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2.
Int J Mol Sci ; 19(11)2018 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-30463316

RESUMO

MicroRNAs (miRNAs) regulate the expression of the majority of genes. However, it is not known whether they regulate genes in random or are organized according to their function. To this end, we chose cardiometabolic disorders as an example and investigated whether genes associated with cardiometabolic disorders are regulated by a random set of miRNAs or a limited number of them. Single-nucleotide polymorphisms (SNPs) reaching genome-wide level significance were retrieved from most recent genome-wide association studies on cardiometabolic traits, which were cross-referenced with Ensembl to identify related genes and combined with miRNA target prediction databases (TargetScan, miRTarBase, or miRecords) to identify miRNAs that regulate them. We retrieved 520 SNPs, of which 355 were intragenic, corresponding to 304 genes. While we found a higher proportion of genes reported from all GWAS that were predicted targets for miRNAs in comparison to all protein-coding genes (75.1%), the proportion was even higher for cardiometabolic genes (80.6%). Enrichment analysis was performed within each database. We found that cardiometabolic genes were over-represented in target genes for 29 miRNAs (based on TargetScan) and 3 miRNAs (miR-181a, miR-302d and miR-372) (based on miRecords) after Benjamini-Hochberg correction for multiple testing. Our work provides evidence for non-random assignment of genes to miRNAs and supports the idea that miRNAs regulate sets of genes that are functionally related.

3.
Nat Genet ; 50(10): 1412-1425, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30224653

RESUMO

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

4.
PLoS Med ; 13(10): e1002139, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27727279

RESUMO

BACKGROUND: Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs. METHODS AND FINDINGS: To define the aldesleukin dose response for Tregs and to find doses that increase Tregs physiologically for treatment of T1D, a statistical and systematic approach was taken by analysing the pharmacokinetics and pharmacodynamics of single doses of subcutaneous aldesleukin in the Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D), a single centre, non-randomised, open label, adaptive dose-finding trial with 40 adult participants with recently diagnosed T1D. The primary endpoint was the maximum percentage increase in Tregs (defined as CD3+CD4+CD25highCD127low) from the baseline frequency in each participant measured over the 7 d following treatment. There was an initial learning phase with five pairs of participants, each pair receiving one of five pre-assigned single doses from 0.04 × 106 to 1.5 × 106 IU/m2, in order to model the dose-response curve. Results from each participant were then incorporated into interim statistical modelling to target the two doses most likely to induce 10% and 20% increases in Treg frequencies. Primary analysis of the evaluable population (n = 39) found that the optimal doses of aldesleukin to induce 10% and 20% increases in Tregs were 0.101 × 106 IU/m2 (standard error [SE] = 0.078, 95% CI = -0.052, 0.254) and 0.497 × 106 IU/m2 (SE = 0.092, 95% CI = 0.316, 0.678), respectively. On analysis of secondary outcomes, using a highly sensitive IL-2 assay, the observed plasma concentrations of the drug at 90 min exceeded the hypothetical Treg-specific therapeutic window determined in vitro (0.015-0.24 IU/ml), even at the lowest doses (0.040 × 106 and 0.045 × 106 IU/m2) administered. A rapid decrease in Treg frequency in the circulation was observed at 90 min and at day 1, which was dose dependent (mean decrease 11.6%, SE = 2.3%, range 10.0%-48.2%, n = 37), rebounding at day 2 and increasing to frequencies above baseline over 7 d. Teffs, natural killer cells, and eosinophils also responded, with their frequencies rapidly and dose-dependently decreased in the blood, then returning to, or exceeding, pretreatment levels. Furthermore, there was a dose-dependent down modulation of one of the two signalling subunits of the IL-2 receptor, the ß chain (CD122) (mean decrease = 58.0%, SE = 2.8%, range 9.8%-85.5%, n = 33), on Tregs and a reduction in their sensitivity to aldesleukin at 90 min and day 1 and 2 post-treatment. Due to blood volume requirements as well as ethical and practical considerations, the study was limited to adults and to analysis of peripheral blood only. CONCLUSIONS: The DILT1D trial results, most notably the early altered trafficking and desensitisation of Tregs induced by a single ultra-low dose of aldesleukin that resolves within 2-3 d, inform the design of the next trial to determine a repeat dosing regimen aimed at establishing a steady-state Treg frequency increase of 20%-50%, with the eventual goal of preventing T1D. TRIAL REGISTRATION: ISRCTN Registry ISRCTN27852285; ClinicalTrials.gov NCT01827735.


