios (ORs) and 95% confidence intervals (CIs) of cancer for allergic disease. RESULTS: We did not observe any evidence to support a causal association between allergic disease and risk of breast cancer overall [OR 1.00 (95% CI 0.96-1.04), p = 0.95] or by subtype (estrogen receptor (ER)+ [0.99 (0.95-1.04), p = 0.71], ER- [1.05 (0.99-1.10), p = 0.11]). We also did not find any evidence for an association with prostate cancer [1.00 (0.94-1.05), p = 0.93] or advanced subtype [0.97 (0.90-1.05), p = 0.46]. Sensitivity analyses did not reveal directional pleiotropy. CONCLUSION: Our study does not support a causal effect of allergic disease on the risk of breast or prostate cancer. Future studies may be conducted to focus on understanding the causal role of allergic disease in cancer prognosis or drug responses (e.g., immunotherapy).


Assuntos
Asma/complicações , Neoplasias da Mama/imunologia , Neoplasias da Próstata/imunologia , Asma/genética , Neoplasias da Mama/genética , Estudos de Casos e Controles , Suscetibilidade a Doenças , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Razão de Chances , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética
16.
J Allergy Clin Immunol ; 145(2): 537-549, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31669095

RESUMO

BACKGROUND: Clinical and epidemiologic studies have shown that obesity is associated with asthma and that these associations differ by asthma subtype. Little is known about the shared genetic components between obesity and asthma. OBJECTIVE: We sought to identify shared genetic associations between obesity-related traits and asthma subtypes in adults. METHODS: A cross-trait genome-wide association study (GWAS) was performed using 457,822 subjects of European ancestry from the UK Biobank. Experimental evidence to support the role of genes significantly associated with both obesity-related traits and asthma through a GWAS was sought by using results from obese versus lean mouse RNA sequencing and RT-PCR experiments. RESULTS: We found a substantial positive genetic correlation between body mass index and later-onset asthma defined by asthma age of onset at 16 years or greater (Rg = 0.25, P = 9.56 × 10-22). Mendelian randomization analysis provided strong evidence in support of body mass index causally increasing asthma risk. Cross-trait meta-analysis identified 34 shared loci among 3 obesity-related traits and 2 asthma subtypes. GWAS functional analyses identified potential causal relationships between the shared loci and Genotype-Tissue Expression (GTEx) quantitative trait loci and shared immune- and cell differentiation-related pathways between obesity and asthma. Finally, RNA sequencing data from lungs of obese versus control mice found that 2 genes (acyl-coenzyme A oxidase-like [ACOXL] and myosin light chain 6 [MYL6]) from the cross-trait meta-analysis were differentially expressed, and these findings were validated by using RT-PCR in an independent set of mice. CONCLUSIONS: Our work identified shared genetic components between obesity-related traits and specific asthma subtypes, reinforcing the hypothesis that obesity causally increases the risk of asthma and identifying molecular pathways that might underlie both obesity and asthma.


Assuntos
Asma/genética , Predisposição Genética para Doença/genética , Obesidade/genética , Adulto , Animais , Bancos de Espécimes Biológicos , Índice de Massa Corporal , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Camundongos , Reino Unido
17.
BMC Pulm Med ; 19(1): 196, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31684936

