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1.
Nat Commun ; 10(1): 4575, 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31594933

RESUMO

IL-7 is a key factor in T cell immunity and common variants at IL7R, encoding its receptor, are associated with autoimmune disease susceptibility. IL7R mRNA is induced in stimulated monocytes, yet a function for IL7R in monocyte biology remains unexplored. Here we characterize genetic regulation of IL7R at the protein level in healthy individuals, and find that monocyte surface and soluble IL7R (sIL7R) are markedly induced by lipopolysaccharide. In monocytes, both surface IL7R and sIL7R expression strongly associate with allelic carriage of rs6897932, a disease-associated IL7R polymorphism. Monocytes produce more sIL7R than CD4 + T cells, and the amount is additionally correlated with the expression of DDX39A, encoding a splicing factor. Synovial fluid-derived monocytes from patients with spondyloarthritis are enriched for IL7R+ cells with a unique transcriptional profile that overlaps with IL-7-induced gene sets. Our data thus suggest a previously unappreciated function for monocytes in IL-7 biology and IL7R-associated diseases.

2.
Nat Genet ; 51(7): 1082-1091, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31253980

RESUMO

Most candidate drugs currently fail later-stage clinical trials, largely due to poor prediction of efficacy on early target selection1. Drug targets with genetic support are more likely to be therapeutically valid2,3, but the translational use of genome-scale data such as from genome-wide association studies for drug target discovery in complex diseases remains challenging4-6. Here, we show that integration of functional genomic and immune-related annotations, together with knowledge of network connectivity, maximizes the informativeness of genetics for target validation, defining the target prioritization landscape for 30 immune traits at the gene and pathway level. We demonstrate how our genetics-led drug target prioritization approach (the priority index) successfully identifies current therapeutics, predicts activity in high-throughput cellular screens (including L1000, CRISPR, mutagenesis and patient-derived cell assays), enables prioritization of under-explored targets and allows for determination of target-level trait relationships. The priority index is an open-access, scalable system accelerating early-stage drug target selection for immune-mediated disease.

3.
Nat Commun ; 9(1): 1014, 2018 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-29523850

RESUMO

Nontyphoidal Salmonella (NTS) is a major cause of bacteraemia in Africa. The disease typically affects HIV-infected individuals and young children, causing substantial morbidity and mortality. Here we present a genome-wide association study (180 cases, 2677 controls) and replication analysis of NTS bacteraemia in Kenyan and Malawian children. We identify a locus in STAT4, rs13390936, associated with NTS bacteraemia. rs13390936 is a context-specific expression quantitative trait locus for STAT4 RNA expression, and individuals carrying the NTS-risk genotype demonstrate decreased interferon-γ (IFNγ) production in stimulated natural killer cells, and decreased circulating IFNγ concentrations during acute NTS bacteraemia. The NTS-risk allele at rs13390936 is associated with protection against a range of autoimmune diseases. These data implicate interleukin-12-dependent IFNγ-mediated immunity as a determinant of invasive NTS disease in African children, and highlight the shared genetic architecture of infectious and autoimmune disease.


Assuntos
Doenças Autoimunes/genética , Bacteriemia/epidemiologia , Predisposição Genética para Doença , Fator de Transcrição STAT4/genética , Infecções por Salmonella/epidemiologia , Salmonella/patogenicidade , Adolescente , Alelos , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/microbiologia , Bacteriemia/genética , Bacteriemia/imunologia , Bacteriemia/microbiologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Seguimentos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Imunidade Celular/genética , Lactente , Recém-Nascido , Interferon gama/sangue , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-12/imunologia , Interleucina-12/metabolismo , Quênia/epidemiologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Malaui/epidemiologia , Masculino , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Fatores de Risco , Salmonella/isolamento & purificação , Infecções por Salmonella/genética , Infecções por Salmonella/imunologia , Infecções por Salmonella/microbiologia
5.
Nat Neurosci ; 20(8): 1052-1061, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28628103

