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1.
Nat Commun ; 10(1): 3009, 2019 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-31285442

RESUMO

Quantitative genetics theory predicts that X-chromosome dosage compensation (DC) will have a detectable effect on the amount of genetic and therefore phenotypic trait variances at associated loci in males and females. Here, we systematically examine the role of DC in humans in 20 complex traits in a sample of more than 450,000 individuals from the UK Biobank and 1600 gene expression traits from a sample of 2000 individuals as well as across-tissue gene expression from the GTEx resource. We find approximately twice as much X-linked genetic variation across the UK Biobank traits in males (mean h2SNP = 0.63%) compared to females (mean h2SNP = 0.30%), confirming the predicted DC effect. Our DC estimates for complex traits and gene expression are consistent with a small proportion of genes escaping X-inactivation in a trait- and tissue-dependent manner. Finally, we highlight examples of biologically relevant X-linked heterogeneity between the sexes that bias DC estimates if unaccounted for.


Assuntos
Genes Ligados ao Cromossomo X/genética , Loci Gênicos/genética , Variação Genética/genética , Herança Multifatorial/genética , Inativação do Cromossomo X/genética , Conjuntos de Dados como Assunto , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Modelos Genéticos , Fenótipo , Fatores Sexuais
2.
Am J Hum Genet ; 105(2): 258-266, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31230719

RESUMO

The transcriptome-wide association studies (TWASs) that test for association between the study trait and the imputed gene expression levels from cis-acting expression quantitative trait loci (cis-eQTL) genotypes have successfully enhanced the discovery of genetic risk loci for complex traits. By using the gene expression imputation models fitted from reference datasets that have both genetic and transcriptomic data, TWASs facilitate gene-based tests with GWAS data while accounting for the reference transcriptomic data. The existing TWAS tools like PrediXcan and FUSION use parametric imputation models that have limitations for modeling the complex genetic architecture of transcriptomic data. Therefore, to improve on this, we employ a nonparametric Bayesian method that was originally proposed for genetic prediction of complex traits, which assumes a data-driven nonparametric prior for cis-eQTL effect sizes. The nonparametric Bayesian method is flexible and general because it includes both of the parametric imputation models used by PrediXcan and FUSION as special cases. Our simulation studies showed that the nonparametric Bayesian model improved both imputation R2 for transcriptomic data and the TWAS power over PrediXcan when ≥1% cis-SNPs co-regulate gene expression and gene expression heritability ≤0.2. In real applications, the nonparametric Bayesian method fitted transcriptomic imputation models for 57.8% more genes over PrediXcan, thus improving the power of follow-up TWASs. We implement both parametric PrediXcan and nonparametric Bayesian methods in a convenient software tool "TIGAR" (Transcriptome-Integrated Genetic Association Resource), which imputes transcriptomic data and performs subsequent TWASs using individual-level or summary-level GWAS data.

3.
Forensic Sci Int Genet ; 41: 177-187, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31154251

RESUMO

In the absence of traditional DNA evidence, detection of sexual contact during intercourse is an important need for forensic analysis that might be addressed by studies of the pubic microbiome. Since 16S sequencing of various other body parts has shown that the microbiome may be individualizing, we reasoned that transfer of the assailant's microbiome to a victim might be detectable. Microbiome profiles were generated from pubic hairs and swabs taken from the pubic mound region of 12 couples and 19 singles, and evaluated for similarity over an average of four collection times with varying degrees of self-reported sexual activity. A model constructed using a Random Forest classifier was able to predict samples belonging to the same individual collected up to 6 months apart, demonstrating the stability of the pubic mound microbiome over this time frame. Couples were found to be significantly more similar to one another than to unrelated members of the opposite sex, in proportion to shared sexual activity. Further analyses using the Deblur method to assign operational taxonomic units (OTUs) establish that at least 10% of the victim's pubic microbiome must be derived from the attacker in order to detect transfer, but that single transfer events will not generally be discovered. Nevertheless, Bayesian SourceTracker software is shown to have potential to establish that sexual contact occurred when the assailant is known, or to exonerate suspects as contributors to a mixed microbiome. Our results establish limited potential of the pubic hair/pubic area microbiome as a tool for forensic associations.


