Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 99
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Int J Obes (Lond) ; 2018 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-30232418

RESUMO

OBJECTIVE: Indices of body fat distribution are heritable, but few genetic signals have been reported from genome-wide association studies (GWAS) of computed tomography (CT) imaging measurements of body fat distribution. We aimed to identify genes associated with adiposity traits and the key drivers that are central to adipose regulatory networks. SUBJECTS: We analyzed gene transcript expression data in blood from participants in the Framingham Heart Study, a large community-based cohort (n up to 4303), as well as implemented an integrative analysis of these data and existing biological information. RESULTS: Our association analyses identified unique and common gene expression signatures across several adiposity traits, including body mass index, waist-hip ratio, waist circumference, and CT-measured indices, including volume and quality of visceral and subcutaneous adipose tissues. We identified six enriched KEGG pathways and two co-expression modules for further exploration of adipose regulatory networks. The integrative analysis revealed four gene sets (Apoptosis, p53 signaling pathway, Proteasome, Ubiquitin-mediated proteolysis) and two co-expression modules with significant genetic variants and 94 key drivers/genes whose local networks were enriched with adiposity-associated genes, suggesting that these enriched pathways or modules have genetic effects on adiposity. Most identified key driver genes are involved in essential biological processes such as controlling cell cycle, DNA repair, and degradation of regulatory proteins are cancer related. CONCLUSIONS: Our integrative analysis of genetic, transcriptional, and biological information provides a list of compelling candidates for further follow-up functional studies to uncover the biological mechanisms underlying obesity. These candidates highlight the value of examining CT-derived and central adiposity traits.

2.
J Infect Dis ; 217(1): 158-167, 2017 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-29099929

RESUMO

Background: The most common clinical manifestation of early Lyme disease is the erythema migrans (EM) skin lesion that develops at the tick bite site typically between 7 and 14 days after infection with Borreliella burgdorferi. The host-pathogen interactions that occur in the skin may have a critical role in determining outcome of infection. Methods: Gene arrays were used to characterize the global transcriptional alterations in skin biopsy samples of EM lesions from untreated adult patients with Lyme disease in comparison to controls. Results: The transcriptional pattern in EM biopsies consisted of 254 differentially regulated genes (180 induced and 74 repressed) characterized by the induction of chemokines, cytokines, Toll-like receptors, antimicrobial peptides, monocytoid cell activation markers, and numerous genes annotated as interferon (IFN)-inducible. The IFN-inducible genes included 3 transcripts involved in tryptophan catabolism (IDO1, KMO, KYNU) that play a pivotal role in immune evasion by certain other microbial pathogens by driving the differentiation of regulatory T cells. Conclusions: This is the first study to globally assess the human skin transcriptional response during early Lyme disease. Borreliella burgdorferi elicits a predominant IFN signature in the EM lesion, suggesting a potential mechanism for spirochetal dissemination via IDO1-mediated localized immunosuppression.

3.
Mol Neurodegener ; 12(1): 67, 2017 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-28923099

RESUMO

BACKGROUND: White matter hyperintensities (WMH) are an important biomarker of cumulative vascular brain injury and have been associated with cognitive decline and an increased risk of dementia, stroke, depression, and gait impairments. The pathogenesis of white matter lesions however, remains uncertain. The characterization of gene expression profiles associated with WMH might help uncover molecular mechanisms underlying WMH. METHODS: We performed a transcriptome-wide association study of gene expression profiles with WMH in 3248 participants from the Framingham Heart Study using the Affymetrix Human Exon 1.0 ST Array. RESULTS: We identified 13 genes that were significantly associated with WMH (FDR < 0.05) after adjusting for age, sex and blood cell components. Many of these genes are involved in inflammation-related pathways. CONCLUSION: Thirteen genes were significantly associated with WMH. Our study confirms the hypothesis that inflammation might be an important factor contributing to white matter lesions. Future work is needed to explore if these gene products might serve as potential therapeutic targets.