RESUMO

A genome-wide survival analysis of 14,406 Alzheimer's disease (AD) cases and 25,849 controls identified eight previously reported AD risk loci and 14 novel loci associated with age at onset. Linkage disequilibrium score regression of 220 cell types implicated the regulation of myeloid gene expression in AD risk. The minor allele of rs1057233 (G), within the previously reported CELF1 AD risk locus, showed association with delayed AD onset and lower expression of SPI1 in monocytes and macrophages. SPI1 encodes PU.1, a transcription factor critical for myeloid cell development and function. AD heritability was enriched within the PU.1 cistrome, implicating a myeloid PU.1 target gene network in AD. Finally, experimentally altered PU.1 levels affected the expression of mouse orthologs of many AD risk genes and the phagocytic activity of mouse microglial cells. Our results suggest that lower SPI1 expression reduces AD risk by regulating myeloid gene expression and cell function.


Assuntos
Doença de Alzheimer/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Haplótipos/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas Proto-Oncogênicas/genética , Transativadores/genética , Alelos , Animais , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Desequilíbrio de Ligação/genética , Masculino , Camundongos , Fatores de Risco , Fatores de Transcrição/genética
6.
Cold Spring Harb Mol Case Stud ; 3(3): a001362, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28487881

RESUMO

Whole-genome sequencing (WGS) has transformed the understanding of the genetic drivers of cancer and is increasingly being used in cancer medicine to identify personalized therapies. Here we describe a case in which the application of WGS identified a tumoral BRCA2 deletion in a patient with aggressive dedifferentiated prostate cancer that was repeat-biopsied after disease progression. This would not have been detected by standard BRCA testing, and it led to additional treatment with a maintenance poly ADP ribose polymerase (PARP) inhibitor following platinum-based chemotherapy. This case demonstrates that repeat biopsy upon disease progression and application of WGS to tumor samples has meaningful clinical utility and the potential to transform outcomes in patients with cancer.


Assuntos
Proteína BRCA2/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/terapia , Proteína BRCA2/metabolismo , Biópsia/métodos , Mutação em Linhagem Germinativa , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/uso terapêutico , Medicina de Precisão , Deleção de Sequência , Sequenciamento Completo do Genoma/métodos
7.
PLoS Genet ; 13(3): e1006643, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28248954

RESUMO

Inappropriate activation or inadequate regulation of CD4+ and CD8+ T cells may contribute to the initiation and progression of multiple autoimmune and inflammatory diseases. Studies on disease-associated genetic polymorphisms have highlighted the importance of biological context for many regulatory variants, which is particularly relevant in understanding the genetic regulation of the immune system and its cellular phenotypes. Here we show cell type-specific regulation of transcript levels of genes associated with several autoimmune diseases in CD4+ and CD8+ T cells including a trans-acting regulatory locus at chr12q13.2 containing the rs1131017 SNP in the RPS26 gene. Most remarkably, we identify a common missense variant in IL27, associated with type 1 diabetes that results in decreased functional activity of the protein and reduced expression levels of downstream IRF1 and STAT1 in CD4+ T cells only. Altogether, our results indicate that eQTL mapping in purified T cells provides novel functional insights into polymorphisms and pathways associated with autoimmune diseases.

8.
Genome Med ; 9(1): 18, 2017 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-28219444

RESUMO

BACKGROUND: Expression quantitative trait loci (eQTL) databases represent a valuable resource to link disease-associated SNPs to specific candidate genes whose gene expression is significantly modulated by the SNP under investigation. We previously identified signal inhibitory receptor on leukocytes-1 (SIRL-1) as a powerful regulator of human innate immune cell function. While it is constitutively high expressed on neutrophils, on monocytes the SIRL-1 surface expression varies strongly between individuals. The underlying mechanism of regulation, its genetic control as well as potential clinical implications had not been explored yet. METHODS: Whole blood eQTL data of a Chinese cohort was used to identify SNPs regulating the expression of VSTM1, the gene encoding SIRL-1. The genotype effect was validated by flow cytometry (cell surface expression), correlated with electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP) and bisulfite sequencing (C-methylation) and its functional impact studied the inhibition of reactive oxygen species (ROS). RESULTS: We found a significant association of a single CpG-SNP, rs612529T/C, located in the promoter of VSTM1. Through flow cytometry analysis we confirmed that primarily in the monocytes the protein level of SIRL-1 is strongly associated with genotype of this SNP. In monocytes, the T allele of this SNP facilitates binding of the transcription factors YY1 and PU.1, of which the latter has been recently shown to act as docking site for modifiers of DNA methylation. In line with this notion rs612529T associates with a complete demethylation of the VSTM1 promoter correlating with the allele-specific upregulation of SIRL-1 expression. In monocytes, this upregulation strongly impacts the IgA-induced production of ROS by these cells. Through targeted association analysis we found a significant Meta P value of 1.14 × 10-6 for rs612529 for association to atopic dermatitis (AD). CONCLUSION: Low expression of SIRL-1 on monocytes is associated with an increased risk for the manifestation of an inflammatory skin disease. It thus underlines the role of both the cell subset and this inhibitory immune receptor in maintaining immune homeostasis in the skin. Notably, the genetic regulation is achieved by a single CpG-SNP, which controls the overall methylation state of the promoter gene segment.