Assuntos
Genitália , Cabelo/microbiologia , Microbiota , Comportamento Sexual , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Componente Principal , RNA Ribossômico 16S , Análise de Sequência de RNA , Adulto Jovem
4.
Toxicol Sci ; 169(1): 280-292, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31059573

RESUMO

Alcohol use prior to and during pregnancy remains a significant societal problem and can lead to developmental fetal abnormalities including compromised myocardia function and increased risk for heart disease later in life. Alcohol-induced cardiac toxicity has traditionally been studied in animal-based models. These models have limitations due to physiological differences from human cardiomyocytes (CMs) and are also not suitable for high-throughput screening. We hypothesized that human-induced pluripotent stem cell-derived CMs (hiPSC-CMs) could serve as a useful tool to study alcohol-induced cardiac defects and/or toxicity. In this study, hiPSC-CMs were treated with ethanol at doses corresponding to the clinically relevant levels of alcohol intoxication. hiPSC-CMs exposed to ethanol showed a dose-dependent increase in cellular damage and decrease in cell viability, corresponding to increased production of reactive oxygen species. Furthermore, ethanol exposure also generated dose-dependent increased irregular Ca2+ transients and contractility in hiPSC-CMs. RNA-seq analysis showed significant alteration in genes belonging to the potassium voltage-gated channel family or solute carrier family, partially explaining the irregular Ca2+ transients and contractility in ethanol-treated hiPSC-CMs. RNA-seq also showed significant upregulation in the expression of genes associated with collagen and extracellular matrix modeling, and downregulation of genes involved in cardiovascular system development and actin filament-based process. These results suggest that hiPSC-CMs can be a novel and physiologically relevant system for the study of alcohol-induced cardiac toxicity.

5.
Genetics ; 212(3): 905-918, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31123039

RESUMO

Expression QTL (eQTL) detection has emerged as an important tool for unraveling the relationship between genetic risk factors and disease or clinical phenotypes. Most studies are predicated on the assumption that only a single causal variant explains the association signal in each interval. This greatly simplifies the statistical modeling, but is liable to biases in scenarios where multiple local causal-variants are responsible. Here, our primary goal was to address the prevalence of secondary cis-eQTL signals regulating peripheral blood gene expression locally, utilizing two large human cohort studies, each >2500 samples with accompanying whole genome genotypes. The CAGE (Consortium for the Architecture of Gene Expression) dataset is a compendium of Illumina microarray studies, and the Framingham Heart Study is a two-generation Affymetrix dataset. We also describe Bayesian colocalization analysis of the extent of sharing of cis-eQTL detected in both studies as well as with the BIOS RNAseq dataset. Stepwise conditional modeling demonstrates that multiple eQTL signals are present for ∼40% of over 3500 eGenes in both microarray datasets, and that the number of loci with additional signals reduces by approximately two-thirds with each conditioning step. Although <20% of the peak signals across platforms fine map to the same credible interval, the colocalization analysis finds that as many as 50-60% of the primary eQTL are actually shared. Subsequently, colocalization of eQTL signals with GWAS hits detected 1349 genes whose expression in peripheral blood is associated with 591 human phenotype traits or diseases, including enrichment for genes with regulatory functions. At least 10%, and possibly as many as 40%, of eQTL-trait colocalized signals are due to nonprimary cis-eQTL peaks, but just one-quarter of these colocalization signals replicated across the gene expression datasets. Our results are provided as a web-based resource for visualization of multi-site regulation of gene expression and its association with human complex traits and disease states.