Assuntos
Encéfalo/patologia , Transcriptoma , Substância Branca/patologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
5.
Am J Hum Genet ; 100(4): 571-580, 2017 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-28285768

RESUMO

Identifying causal genetic variants and understanding their mechanisms of effect on traits remains a challenge in genome-wide association studies (GWASs). In particular, how genetic variants (i.e., trans-eQTLs) affect expression of remote genes (i.e., trans-eGenes) remains unknown. We hypothesized that some trans-eQTLs regulate expression of distant genes by altering the expression of nearby genes (cis-eGenes). Using published GWAS datasets with 39,165 single-nucleotide polymorphisms (SNPs) associated with 1,960 traits, we explored whole blood gene expression associations of trait-associated SNPs in 5,257 individuals from the Framingham Heart Study. We identified 2,350 trans-eQTLs (at p < 10-7); more than 80% of them were found to have cis-associated eGenes. Mediation testing suggested that for 35% of trans-eQTL-trans-eGene pairs in different chromosomes and 90% pairs in the same chromosome, the disease-associated SNP may alter expression of the trans-eGene via cis-eGene expression. In addition, we identified 13 trans-eQTL hotspots, affecting from ten to hundreds of genes, suggesting the existence of master genetic regulators. Using causal inference testing, we searched causal variants across eight cardiometabolic traits (BMI, systolic and diastolic blood pressure, LDL cholesterol, HDL cholesterol, total cholesterol, triglycerides, and fasting blood glucose) and identified several cis-eGenes (ALDH2 for systolic and diastolic blood pressure, MCM6 and DARS for total cholesterol, and TRIB1 for triglycerides) that were causal mediators for the corresponding traits, as well as examples of trans-mediators (TAGAP for LDL cholesterol). The finding of extensive evidence of genome-wide mediation effects suggests a critical role of cryptic gene regulation underlying many disease traits.


Assuntos
Doenças Cardiovasculares/genética , Estudo de Associação Genômica Ampla , Doenças Cardiovasculares/sangue , Estudos Clínicos como Assunto , Feminino , Perfilação da Expressão Gênica , Projeto Genoma Humano , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Mapas de Interação de Proteínas , Locos de Características Quantitativas
6.
BMC Genomics ; 18(1): 139, 2017 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-28178938

RESUMO

BACKGROUND: Cardiometabolic (CM) risk factors are heritable and cluster in individuals. We hypothesized that CM risk factors are associated with multiple shared and unique mRNA and microRNA (miRNA) signatures. We examined associations of mRNA and miRNA levels with 6 CM traits: body mass index, HDL-cholesterol and triglycerides, fasting glucose, and systolic and diastolic blood pressures through cross-sectional analysis of 2812 Framingham Heart Study who had whole blood collection for RNA isolation for mRNA and miRNA expression studies and who consented to genetic research. We excluded participants taking medication for hypertension, dyslipidemia, or diabetes. We measured mRNA (n = 17,318; using the Affymetrix GeneChip Human Exon 1.0 ST Array) and miRNA (n = 315; using qRT-PCR) expression in whole blood. We used linear regression for mRNA analyses and a combination of linear and logistic regression for miRNA analyses. We conducted miRNA-mRNA coexpression and gene ontology enrichment analyses to explore relations between pleiotropic miRNAs, mRNA expression, and CM trait clustering. RESULTS: We identified hundreds of significant associations between mRNAs, miRNAs, and individual CM traits. Four mRNAs (FAM13A, CSF2RB, HIST1H2AC, WNK1) were associated with all 6 CM traits (FDR < 0.001) and four miRNAs (miR-197-3p, miR-328, miR-505-5p, miR-145-5p) were associated with four CM traits (FDR < 0.05). Twelve mRNAs, including WNK1, that were coexpressed with the four most pleiotropic miRNAs, were also miRNA targets. mRNAs coexpressed with pleiotropic miRNAs were enriched for RNA metabolism (miR-505-5p), ubiquitin-dependent protein catabolism (miR-197-3p, miR-328) and chromatin assembly (miR-328). CONCLUSIONS: We identified mRNA and miRNA signatures of individual CM traits and their clustering. Implicated transcripts may play causal roles in CM risk or be downstream consequences of CM risk factors on the transcriptome. Studies are needed to establish whether or not pleiotropic circulating transcripts illuminate causal pathways for CM risk.