RESUMO

BACKGROUND: Epidemiologic studies have shown inconsistent conclusions about the effect of ulinastain treatment for acute respiratory distress syndrome (ARDS). It is necessary to perform a meta-analysis of ulinastatin's randomized controlled trials (RCTS) to evaluate its efficacy for treating ARDS. METHODS: We searched the published RCTs of ulinastatin treatment for ARDS from nine databases (the latest search on April 30th, 2017). Two authors independently screened citations and extracted data. The meta-analysis was performed using Rev. Man 5.3 software. RESULTS: A total of 33 RCTs involving 2344 patients satisfied the selection criteria and were included in meta-analysis. The meta-analysis showed that, compared to conventional therapy, ulinastatin has a significant benefit for ARDS patients by reducing mortality (RR = 0.51, 95% CI:0.43~0.61) and ventilator associated pneumonia rate (RR = 0.50, 95% CI: 0.36~0.69), and shortening duration of mechanical ventilation (SMD = -1.29, 95% CI: -1.76~-0.83), length of intensive care unit stay (SMD = -1.38, 95% CI: -1.95~-0.80), and hospital stay (SMD = -1.70, 95% CI:-2.63~-0.77). Meanwhile, ulinastatin significantly increased the patients' oxygenation index (SMD = 2.04, 95% CI: 1.62~2.46) and decreased respiratory rate (SMD = -1.08, 95% CI: -1.29~-0.88) and serum inflammatory factors (tumor necrosis factor-α: SMD = -3.06, 95% CI:-4.34~-1.78; interleukin-1ß: SMD = -3.49, 95% CI: -4.64~-2.34; interleukin-6: SMD = -2.39, 95% CI: -3.34~-1.45; interleukin-8: SMD = -2.43, 95% CI: -3.86~-1.00). CONCLUSIONS: Ulinastatin seemly showed a beneficial effect for ARDS patients treatment and larger sample sized RCTs are needed to confirm our findings.


Assuntos
Glicoproteínas/uso terapêutico , Pneumonia Associada à Ventilação Mecânica/etiologia , Respiração Artificial/efeitos adversos , /terapia , Humanos , Unidades de Terapia Intensiva , Tempo de Internação , Pneumonia Associada à Ventilação Mecânica/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
18.
J Am Coll Cardiol ; 74(17): 2162-2174, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31648709

RESUMO

BACKGROUND: High resting heart rate (RHR) occurs in parallel with type 2 diabetes (T2D) and metabolic disorders, implying shared etiology between them. However, it is unknown if they are causally related, and no study has been conducted to investigate the shared mechanisms underlying these associations. OBJECTIVES: The objective of this study was to understand the genetic basis of the association between resting heart rate and cardiometabolic disorders/T2D. METHODS: This study examined the genetic correlation, causality, and shared genetics between RHR and T2D using LD Score regression, generalized summary data-based Mendelian randomization, and transcriptome wide association scan (TWAS) in UK Biobank data (n = 428,250) and summary-level data for T2D (74,124 cases and 824,006 control subjects) and 8 cardiometabolic traits (sample size ranges from 51,750 to 236,231). RESULTS: Significant genetic correlation between RHR and T2D (rg = 0.22; 95% confidence interval: 0.18 to 0.26; p = 1.99 × 10-22), and 6 cardiometabolic traits (fasting insulin, fasting glucose, waist-hip ratio, triglycerides, high-density lipoprotein, and body mass index; rg range -0.12 to 0.24; all p < 0.05) were observed. RHR has significant estimated causal effect on T2D (odds ratio: 1.12 per 10-beats/min increment; p = 7.79 × 10-11) and weaker causal estimates from T2D to RHR (0.32 beats/min per doubling increment in T2D prevalence; p = 6.14 × 10-54). Sensitivity analysis by controlling for the included cardiometabolic traits did not modify the relationship between RHR and T2D. TWAS found locus chr2q23.3 (rs1260326) was highly pleiotropic among RHR, cardiometabolic traits, and T2D, and identified 7 genes (SMARCAD1, RP11-53O19.3, CTC-498M16.4, PDE8B, AKTIP, KDM4B, and TSHZ3) that were statistically independent and shared between RHR and T2D in tissues from the nervous and cardiovascular systems. These shared genes suggested the involvement of epigenetic regulation of energy and glucose metabolism, and AKT activation-related telomere dysfunction and vascular endothelial aging in the shared etiologies between RHR and T2D. Finally, FADS1 was found to be shared among RHR, fasting glucose, high-density lipoprotein, and triglycerides. CONCLUSIONS: These findings provide evidence of significant genetic correlations and causation between RHR and T2D/cardiometabolic traits, advance our understanding of RHR, and provide insight into shared etiology for high RHR and T2D.