6.
Circ Genom Precis Med ; 12(6): e002403, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31100989

RESUMO

BACKGROUND: Congenital heart defects are a leading cause of morbidity and mortality in children, and despite advanced surgical treatments, many patients progress to heart failure. Currently, transplantation is the only effective cure and is limited by donor availability and organ rejection. Recently, cell therapy has emerged as a novel method for treating pediatric heart failure with several ongoing clinical trials. However, efficacy of stem cell therapy is variable, and choosing stem cells with the highest reparative effects has been a challenge. METHODS: We previously demonstrated the age-dependent reparative effects of human c-kit+ progenitor cells (hCPCs) in a rat model of juvenile heart failure. Using a small subset of patient samples, computational modeling analysis showed that regression models could be made linking sequencing data to phenotypic outcomes. In the current study, we used a similar quantitative model to determine whether predictions can be made in a larger population of patients and validated the model using neonatal hCPCs. We performed RNA sequencing from c-kit+ progenitor cells isolated from 32 patients, including 8 neonatal samples. We tested 2 functional parameters of our model, cellular proliferation and chemotactic potential of conditioned media. RESULTS: Interestingly, the observed proliferation and migration responses in each of the selected neonatal hCPC lines matched their predicted counterparts. We then performed canonical pathway analysis to determine potential mechanistic signals that regulated hCPC performance and identified several immune response genes that correlated with performance. ELISA analysis confirmed the presence of selected cytokines in good performing hCPCs and provided many more signals to further validate. CONCLUSIONS: These data show that cell behavior may be predicted using large datasets like RNA sequencing and that we may be able to identify patients whose c-kit+ progenitor cells exceed or underperform expectations. With systems biology approaches, interventions can be tailored to improve cell therapy or mimic the qualities of reparative cells.

7.
JCI Insight ; 4(9)2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-31045577

RESUMO

Human antibody-secreting cells (ASCs) triggered by immunization are globally recognized as CD19loCD38hiCD27hi. Yet, different vaccines give rise to antibody responses of different longevity, suggesting ASC populations are heterogeneous. We define circulating-ASC heterogeneity in vaccine responses using multicolor flow cytometry, morphology, VH repertoire, and RNA transcriptome analysis. We also tested differential survival using a human cell-free system that mimics the bone marrow (BM) microniche. In peripheral blood, we identified 3 CD19+ and 2 CD19- ASC subsets. All subsets contributed to the vaccine-specific responses and were characterized by in vivo proliferation and activation. The VH repertoire demonstrated strong oligoclonality with extensive interconnectivity among the 5 subsets and switched memory B cells. Transcriptome analysis showed separation of CD19+ and CD19- subsets that included pathways such as cell cycle, hypoxia, TNF-α, and unfolded protein response. They also demonstrated similar long-term in vitro survival after 48 days. In summary, vaccine-induced ASCs with different surface markers (CD19 and CD138) are derived from shared proliferative precursors yet express distinctive transcriptomes. Equal survival indicates that all ASC compartments are endowed with long-lived potential. Accordingly, in vivo survival of peripheral long-lived plasma cells may be determined in part by their homing and residence in the BM microniche.

8.
Muscle Nerve ; 60(1): 98-103, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30990900

RESUMO

INTRODUCTION: UDP N-acetylglucosamine2-epimerase/N-acetylmannosamine-kinase (GNE) gene mutations can cause mostly autosomal-recessive myopathy with juvenile-onset known as hereditary inclusion-body myopathy (HIBM). METHODS: We describe a family of a patient showing an unusual HIBM with both vacuolar myopathy and myositis without quadriceps-sparing, hindering diagnosis. We show how genetic testing with functional assays, clinical transcriptome sequencing (RNA-seq) in particular, helped facilitate both the diagnosis and a better understanding of the genotype-phenotype relationship. RESULTS: We identified a novel 7.08 kb pathogenic deletion upstream of GNE using array comparative genomic hybridization (aCGH) and a common Val727Met variant. Using RNA-seq, we found only monoallelic (Val727Met-allele) expression, leading to ~50% GNE reduction in muscle. Importantly, α-dystroglycan is hypoglycosylated in the patient muscle, suggesting HIBM could be a "dystroglycanopathy." CONCLUSIONS: Our study shows the importance of considering aCGH for GNE-myopathies, and the potential of RNA-seq for faster, definitive molecular diagnosis of unusual myopathies. Muscle Nerve, 2019.