Assuntos
Metilação de DNA , Dermatite Atópica/metabolismo , Regulação da Expressão Gênica , Monócitos/metabolismo , Polimorfismo de Nucleotídeo Único , Receptores Imunológicos/genética , Grupo com Ancestrais do Continente Asiático/genética , Dermatite Atópica/genética , Feminino , Humanos , Masculino , Regiões Promotoras Genéticas , Adulto Jovem
9.
Am J Hum Genet ; 99(6): 1353-1358, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27817866

RESUMO

Differential HLA-C levels influence several human diseases, but the mechanisms responsible are incompletely characterized. Using a validated prediction algorithm, we imputed HLA-C cell surface levels in 228 individuals from the 1000 Genomes dataset. We tested 68,726 SNPs within the MHC for association with HLA-C level. The HLA-C promoter region variant, rs2395471, 800 bp upstream of the transcription start site, gave the most significant association with HLA-C levels (p = 4.2 × 10-66). This imputed expression quantitative trait locus, termed impeQTL, was also shown to associate with HLA-C expression in a genome-wide association study of 273 donors in which HLA-C mRNA expression levels were determined by quantitative PCR (qPCR) (p = 1.8 × 10-20) and in two cohorts where HLA-C cell surface levels were determined directly by flow cytometry (n = 369 combined, p < 10-15). rs2395471 is located in an Oct1 transcription factor consensus binding site motif where the A allele is predicted to have higher affinity for Oct1 than the G allele. Mobility shift electrophoresis demonstrated that Oct1 binds to both alleles in vitro, but decreased HLA-C promoter activity was observed in a luciferase reporter assay for rs2395471_G relative to rs2395471_A on a fixed promoter background. The rs2395471 variant accounts for up to 36% of the explained variation of HLA-C level. These data strengthen our understanding of HLA-C transcriptional regulation and provide a basis for understanding the potential consequences of manipulating HLA-C levels therapeutically.


Assuntos
Antígenos HLA-C/biossíntese , Antígenos HLA-C/genética , Fator 1 de Transcrição de Octâmero/metabolismo , Regiões Promotoras Genéticas/genética , Algoritmos , Alelos , Sítios de Ligação/genética , Conjuntos de Dados como Assunto , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Células HeLa , Humanos , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Sítio de Iniciação de Transcrição , Transcrição Genética
10.
Nat Genet ; 47(12): 1457-1464, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26502338

RESUMO

Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry, constituting a new GWAS, a meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including ten new associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n = 16) of transcription factors among SLE susceptibility genes. This finding supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE.


Assuntos
Imunidade Adaptativa/genética , Regulação da Expressão Gênica , Estudos de Associação Genética , Marcadores Genéticos/genética , Imunidade Inata/genética , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/patologia , Estudos de Casos e Controles , Loci Gênicos , Predisposição Genética para Doença , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Metanálise como Assunto , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
11.
Lancet ; 385 Suppl 1: S13, 2015 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-26312835