Assuntos
Doenças Cardiovasculares/genética , MicroRNAs/metabolismo , RNA Mensageiro/metabolismo , Transcriptoma , Adulto , Idoso , Doenças Cardiovasculares/etiologia , Estudos de Coortes , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica , Humanos , Modelos Logísticos , Masculino , MicroRNAs/sangue , MicroRNAs/genética , Pessoa de Meia-Idade , Fenótipo , Estudos Prospectivos , RNA Mensageiro/sangue , RNA Mensageiro/genética , Fatores de Risco
7.
Genome Biol ; 18(1): 16, 2017 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-28122634

RESUMO

BACKGROUND: Identification of single nucleotide polymorphisms (SNPs) associated with gene expression levels, known as expression quantitative trait loci (eQTLs), may improve understanding of the functional role of phenotype-associated SNPs in genome-wide association studies (GWAS). The small sample sizes of some previous eQTL studies have limited their statistical power. We conducted an eQTL investigation of microarray-based gene and exon expression levels in whole blood in a cohort of 5257 individuals, exceeding the single cohort size of previous studies by more than a factor of 2. RESULTS: We detected over 19,000 independent lead cis-eQTLs and over 6000 independent lead trans-eQTLs, targeting over 10,000 gene targets (eGenes), with a false discovery rate (FDR) < 5%. Of previously published significant GWAS SNPs, 48% are identified to be significant eQTLs in our study. Some trans-eQTLs point toward novel mechanistic explanations for the association of the SNP with the GWAS-related phenotype. We also identify 59 distinct blocks or clusters of trans-eQTLs, each targeting the expression of sets of six to 229 distinct trans-eGenes. Ten of these sets of target genes are significantly enriched for microRNA targets (FDR < 5%). Many of these clusters are associated in GWAS with multiple phenotypes. CONCLUSIONS: These findings provide insights into the molecular regulatory patterns involved in human physiology and pathophysiology. We illustrate the value of our eQTL database in the context of a recent GWAS meta-analysis of coronary artery disease and provide a list of targeted eGenes for 21 of 58 GWAS loci.


Assuntos
Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica , Locos de Características Quantitativas , Adulto , Idoso , Alelos , Análise por Conglomerados , Feminino , Perfilação da Expressão Gênica , Frequência do Gene , Estudo de Associação Genômica Ampla/métodos , Genômica/métodos , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Sequências Reguladoras de Ácido Nucleico , Reprodutibilidade dos Testes , Navegador
8.
Invest Ophthalmol Vis Sci ; 57(11): 4641-54, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27603725

RESUMO

PURPOSE: The purpose of this study was to examine the rpea1 mouse whose retina spontaneously detaches from the underlying RPE as a potential model for studying the cellular effects of serous retinal detachment (SRD). METHODS: Optical coherence tomography (OCT) was performed immediately prior to euthanasia; retinal tissue was subsequently prepared for Western blotting, microarray analysis, immunocytochemistry, and light and electron microscopy (LM, EM). RESULTS: By postnatal day (P) 30, OCT, LM, and EM revealed the presence of small shallow detachments that increased in number and size over time. By P60 in regions of detachment, there was a dramatic loss of PNA binding around cones in the interphotoreceptor matrix and a concomitant increase in labeling of the outer nuclear layer and rod synaptic terminals. Retinal pigment epithelium wholemounts revealed a patchy loss in immunolabeling for both ezrin and aquaporin 1. Anti-ezrin labeling was lost from small regions of the RPE apical surface underlying detachments at P30. Labeling for tight-junction proteins provided a regular array of profiles outlining the periphery of RPE cells in wild-type tissue, however, this pattern was disrupted in the mutant as early as P30. Microarray analysis revealed a broad range of changes in genes involved in metabolism, signaling, cell polarity, and tight-junction organization. CONCLUSIONS: These data indicate changes in this mutant mouse that may provide clues to the underlying mechanisms of SRD in humans. Importantly, these changes include the production of multiple spontaneous detachments without the presence of a retinal tear or significant degeneration of outer segments, changes in the expression of proteins involved in adhesion and fluid transport, and a disrupted organization of RPE tight junctions that may contribute to the formation of focal detachments.