Assuntos
Diabetes Mellitus Tipo 1/prevenção & controle , Interleucina-2/análogos & derivados , Linfócitos T Reguladores/efeitos dos fármacos , Adolescente , Adulto , Biomarcadores , Quimiocinas/biossíntese , Relação Dose-Resposta a Droga , Eosinófilos/efeitos dos fármacos , Feminino , Humanos , Imunofenotipagem , Mediadores da Inflamação/metabolismo , Interleucina-2/efeitos adversos , Interleucina-2/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/farmacologia , Adulto Jovem
5.
BMJ Open ; 5(12): e009799, 2015 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-26646829

RESUMO

INTRODUCTION: Type 1 diabetes (T1D) is caused by autoimmune destruction of the insulin-producing ß cells in the pancreatic islets, leading to insulinopenia and hyperglycaemia. Genetic analyses indicate that alterations of the interleukin-2 (IL-2) pathway mediating immune activation and tolerance predispose to T1D, specifically the polymorphic expression of the IL-2 receptor-α chain (CD25) on T lymphocytes. Replacement of physiological doses of IL-2 could restore self-tolerance and prevent further autoimmunity by enhancing the function of CD4(+) T regulatory cells (Tregs) to limit the activation of auto reactive T effector cells (Teffs). In this experimental medicine study, we use an adaptive trial design to determine the optimal dosing regimen for IL-2 to improve Treg function while limiting activation of Teffs in participants with T1D. METHODS AND ANALYSIS: The Adaptive study of IL-2 dose frequency on Tregs in type 1 diabetes(DILfrequency) is a mechanistic, non-randomised, repeat dose open-label, response-adaptive study of 36 participants with T1D. The objective is to establish the optimal dose and frequency of ultra-low dose IL-2: to increase Treg frequency within the physiological range, to increase CD25 expression on Tregs, without increasing CD4(+) Teffs. DILfrequency has an initial learning phase where 12 participants are allocated to six different doses and frequencies followed by an interim statistical analysis. After analysis of the learning phase, the Dose and Frequency Committee will select the optimal targets for Treg frequency, Treg CD25 expression and Teff frequency. Three groups of eight participants will be treated consecutively in the confirming phase. Each dose and frequency selected will be based on statistical analysis of all data collected from the previous groups. ETHICS: Ethical approval for DILfrequency was granted on 12 August 2014. RESULTS: The results of this study will be reported, through peer-reviewed journals, conference presentations and an internal organisational report. TRIAL REGISTRATION NUMBERS: NCT02265809, ISRCTN40319192, CRN17571.


Assuntos
Diabetes Mellitus Tipo 1/imunologia , Interleucina-2/administração & dosagem , Linfócitos T Reguladores/efeitos dos fármacos , Adolescente , Adulto , Idoso , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Masculino , Pessoa de Meia-Idade , Adulto Jovem
6.
Nat Commun ; 6: 7000, 2015 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-25965853

RESUMO

Seasonal variations are rarely considered a contributing component to human tissue function or health, although many diseases and physiological process display annual periodicities. Here we find more than 4,000 protein-coding mRNAs in white blood cells and adipose tissue to have seasonal expression profiles, with inverted patterns observed between Europe and Oceania. We also find the cellular composition of blood to vary by season, and these changes, which differ between the United Kingdom and The Gambia, could explain the gene expression periodicity. With regards to tissue function, the immune system has a profound pro-inflammatory transcriptomic profile during European winter, with increased levels of soluble IL-6 receptor and C-reactive protein, risk biomarkers for cardiovascular, psychiatric and autoimmune diseases that have peak incidences in winter. Circannual rhythms thus require further exploration as contributors to various aspects of human physiology and disease.