RESUMO

BACKGROUND: Non-typhoidal Salmonella (NTS) causes invasive and frequently fatal disease in African children. Existing strategies to prevent, diagnose, and treat NTS disease are inadequate. An improved understanding of the biology of invasive Salmonella infection will facilitate the development of novel NTS control measures. Despite evidence in mice and man showing a clear role for host genetics in NTS susceptibility, there are no published studies investigating host genetic susceptibility to NTS in African populations. METHODS: We conducted a genome-wide association study (SNP Array 6.0, Affymetrix, CA, USA) of NTS bacteraemia in Kenyan children, with replication in Malawian children. We assessed the function of NTS-associated variants in an expression quantitative trait locus (eQTL) dataset of interferon γ (IFNγ) and lipopolysaccharide-stimulated monocytes from 432 healthy European adults. Serum IFNγ (Bio-Plex immunoassay, Bio-Rad Laboratories, CA, USA) in Malawian NTS cases (n=106) during acute disease was correlated with genotype by linear regression. FINDINGS: After whole-genome imputation and quality control, 180 Kenyan cases and 2677 controls were included in an association analysis at 7 951 614 (additive model) and 4 669 537 (genotypic model) loci. After quality control, 143 Malawian cases and 336 controls were included in the replication analysis. An intronic variant in STAT4 was associated (recessive model) with NTS in both Kenyan and Malawian children (Kenya p=5·6 × 10(-9), Malawi p=0·02, combined p=1·4 × 10(-9); odds ratio 7·2, 95% CI 3·8-13·5). The NTS-associated variant was an eQTL for STAT4 expression in IFNγ-stimulated monocytes (p=9·59 × 10(-6)), the NTS risk allele being associated with lower STAT4 expression. In Malawian children with NTS bacteraemia, the same NTS risk allele was associated with lower serum concentrations of IFNγ (p=0·02) at presentation. INTERPRETATION: STAT4 is highly plausible as a susceptibility locus for invasive NTS disease. STAT4 mediates IFNγ release in T cells and natural killer cells in response to interleukin 12 (IL12). Individuals with rare mutations elsewhere in the IL12-IFNγ axis are at risk of disseminated NTS infection. We provide the first evidence, to our knowledge, of a host genetic determinant of NTS disease in African children, and of a STAT4 variant conferring susceptibility to an infectious disease in man. FUNDING: Wellcome Trust.

12.
Nat Commun ; 6: 7545, 2015 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-26151758

RESUMO

Neutrophils form the most abundant leukocyte subset and are central to many disease processes. Technical challenges in transcriptomic profiling have prohibited genomic approaches to date. Here we map expression quantitative trait loci (eQTL) in peripheral blood CD16+ neutrophils from 101 healthy European adults. We identify cis-eQTL for 3281 neutrophil-expressed genes including many implicated in neutrophil function, with 450 of these not previously observed in myeloid or lymphoid cells. Paired comparison with monocyte eQTL demonstrates nuanced conditioning of genetic regulation of gene expression by cellular context, which relates to cell-type-specific DNA methylation and histone modifications. Neutrophil eQTL are markedly enriched for trait-associated variants particularly autoimmune, allergy and infectious disease. We further demonstrate how eQTL in PADI4 and NOD2 delineate risk variant function in rheumatoid arthritis, leprosy and Crohn's disease. Taken together, these data help advance understanding of the genetics of gene expression, neutrophil biology and immune-related diseases.


Assuntos
Regulação da Expressão Gênica/fisiologia , Genômica/métodos , Neutrófilos/metabolismo , Adulto , Feminino , Variação Genética , Genótipo , Humanos , Masculino , Locos de Características Quantitativas
13.
PLoS Genet ; 11(5): e1005223, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25955312

RESUMO

The functional consequences of trait associated SNPs are often investigated using expression quantitative trait locus (eQTL) mapping. While trait-associated variants may operate in a cell-type specific manner, eQTL datasets for such cell-types may not always be available. We performed a genome-environment interaction (GxE) meta-analysis on data from 5,683 samples to infer the cell type specificity of whole blood cis-eQTLs. We demonstrate that this method is able to predict neutrophil and lymphocyte specific cis-eQTLs and replicate these predictions in independent cell-type specific datasets. Finally, we show that SNPs associated with Crohn's disease preferentially affect gene expression within neutrophils, including the archetypal NOD2 locus.