Assuntos
Miopatias Distais/genética , Complexos Multienzimáticos/genética , Regiões Promotoras Genéticas/genética , Hibridização Genômica Comparativa , Miopatias Distais/diagnóstico , Miopatias Distais/metabolismo , Miopatias Distais/patologia , Distroglicanas/metabolismo , Família , Deleção de Genes , Glicosilação , Humanos , Masculino , Técnicas de Diagnóstico Molecular , Músculo Quadríceps/patologia , Análise de Sequência de RNA , Adulto Jovem
9.
Lancet ; 393(10182): 1708-1720, 2019 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-30935734

RESUMO

BACKGROUND: Lack of evidence-based outcomes data leads to uncertainty in developing treatment regimens in children who are newly diagnosed with ulcerative colitis. We hypothesised that pretreatment clinical, transcriptomic, and microbial factors predict disease course. METHODS: In this inception cohort study, we recruited paediatric patients aged 4-17 years with newly diagnosed ulcerative colitis from 29 centres in the USA and Canada. Patients initially received standardised mesalazine or corticosteroids, with pre-established criteria for escalation to immunomodulators (ie, thiopurines) or anti-tumor necrosis factor-α (TNFα) therapy. We used RNA sequencing to define rectal gene expression before treatment, and 16S sequencing to characterise rectal and faecal microbiota. The primary outcome was week 52 corticosteroid-free remission with no therapy beyond mesalazine. We assessed factors associated with the primary outcome using logistic regression models of the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT01536535. FINDINGS: Between July 10, 2012, and April 21, 2015, of 467 patients recruited, 428 started medical therapy, of whom 400 (93%) were evaluable at 52 weeks and 386 (90%) completed the study period with no protocol violations. 150 (38%) of 400 participants achieved week 52 corticosteroid-free remission, of whom 147 (98%) were taking mesalazine and three (2%) were taking no medication. 74 (19%) of 400 were escalated to immunomodulators alone, 123 (31%) anti-TNFα therapy, and 25 (6%) colectomy. Low baseline clinical severity, high baseline haemoglobin, and week 4 clinical remission were associated with achieving week 52 corticosteroid-free remission (n=386, logistic model area under the curve [AUC] 0·70, 95% CI 0·65-0·75; specificity 77%, 95% CI 71-82). Baseline severity and remission by week 4 were validated in an independent cohort of 274 paediatric patients with newly diagnosed ulcerative colitis. After adjusting for clinical predictors, an antimicrobial peptide gene signature (odds ratio [OR] 0·57, 95% CI 0·39-0·81; p=0·002) and abundance of Ruminococcaceae (OR 1·43, 1·02-2·00; p=0·04), and Sutterella (OR 0·81, 0·65-1·00; p=0·05) were independently associated with week 52 corticosteroid-free remission. INTERPRETATION: Our findings support the utility of initial clinical activity and treatment response by 4 weeks to predict week 52 corticosteroid-free remission with mesalazine alone in children who are newly diagnosed with ulcerative colitis. The development of personalised clinical and biological signatures holds the promise of informing ulcerative colitis therapeutic decisions. FUNDING: US National Institutes of Health.


Assuntos
Corticosteroides/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Mesalamina/uso terapêutico , Adolescente , Biomarcadores/metabolismo , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Resultado do Tratamento
10.
PLoS Genet ; 15(4): e1008060, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31022172

RESUMO

The promise of personalized genomic medicine is that knowledge of a person's gene sequences and activity will facilitate more appropriate medical interventions, particularly drug prescriptions, to reduce the burden of disease. Early successes in oncology and pediatrics have affirmed the power of positive diagnosis and are mostly based on detection of one or a few mutations that drive the specific pathology. However, genetically more complex diseases require the development of polygenic risk scores (PRSs) that have variable accuracy. The rarity of events often means that they have necessarily low precision: many called positives are actually not at risk, and only a fraction of cases are prevented by targeted therapy. In some situations, negative prediction may better define the population at low risk. Here, I review five conditions across a broad spectrum of chronic disease (opioid pain medication, hypertension, type 2 diabetes, major depression, and osteoporotic bone fracture), considering in each case how genetic prediction might be used to target drug prescription. This leads to a call for more research designed to evaluate genetic likelihood of response to therapy and a call for evaluation of PRS, not just in terms of sensitivity and specificity but also with respect to potential clinical efficacy.