Assuntos
DNA/genética , Proteínas do Olho/genética , Expressão Gênica , Descolamento Retiniano/genética , Epitélio Pigmentado da Retina/ultraestrutura , Tomografia de Coerência Óptica/métodos , Animais , Atrofia , Western Blotting , Proteínas do Olho/biossíntese , Angiofluoresceinografia , Fundo de Olho , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica , Células Fotorreceptoras de Vertebrados/metabolismo , Células Fotorreceptoras de Vertebrados/ultraestrutura , Reação em Cadeia da Polimerase em Tempo Real , Descolamento Retiniano/metabolismo , Descolamento Retiniano/patologia
9.
Diabetes ; 65(12): 3794-3804, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27625022

RESUMO

Genome-wide association studies (GWAS) have successfully identified genetic loci associated with glycemic traits. However, characterizing the functional significance of these loci has proven challenging. We sought to gain insights into the regulation of fasting insulin and fasting glucose through the use of gene expression microarray data from peripheral blood samples of participants without diabetes in the Framingham Heart Study (FHS) (n = 5,056), the Rotterdam Study (RS) (n = 723), and the InCHIANTI Study (Invecchiare in Chianti) (n = 595). Using a false discovery rate q <0.05, we identified three transcripts associated with fasting glucose and 433 transcripts associated with fasting insulin levels after adjusting for age, sex, technical covariates, and complete blood cell counts. Among the findings, circulating IGF2BP2 transcript levels were positively associated with fasting insulin in both the FHS and RS. Using 1000 Genomes-imputed genotype data, we identified 47,587 cis-expression quantitative trait loci (eQTL) and 6,695 trans-eQTL associated with the 433 significant insulin-associated transcripts. Of note, we identified a trans-eQTL (rs592423), where the A allele was associated with higher IGF2BP2 levels and with fasting insulin in an independent genetic meta-analysis comprised of 50,823 individuals. We conclude that integration of genomic and transcriptomic data implicate circulating IGF2BP2 mRNA levels associated with glucose and insulin homeostasis.


Assuntos
Glicemia/metabolismo , Jejum/sangue , Insulina/sangue , Transcriptoma/genética , Adulto , Idoso , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Locos de Características Quantitativas/genética , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética
10.
PLoS One ; 11(2): e0148047, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26829716

RESUMO

OBJECTIVES: There is much speculation on which hypervariable region provides the highest bacterial specificity in 16S rRNA sequencing. The optimum solution to prevent bias and to obtain a comprehensive view of complex bacterial communities would be to sequence the entire 16S rRNA gene; however, this is not possible with second generation standard library design and short-read next-generation sequencing technology. METHODS: This paper examines a new process using seven hypervariable or V regions of the 16S rRNA (six amplicons: V2, V3, V4, V6-7, V8, and V9) processed simultaneously on the Ion Torrent Personal Genome Machine (Life Technologies, Grand Island, NY). Four mock samples were amplified using the 16S Ion Metagenomics Kit™ (Life Technologies) and their sequencing data is subjected to a novel analytical pipeline. RESULTS: Results are presented at family and genus level. The Kullback-Leibler divergence (DKL), a measure of the departure of the computed from the nominal bacterial distribution in the mock samples, was used to infer which region performed best at the family and genus levels. Three different hypervariable regions, V2, V4, and V6-7, produced the lowest divergence compared to the known mock sample. The V9 region gave the highest (worst) average DKL while the V4 gave the lowest (best) average DKL. In addition to having a high DKL, the V9 region in both the forward and reverse directions performed the worst finding only 17% and 53% of the known family level and 12% and 47% of the genus level bacteria, while results from the forward and reverse V4 region identified all 17 family level bacteria. CONCLUSIONS: The results of our analysis have shown that our sequencing methods using 6 hypervariable regions of the 16S rRNA and subsequent analysis is valid. This method also allowed for the assessment of how well each of the variable regions might perform simultaneously. Our findings will provide the basis for future work intended to assess microbial abundance at different time points throughout a clinical protocol.