Assuntos
Linfócitos/citologia , Neutrófilos/citologia , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Linhagem Celular , Doença de Crohn/genética , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla/métodos , Humanos , Linfócitos/metabolismo , Neutrófilos/metabolismo , Proteína Adaptadora de Sinalização NOD2/genética , Proteína Adaptadora de Sinalização NOD2/metabolismo , Fenótipo , Análise de Componente Principal , Reprodutibilidade dos Testes
14.
EBioMedicine ; 2(11): 1619-26, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26870787

RESUMO

The ratio of monocytes and lymphocytes (ML ratio) in peripheral blood is associated with tuberculosis and malaria disease risk and cancer and cardiovascular disease outcomes. We studied anti-mycobacterial function and the transcriptome of monocytes in relation to the ML ratio. Mycobacterial growth inhibition assays of whole or sorted blood were performed and mycobacteria were enumerated by liquid culture. Transcriptomes of unstimulated CD14 + monocytes isolated by magnetic bead sorting were characterised by microarray. Transcript expression was tested for association with ML ratio calculated from leucocyte differential counts by linear regression. The ML ratio was associated with mycobacterial growth in vitro (ß = 2.23, SE 0.91, p = 0.02). Using sorted monocytes and lymphocytes, in vivo ML ratio (% variance explained R(2) = 11%, p = 0.02) dominated over in vitro ratios (R(2) = 5%, p = 0.10) in explaining mycobacterial growth. Expression of 906 genes was associated with the ML ratio and 53 with monocyte count alone. ML-ratio associated genes were enriched for type-I and -II interferon signalling (p = 1.2 × 10(− 8)), and for genes under transcriptional control of IRF1, IRF2, RUNX1, RELA and ESRRB. The ML-ratio-associated gene set was enriched in TB disease (3.11-fold, 95% CI: 2.28-4.19, p = 5.7 × 10(− 12)) and other inflammatory diseases including atopy, HIV, IBD and SLE. The ML ratio is associated with distinct transcriptional and anti-mycobacterial profiles of monocytes that may explain the disease associations of the ML ratio.


Assuntos
Contagem de Leucócitos , Monócitos/imunologia , Monócitos/metabolismo , Mycobacterium/imunologia , Transcriptoma , Tuberculose/genética , Tuberculose/imunologia , Adulto , Sítios de Ligação , Resistência à Doença/genética , Resistência à Doença/imunologia , Suscetibilidade a Doenças , Feminino , Perfilação da Expressão Gênica , Humanos , Interferons/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Masculino , Monócitos/microbiologia , Ligação Proteica , Transdução de Sinais , Fatores de Transcrição/metabolismo , Tuberculose/metabolismo , Tuberculose/microbiologia , Adulto Jovem
15.
EBioMedicine ; 2(11): 1619-1626, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28958495

RESUMO

The ratio of monocytes and lymphocytes (ML ratio) in peripheral blood is associated with tuberculosis and malaria disease risk and cancer and cardiovascular disease outcomes. We studied anti-mycobacterial function and the transcriptome of monocytes in relation to the ML ratio. Mycobacterial growth inhibition assays of whole or sorted blood were performed and mycobacteria were enumerated by liquid culture. Transcriptomes of unstimulated CD14+ monocytes isolated by magnetic bead sorting were characterised by microarray. Transcript expression was tested for association with ML ratio calculated from leucocyte differential counts by linear regression. The ML ratio was associated with mycobacterial growth in vitro (ß=2.23, SE 0.91, p=0.02). Using sorted monocytes and lymphocytes, in vivo ML ratio (% variance explained R2=11%, p=0.02) dominated over in vitro ratios (R2=5%, p=0.10) in explaining mycobacterial growth. Expression of 906 genes was associated with the ML ratio and 53 with monocyte count alone. ML-ratio associated genes were enriched for type-I and -II interferon signalling (p=1.2×10-8), and for genes under transcriptional control of IRF1, IRF2, RUNX1, RELA and ESRRB. The ML-ratio-associated gene set was enriched in TB disease (3.11-fold, 95% CI: 2.28-4.19, p=5.7×10-12) and other inflammatory diseases including atopy, HIV, IBD and SLE. The ML ratio is associated with distinct transcriptional and anti-mycobacterial profiles of monocytes that may explain the disease associations of the ML ratio.