Assuntos
Herança Multifatorial , Medicina de Precisão/métodos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Feminino , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/genética , Masculino , Mutação , Transtornos Relacionados ao Uso de Opioides/genética , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Osteoporose/genética , Osteoporose/prevenção & controle , Testes Farmacogenômicos/métodos , Medicina Preventiva/métodos , Fatores de Risco
11.
Stem Cells ; 37(8): 1075-1082, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31033095

RESUMO

Defining the immune physiology of culture-adapted mesenchymal stromal cells (MSCs) derived from distinct tissue compartments informs their potential utility as pharmaceuticals. Here, we have investigated the comparative immune plasticity of MSCs and hepatic stellate cells (HeSCs) isolated from human and murine bone marrow (BM) and liver, respectively. Although both BM-MSCs and HeSCs share mesenchymal phenotype and overall molecular genetic responses to inflammatory cues, HeSCs differ from BM-MSCs in a meaningful manner. We show that culture-adapted HeSCs express substantially higher levels of hepatocyte growth factor (HGF), matrix metalloproteinase-1, and chemokine (CC motif) ligand 2 (CCL2) than BM-MSCs. Both human BM-MSCs and HeSCs inhibit T-cell proliferation by a shared indoleamine 2,3-dioxygenase (IDO)-dependent mechanism. However, HeSCs are distinct from BM-MSCs by their significant differential expression of HGF, CCL2, IL-8, CCL11, and GMCSF when cocultured with and/or without activated peripheral blood mononuclear cells. We have investigated MSCs and HeSCs derived from murine systems to describe interspecies comparability. Murine BM-MSCs inhibit T-cell proliferation through inducible nitric oxide synthase (iNOS) but not IDO. However, murine HeSCs inhibit T-cell proliferation through a mechanism distinct from either IDO or iNOS. Altogether, these results suggest that although culture-adapted BM-MSCs and HeSCs display a similar phenotype, their secretome and immune plasticity are in part distinct likely mirroring their tissular origins. In addition, the discordance in immune biology between mouse and human sourced HeSC and BM-MSCs speaks to the importance of comparative biology when interrogating rodent systems for human translational insights. Stem Cells 2019;37:1075-1082.

12.
Gastroenterology ; 156(8): 2254-2265.e3, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30779925

RESUMO

BACKGROUND & AIMS: Crohn's disease is a relapsing and remitting inflammatory disorder with a variable clinical course. Although most patients present with an inflammatory phenotype (B1), approximately 20% of patients rapidly progress to complicated disease, which includes stricturing (B2), within 5 years. We analyzed DNA methylation patterns in blood samples of pediatric patients with Crohn's disease at diagnosis and later time points to identify changes that associate with and might contribute to disease development and progression. METHODS: We obtained blood samples from 164 pediatric patients (1-17 years old) with Crohn's disease (B1 or B2) who participated in a North American study and were followed for 5 years. Participants without intestinal inflammation or symptoms served as controls (n = 74). DNA methylation patterns were analyzed in samples collected at time of diagnosis and 1-3 years later at approximately 850,000 sites. We used genetic association and the concept of Mendelian randomization to identify changes in DNA methylation patterns that might contribute to the development of or result from Crohn's disease. RESULTS: We identified 1189 5'-cytosine-phosphate-guanosine-3' (CpG) sites that were differentially methylated between patients with Crohn's disease (at diagnosis) and controls. Methylation changes at these sites correlated with plasma levels of C-reactive protein. A comparison of methylation profiles of DNA collected at diagnosis of Crohn's disease vs during the follow-up period showed that, during treatment, alterations identified in methylation profiles at the time of diagnosis of Crohn's disease more closely resembled patterns observed in controls, irrespective of disease progression to B2. We identified methylation changes at 3 CpG sites that might contribute to the development of Crohn's disease. Most CpG methylation changes associated with Crohn's disease disappeared with treatment of inflammation and might be a result of Crohn's disease. CONCLUSIONS: Methylation patterns observed in blood samples from patients with Crohn's disease accompany acute inflammation; with treatment, these change to resemble methylation patterns observed in patients without intestinal inflammation. These findings indicate that Crohn's disease-associated patterns of DNA methylation observed in blood samples are a result of the inflammatory features of the disease and are less likely to contribute to disease development or progression.