Assuntos
Fatores de Transcrição ARNTL/metabolismo , Regulação da Expressão Gênica/fisiologia , Genes MHC da Classe II/fisiologia , Estações do Ano , Fatores de Transcrição ARNTL/genética , Adaptação Fisiológica , Tecido Adiposo/metabolismo , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Europa (Continente) , Gâmbia , Humanos , Lactente , Recém-Nascido , Leucócitos/metabolismo , Pessoa de Meia-Idade , Oceania , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcriptoma , Adulto Jovem
7.
Trials ; 16: 86, 2015 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-25881192

RESUMO

BACKGROUND: A barrier to the successful development of new disease treatments is the timely recruitment of participants to experimental medicine studies that are primarily designed to investigate biological mechanisms rather than evaluate clinical efficacy. The aim of this study was to analyse the performance of three recruitment sources and the effect of publicity events during the Adaptive study of IL-2 dose on regulatory T cells in type 1 diabetes (DILT1D). METHODS: The final study outcome, demography, disease duration, residence and the effect of publicity events on the performance of three recruitment sources (clinics, type 1 diabetes (T1D) disease register and the internet) were analysed from a bespoke DILT1D recruitment database. For the internet source, the origin of website hits in relation to publicity events was also evaluated. RESULTS: A total of 735 potentially eligible participants were approached to identify the final 45 DILT1D participants. A total of 477 (64%) were identified via the disease register, but only 59 (12%) responded to contact. A total of 317 individuals registered with the DILT1D study team. Self-referral via the study website generated 170 (54%) registered individuals and was the most popular and successful source, with 88 (28%) sourced from diabetes clinics and 59 (19%) from the disease register. Of those with known T1D duration (N = 272), the internet and clinics sources identified a larger number (57, 21%) of newly diagnosed T1D (<100 days post-diagnosis) compared to the register (1, 0.4%). The internet extended the geographical reach of the study, enabling both national and international participation. Targeted website posts and promotional events from organisations supporting T1D research and treatment during the trial were essential to the success of the internet recruitment strategy. CONCLUSIONS: Analysis of the DILT1D study recruitment outcomes illustrates the utility of an active internet recruitment strategy, supported by patient groups and charities, funding agencies and sponsors, in successfully conducting an early phase study in T1D. This recruitment strategy should now be evaluated in late-stage trials to develop treatments for T1D and other diseases. TRIAL REGISTRATION: NCT01827735 (registered: 4 April 2013); ISRCTN27852285 (registered: 23 March 2013); DRN767 (registered: 21 January 2013).


Assuntos
Instituições de Caridade , Diabetes Mellitus Tipo 1/imunologia , Interleucina-2/administração & dosagem , Internet , Seleção de Pacientes , Linfócitos T Reguladores/efeitos dos fármacos , Adulto , Feminino , Humanos , Masculino
8.
Genet Epidemiol ; 38(8): 661-70, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25371288

RESUMO

Pathway analysis can complement point-wise single nucleotide polymorphism (SNP) analysis in exploring genomewide association study (GWAS) data to identify specific disease-associated genes that can be candidate causal genes. We propose a straightforward methodology that can be used for conducting a gene-based pathway analysis using summary GWAS statistics in combination with widely available reference genotype data. We used this method to perform a gene-based pathway analysis of a type 1 diabetes (T1D) meta-analysis GWAS (of 7,514 cases and 9,045 controls). An important feature of the conducted analysis is the removal of the major histocompatibility complex gene region, the major genetic risk factor for T1D. Thirty-one of the 1,583 (2%) tested pathways were identified to be enriched for association with T1D at a 5% false discovery rate. We analyzed these 31 pathways and their genes to identify SNPs in or near these pathway genes that showed potentially novel association with T1D and attempted to replicate the association of 22 SNPs in additional samples. Replication P-values were skewed (P=9.85×10-11) with 12 of the 22 SNPs showing P<0.05. Support, including replication evidence, was obtained for nine T1D associated variants in genes ITGB7 (rs11170466, P=7.86×10-9), NRP1 (rs722988, 4.88×10-8), BAD (rs694739, 2.37×10-7), CTSB (rs1296023, 2.79×10-7), FYN (rs11964650, P=5.60×10-7), UBE2G1 (rs9906760, 5.08×10-7), MAP3K14 (rs17759555, 9.67×10-7), ITGB1 (rs1557150, 1.93×10-6), and IL7R (rs1445898, 2.76×10-6). The proposed methodology can be applied to other GWAS datasets for which only summary level data are available.