16.
Genome Biol ; 15(10): 494, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25366989

RESUMO

BACKGROUND: The master transactivator CIITA is essential to the regulation of Major Histocompatibility Complex (MHC)class II genes and an effective immune response. CIITA is known to modulate a small number of non-MHC genes involved in antigen presentation such as CD74 and B2M but its broader genome-wide function and relationship with underlying genetic diversity has not been resolved. RESULTS: We report the first genome-wide ChIP-seq map for CIITA and complement this by mapping inter-individual variation in CIITA expression as a quantitative trait. We analyse CIITA recruitment for pathophysiologically relevant primary human B cells and monocytes, resting and treated with interferon-gamma, in the context of the epigenomic regulatory landscape and DNA-binding proteins associated with the CIITA enhanceosome including RFX, CREB1/ATF1 and NFY. We confirm recruitment to proximal promoter sequences in MHC class II genes and more distally involving the canonical CIITA enhanceosome. Overall, we map 843 CIITA binding intervals involving 442 genes and find 95% of intervals are located outside the MHC and 60% not associated with RFX5 binding. Binding intervals are enriched for genes involved in immune function n and infectious disease with novel loci including major histone gene clusters. Were solve differentially expressed genes associated in trans with a CIITA intronic sequence variant, integrate with CIITA recruitment and show how this is mediated by allele-specific recruitment of NF-kB. CONCLUSIONS: Our results indicate a broader role for CIITA beyond the MHC involving immune-related genes.We provide new insights into allele-specific regulation of CIITA informative for understanding gene function and disease.


Assuntos
Mapeamento Cromossômico , Proteínas Nucleares/genética , Transativadores/genética , Alelos , Linfócitos B/metabolismo , Imunoprecipitação da Cromatina , Regulação da Expressão Gênica , Genômica/métodos , Humanos , Complexo Principal de Histocompatibilidade/genética , NF-kappa B/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Nucleares/fisiologia , Locos de Características Quantitativas , Transativadores/metabolismo , Transativadores/fisiologia
17.
Curr Opin Immunol ; 30: 63-71, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25078545

RESUMO

Mapping gene expression as a quantitative trait (eQTL mapping) can reveal local and distant associations with functionally important genetic variation informative for disease. Recent studies are reviewed which have demonstrated that this approach is particularly informative when applied to diverse immune cell populations and situations relevant to infection and immunity. Context-specific eQTL have now been characterised following endotoxin activation, induction with interferons, mycobacteria, and influenza, together with genetic determinants of response to vaccination. The application of genetical genomic approaches offers new opportunities to advance our understanding of gene-environment interactions and fundamental processes in innate and adaptive immunity.


Assuntos
Doenças Transmissíveis/genética , Expressão Gênica , Mapeamento Cromossômico , Doenças Transmissíveis/imunologia , Humanos , Mycobacterium tuberculosis/imunologia , Locos de Características Quantitativas , Vacinação
18.
Science ; 343(6175): 1246949, 2014 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-24604202

RESUMO

To systematically investigate the impact of immune stimulation upon regulatory variant activity, we exposed primary monocytes from 432 healthy Europeans to interferon-γ (IFN-γ) or differing durations of lipopolysaccharide and mapped expression quantitative trait loci (eQTLs). More than half of cis-eQTLs identified, involving hundreds of genes and associated pathways, are detected specifically in stimulated monocytes. Induced innate immune activity reveals multiple master regulatory trans-eQTLs including the major histocompatibility complex (MHC), coding variants altering enzyme and receptor function, an IFN-ß cytokine network showing temporal specificity, and an interferon regulatory factor 2 (IRF2) transcription factor-modulated network. Induced eQTL are significantly enriched for genome-wide association study loci, identifying context-specific associations to putative causal genes including CARD9, ATM, and IRF8. Thus, applying pathophysiologically relevant immune stimuli assists resolution of functional genetic variants.