Assuntos
Doença de Crohn/genética , Metilação de DNA/genética , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana/métodos , Adolescente , Fatores Etários , Estudos de Casos e Controles , Criança , Pré-Escolar , Doença de Crohn/sangue , Progressão da Doença , Feminino , Seguimentos , Genótipo , Humanos , Lactente , Inflamação/genética , Masculino , América do Norte , Medição de Risco , Índice de Gravidade de Doença , Fatores Sexuais
13.
Nat Commun ; 10(1): 372, 2019 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-30655540

RESUMO

The original version of this Article omitted a declaration from the Competing Interests statement, which should have included the following: 'A patent has been applied for by Emory University with F.E.L, I.S. and D.C. N. as named inventors. The patent application number is PCT/US2016/036650'. This has now been corrected in both the PDF and HTML versions of the Article.

14.
Nat Commun ; 10(1): 330, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-30659175

RESUMO

Computational prediction of the phenotypic propensities of noncoding single nucleotide variants typically combines annotation of genomic, functional and evolutionary attributes into a single score. Here, we evaluate if the claimed excellent accuracies of these predictions translate into high rates of success in addressing questions important in biological research, such as fine mapping causal variants, distinguishing pathogenic allele(s) at a given position, and prioritizing variants for genetic risk assessment. A significant disconnect is found to exist between the statistical modelling and biological performance of predictive approaches. We discuss fundamental reasons underlying these deficiencies and suggest that future improvements of computational predictions need to address confounding of allelic, positional and regional effects as well as imbalance of the proportion of true positive variants in candidate lists.


Assuntos
Doença/genética , Modelos Estatísticos , RNA não Traduzido/genética , Algoritmos , Animais , Biologia Computacional , Evolução Molecular , Estudo de Associação Genômica Ampla , Humanos , Aprendizado de Máquina , Mamíferos/genética , Polimorfismo de Nucleotídeo Único
15.
Nat Commun ; 10(1): 38, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30604764

RESUMO

Molecular mechanisms driving disease course and response to therapy in ulcerative colitis (UC) are not well understood. Here, we use RNAseq to define pre-treatment rectal gene expression, and fecal microbiota profiles, in 206 pediatric UC patients receiving standardised therapy. We validate our key findings in adult and paediatric UC cohorts of 408 participants. We observe a marked suppression of mitochondrial genes and function across cohorts in active UC, and that increasing disease severity is notable for enrichment of adenoma/adenocarcinoma and innate immune genes. A subset of severity genes improves prediction of corticosteroid-induced remission in the discovery cohort; this gene signature is also associated with response to anti-TNFα and anti-α4ß7 integrin in adults. The severity and therapeutic response gene signatures were in turn associated with shifts in microbes previously implicated in mucosal homeostasis. Our data provide insights into UC pathogenesis, and may prioritise future therapies for nonresponders to current approaches.


Assuntos
Colite Ulcerativa/genética , Genes Mitocondriais/genética , Mucosa Intestinal/metabolismo , Doenças Mitocondriais/genética , Transcriptoma/genética , Adolescente , Adulto , Anti-Inflamatórios não Esteroides/uso terapêutico , Criança , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/microbiologia , Colite Ulcerativa/patologia , Fezes/microbiologia , Feminino , Perfilação da Expressão Gênica , Glucocorticoides/uso terapêutico , Humanos , Integrinas/antagonistas & inibidores , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Masculino , Mesalamina/uso terapêutico , Microbiota , Mitocôndrias/genética , Mitocôndrias/patologia , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/microbiologia , Doenças Mitocondriais/patologia , Medicina de Precisão/métodos , Estudos Prospectivos , Reto/metabolismo , Reto/microbiologia , Reto/patologia , Indução de Remissão/métodos , Análise de Sequência de RNA , Índice de Gravidade de Doença , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores
16.
Nat Rev Genet ; 2018 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-30348998