Assuntos
Doenças Cardiovasculares/genética , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla , Frequência Cardíaca , Transcriptoma , 3',5'-AMP Cíclico Fosfodiesterases/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Bancos de Espécimes Biológicos , Glicemia/análise , Sistema Cardiovascular , Comorbidade , DNA Helicases/genética , Endotélio Vascular/patologia , Epigênese Genética , Proteínas de Homeodomínio/genética , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Desequilíbrio de Ligação , Lipoproteínas HDL/metabolismo , Análise da Randomização Mendeliana , Fosforilação , Prevalência , Telômero/ultraestrutura , Triglicerídeos/metabolismo , Reino Unido
19.
Eur Respir J ; 54(6)2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31619474

RESUMO

Epidemiological studies demonstrate an association between asthma and mental health disorders, although little is known about the shared genetics and causality of this association. Thus, we aimed to investigate shared genetics and the causal link between asthma and mental health disorders.We conducted a large-scale genome-wide cross-trait association study to investigate genetic overlap between asthma from the UK Biobank and eight mental health disorders from the Psychiatric Genomics Consortium: attention deficit hyperactivity disorder (ADHD), anxiety disorder (ANX), autism spectrum disorder, bipolar disorder, eating disorder, major depressive disorder (MDD), post-traumatic stress disorder and schizophrenia (sample size 9537-394 283).In the single-trait genome-wide association analysis, we replicated 130 previously reported loci and discovered 31 novel independent loci that are associated with asthma. We identified that ADHD, ANX and MDD have a strong genetic correlation with asthma at the genome-wide level. Cross-trait meta-analysis identified seven loci jointly associated with asthma and ADHD, one locus with asthma and ANX, and 10 loci with asthma and MDD. Functional analysis revealed that the identified variants regulated gene expression in major tissues belonging to the exocrine/endocrine, digestive, respiratory and haemic/immune systems. Mendelian randomisation analyses suggested that ADHD and MDD (including 6.7% sample overlap with asthma) might increase the risk of asthma.This large-scale genome-wide cross-trait analysis identified shared genetics and potential causal links between asthma and three mental health disorders (ADHD, ANX and MDD). Such shared genetics implicate potential new biological functions that are in common among them.


Assuntos
Transtornos de Ansiedade/genética , Asma/genética , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno Depressivo/genética , Adulto , Criança , Estudo de Associação Genômica Ampla , Humanos , Reino Unido
20.
BMJ Open ; 9(10): e026449, 2019 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-31585969

RESUMO

OBJECTIVE: To determine the magnitude of relationships of early life factors with child development in low/middle-income countries (LMICs). DESIGN: Meta-analyses of standardised mean differences (SMDs) estimated from published and unpublished data. DATA SOURCES: We searched Medline, bibliographies of key articles and reviews, and grey literature to identify studies from LMICs that collected data on early life exposures and child development. The most recent search was done on 4 November 2014. We then invited the first authors of the publications and investigators of unpublished studies to participate in the study. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Studies that assessed at least one domain of child development in at least 100 children under 7 years of age and collected at least one early life factor of interest were included in the study. ANALYSES: Linear regression models were used to assess SMDs in child development by parental and child factors within each study. We then produced pooled estimates across studies using random effects meta-analyses. RESULTS: We retrieved data from 21 studies including 20 882 children across 13 LMICs, to assess the associations of exposure to 14 major risk factors with child development. Children of mothers with secondary schooling had 0.14 SD (95% CI 0.05 to 0.25) higher cognitive scores compared with children whose mothers had primary education. Preterm birth was associated with 0.14 SD (-0.24 to -0.05) and 0.23 SD (-0.42 to -0.03) reductions in cognitive and motor scores, respectively. Maternal short stature, anaemia in infancy and lack of access to clean water and sanitation had significant negative associations with cognitive and motor development with effects ranging from -0.18 to -0.10 SDs. CONCLUSIONS: Differential parental, environmental and nutritional factors contribute to disparities in child development across LMICs. Targeting these factors from prepregnancy through childhood may improve health and development of children.


Assuntos
Desenvolvimento Infantil , Cognição , Países em Desenvolvimento/estatística & dados numéricos , Deficiências do Desenvolvimento/epidemiologia , Destreza Motora , Criança , Pré-Escolar , Humanos , Lactente , Desenvolvimento da Linguagem , Fatores de Proteção , Fatores de Risco
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