Assuntos
Doença de Crohn/genética , Regulação da Expressão Gênica/imunologia , Predisposição Genética para Doença , Imunidade Inata/genética , Monócitos/imunologia , Adulto , Hidrocarboneto de Aril Hidroxilases/genética , Fatores de Transcrição de Zíper de Leucina Básica/genética , Proteínas Adaptadoras de Sinalização CARD/genética , Mapeamento Cromossômico , Doença de Crohn/epidemiologia , Citocromo P-450 CYP1B1 , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Fator Regulador 2 de Interferon/genética , Fatores Reguladores de Interferon/genética , Interferon gama/farmacologia , Receptores de Lipopolissacarídeos/imunologia , Masculino , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Receptores Purinérgicos P2/genética , Adulto Jovem
19.
Eur J Hum Genet ; 22(4): 568-71, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24193346

RESUMO

ZFP57 is an important transcriptional regulator involved in DNA methylation and genomic imprinting during development. Here we demonstrate that gene expression also occurs at a low level in adult peripheral blood cells and other tissues including the kidney and thymus, but is critically dependent on underlying local genetic variation within the MHC. We resolve a highly significant expression quantitative trait locus for ZFP57 involving single-nucleotide polymorphisms (SNPs) in the first intron of the gene co-localizing with a DNase I hypersensitive site and evidence of CTCF recruitment. These data identify ZFP57 as a candidate gene underlying reported MHC disease associations, notably for putative regulatory variants associated with cancer and HIV-1. The work highlights the role that ZFP57 may play in DNA methylation and epigenetic regulation beyond early development into adult life dependent on genetic background, with important potential implications for disease.


Assuntos
Mapeamento Cromossômico , Regulação da Expressão Gênica , Genes MHC Classe I/genética , Fatores de Transcrição Kruppel-Like/genética , Polimorfismo de Nucleotídeo Único , Síndrome de Imunodeficiência Adquirida/genética , Doenças Autoimunes/genética , Fator de Ligação a CCCTC , Metilação de DNA , Desoxirribonuclease I/genética , Epigênese Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Impressão Genômica , Humanos , Desequilíbrio de Ligação , Neoplasias/genética , Locos de Características Quantitativas , Proteínas Repressoras/genética , Dedos de Zinco/genética
20.
Dev Med Child Neurol ; 56(4): 346-53, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24117048

RESUMO

AIM: Sex chromosome aneuploidies increase the risk of spoken or written language disorders but individuals with specific language impairment (SLI) or dyslexia do not routinely undergo cytogenetic analysis. We assess the frequency of sex chromosome aneuploidies in individuals with language impairment or dyslexia. METHOD: Genome-wide single nucleotide polymorphism genotyping was performed in three sample sets: a clinical cohort of individuals with speech and language deficits (87 probands: 61 males, 26 females; age range 4 to 23 years), a replication cohort of individuals with SLI, from both clinical and epidemiological samples (209 probands: 139 males, 70 females; age range 4 to 17 years), and a set of individuals with dyslexia (314 probands: 224 males, 90 females; age range 7 to 18 years). RESULTS: In the clinical language-impaired cohort, three abnormal karyotypic results were identified in probands (proband yield 3.4%). In the SLI replication cohort, six abnormalities were identified providing a consistent proband yield (2.9%). In the sample of individuals with dyslexia, two sex chromosome aneuploidies were found giving a lower proband yield of 0.6%. In total, two XYY, four XXY (Klinefelter syndrome), three XXX, one XO (Turner syndrome), and one unresolved karyotype were identified. INTERPRETATION: The frequency of sex chromosome aneuploidies within each of the three cohorts was increased over the expected population frequency (approximately 0.25%) suggesting that genetic testing may prove worthwhile for individuals with language and literacy problems and normal non-verbal IQ. Early detection of these aneuploidies can provide information and direct the appropriate management for individuals.


Assuntos
Aneuploidia , Dislexia/epidemiologia , Dislexia/genética , Transtornos do Desenvolvimento da Linguagem/epidemiologia , Transtornos do Desenvolvimento da Linguagem/genética , Cromossomos Sexuais , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Genótipo , Humanos , Cariotipagem , Masculino , Idade Paterna , Polimorfismo de Nucleotídeo Único , Prevalência , Adulto Jovem
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