RESUMO

Personalized medicine promises to advance and improve health by targeting the right medication to the right person at the right time, thus maximizing the proportion of treated patients who achieve an effective response to therapy. This Comment article makes the complementary argument that equally important benefits will derive from negative prediction, namely by identifying those individuals who are either not actually in need of, or unlikely to respond to, a drug. Reduction of unnecessary prescription could conceivably save health-care systems many billions of dollars with very little detrimental impact on outcomes.

17.
Immunity ; 49(4): 725-739.e6, 2018 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-30314758

RESUMO

Systemic Lupus Erythematosus (SLE) is characterized by B cells lacking IgD and CD27 (double negative; DN). We show that DN cell expansions reflected a subset of CXCR5- CD11c+ cells (DN2) representing pre-plasma cells (PC). DN2 cells predominated in African-American patients with active disease and nephritis, anti-Smith and anti-RNA autoantibodies. They expressed a T-bet transcriptional network; increased Toll-like receptor-7 (TLR7); lacked the negative TLR regulator TRAF5; and were hyper-responsive to TLR7. DN2 cells shared with activated naive cells (aNAV), phenotypic and functional features, and similar transcriptomes. Their PC differentiation and autoantibody production was driven by TLR7 in an interleukin-21 (IL-21)-mediated fashion. An in vivo developmental link between aNAV, DN2 cells, and PC was demonstrated by clonal sharing. This study defines a distinct differentiation fate of autoreactive naive B cells into PC precursors with hyper-responsiveness to innate stimuli, as well as establishes prominence of extra-follicular B cell activation in SLE, and identifies therapeutic targets.

19.
J Pers Med ; 8(3)2018 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-30223463

RESUMO

To evaluate whether recovery from complicated malaria follows a common trajectory in terms of immunological mechanism or, rather, is highly individualized for each patient, we performed longitudinal gene expression profiling of whole blood. RNA sequencing (RNAseq) was performed on blood samples obtained from eight patients on four consecutive days between hospital admission and discharge. Six patients were infected with Plasmodium falciparum, and two with Plasmodium vivax; one patient was a pregnant woman infected with P. falciparum, who was hospitalized for several weeks. The characterization of blood transcript modules (BTM) and blood informative transcripts (BIT) revealed that patients' responses showed little commonality, being dominated by the balance of gene activity relating to lymphocyte function, inflammation, and interferon responses specific to each patient. Only weak correlations with specific complicated malaria symptoms such as jaundice, thrombocytopenia, or anemia were observed. The differential expression of individual genes, including transcripts derived from the human leukocyte antigen (HLA) complex, generally reflected differences in the underlying immune processes. Although the results of this pilot study do not point to any single process that might provide a target for complicated malaria treatment or prevention or personalized medical strategies, larger patient series and more extensive blood sampling may allow the classification of patients according to their type of response in order to develop novel therapeutic approaches.

20.
Nat Commun ; 9(1): 3698, 2018 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-30209264

RESUMO

Human antibody-secreting cells (ASC) in peripheral blood are found after vaccination or infection but rapidly apoptose unless they migrate to the bone marrow (BM). Yet, elements of the BM microenvironment required to sustain long-lived plasma cells (LLPC) remain elusive. Here, we identify BM factors that maintain human ASC > 50 days in vitro. The critical components of the cell-free in vitro BM mimic consist of products from primary BM mesenchymal stromal cells (MSC), a proliferation-inducing ligand (APRIL), and hypoxic conditions. Comparative analysis of protein-protein interactions between BM-MSC proteomics with differential RNA transcriptomics of blood ASC and BM LLPC identify two major survival factors, fibronectin and YWHAZ. The MSC secretome proteins and hypoxic conditions play a role in LLPC survival utilizing mechanisms that downregulate mTORC1 signaling and upregulate hypoxia signatures. In summary, we identify elements of the BM survival niche critical for maturation of blood ASC to BM LLPC.

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