Assuntos
Diabetes Mellitus Tipo 1/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Reprodutibilidade dos Testes
9.
Bioinformatics ; 30(5): 690-7, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24123673

RESUMO

MOTIVATION: Over the past few years several pathway analysis methods have been proposed for exploring and enhancing the analysis of genome-wide association data. Hierarchical models have been advocated as a way to integrate SNP and pathway effects in the same model, but their computational complexity has prevented them being applied on a genome-wide scale to date. METHODS: We present two novel methods for identifying associated pathways. In the proposed hierarchical model, the SNP effects are analytically integrated out of the analysis, allowing computationally tractable model fitting to genome-wide data. The first method uses Bayes factors for calculating the effect of the pathways, whereas the second method uses a machine learning algorithm and adaptive lasso for finding a sparse solution of associated pathways. RESULTS: The performance of the proposed methods was explored on both simulated and real data. The results of the simulation study showed that the methods outperformed some well-established association methods: the commonly used Fisher's method for combining P-values and also the recently published BGSA. The methods were applied to two genome-wide association study datasets that aimed to find the genetic structure of platelet function and body mass index, respectively. The results of the analyses replicated the results of previously published pathway analysis of these phenotypes but also identified novel pathways that are potentially involved. AVAILABILITY: An R package is under preparation. In the meantime, the scripts of the methods are available on request from the authors.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Algoritmos , Teorema de Bayes , Plaquetas/fisiologia , Índice de Massa Corporal , Simulação por Computador , Humanos , Fenótipo
10.
PLoS One ; 7(7): e41018, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22859961

RESUMO

It has been suggested that pathway analysis can complement single-SNP analysis in exploring genomewide association data. Pathway analysis incorporates the available biological knowledge of genes and SNPs and is expected to improve the chances of revealing the underlying genetic architecture of complex traits. Methods for pathway analysis can be classified as competitive (enrichment) or self-contained (association) according to the hypothesis tested. Although association tests are statistically more powerful than enrichment tests they can be difficult to calibrate because biases in analysis accumulate across multiple SNPs or genes. Furthermore, enrichment tests can be more scientifically relevant than association tests, as they detect pathways with relatively more evidence for association than the remaining genes. Here we show how some well known association tests can be simply adapted to test for enrichment, and compare their performance to some established enrichment tests. We propose versions of the Adaptive Rank Truncated Product (ARTP), Tail Strength Measure and Fisher's combination of p-values for testing the enrichment null hypothesis. We compare the behaviour of these proposed methods with the established Hypergeometric Test and Gene-Set Enrichment Analysis (GSEA). The results of the simulation study show that the modified version of the ARTP method has generally the best performance across the situations considered. The methods were also applied for finding enriched pathways for body mass index (BMI) and platelet function phenotypes. The pathway analysis of BMI identified the Vasoactive Intestinal Peptide pathway as significantly associated with BMI. This pathway has been previously reported as associated with BMI and the risk of obesity. The ARTP method was the method that identified the largest number of enriched pathways across all tested pathway databases and phenotypes. The simulation and data application results are in agreement with previous work on association tests and suggests that the ARTP should be preferred for both enrichment and association testing.


Assuntos
Redes e Vias Metabólicas/genética , Algoritmos , Plaquetas/metabolismo , Plaquetas/fisiologia , Índice de Massa Corporal , Simulação por Computador , Estudo de Associação Genômica Ampla , Humanos , Modelos Genéticos , Anotação de Sequência Molecular , Fenótipo , Polimorfismo de Nucleotídeo Único
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