Assuntos
Bactérias/genética , Variação Genética , RNA Ribossômico 16S/genética , Bactérias/classificação , Biologia Computacional/métodos , Código de Barras de DNA Taxonômico , Ordem dos Genes , Loci Gênicos , Sequenciamento de Nucleotídeos em Larga Escala , Metagenômica/métodos , Óperon , Análise de Sequência de DNA
11.
Hum Mol Genet ; 25(21): 4611-4623, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28158590

RESUMO

Cigarette smoking is a leading modifiable cause of death worldwide. We hypothesized that cigarette smoking induces extensive transcriptomic changes that lead to target-organ damage and smoking-related diseases. We performed a meta-analysis of transcriptome-wide gene expression using whole blood-derived RNA from 10,233 participants of European ancestry in six cohorts (including 1421 current and 3955 former smokers) to identify associations between smoking and altered gene expression levels. At a false discovery rate (FDR) <0.1, we identified 1270 differentially expressed genes in current vs. never smokers, and 39 genes in former vs. never smokers. Expression levels of 12 genes remained elevated up to 30 years after smoking cessation, suggesting that the molecular consequence of smoking may persist for decades. Gene ontology analysis revealed enrichment of smoking-related genes for activation of platelets and lymphocytes, immune response, and apoptosis. Many of the top smoking-related differentially expressed genes, including LRRN3 and GPR15, have DNA methylation loci in promoter regions that were recently reported to be hypomethylated among smokers. By linking differential gene expression with smoking-related disease phenotypes, we demonstrated that stroke and pulmonary function show enrichment for smoking-related gene expression signatures. Mediation analysis revealed the expression of several genes (e.g. ALAS2) to be putative mediators of the associations between smoking and inflammatory biomarkers (IL6 and C-reactive protein levels). Our transcriptomic study provides potential insights into the effects of cigarette smoking on gene expression in whole blood and their relations to smoking-related diseases. The results of such analyses may highlight attractive targets for treating or preventing smoking-related health effects.


Assuntos
Fumar Cigarros/genética , Expressão Gênica/efeitos dos fármacos , Adulto , Idoso , Fumar Cigarros/sangue , Estudos de Coortes , Ilhas de CpG , Metilação de DNA , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/genética , Humanos , Leucócitos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Fumar/genética , Transcriptoma/efeitos dos fármacos
12.
Nat Commun ; 6: 8570, 2015 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-26490707

RESUMO

Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the 'transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.


Assuntos
Envelhecimento/sangue , Transcriptoma , Biomarcadores/sangue , Metilação de DNA , Grupo com Ancestrais do Continente Europeu , Perfilação da Expressão Gênica , Humanos
13.
Mol Syst Biol ; 11(1): 799, 2015 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-25882670

RESUMO

Genome-wide association studies (GWAS) have identified numerous loci associated with blood pressure (BP). The molecular mechanisms underlying BP regulation, however, remain unclear. We investigated BP-associated molecular mechanisms by integrating BP GWAS with whole blood mRNA expression profiles in 3,679 individuals, using network approaches. BP transcriptomic signatures at the single-gene and the coexpression network module levels were identified. Four coexpression modules were identified as potentially causal based on genetic inference because expression-related SNPs for their corresponding genes demonstrated enrichment for BP GWAS signals. Genes from the four modules were further projected onto predefined molecular interaction networks, revealing key drivers. Gene subnetworks entailing molecular interactions between key drivers and BP-related genes were uncovered. As proof-of-concept, we validated SH2B3, one of the top key drivers, using Sh2b3(-/-) mice. We found that a significant number of genes predicted to be regulated by SH2B3 in gene networks are perturbed in Sh2b3(-/-) mice, which demonstrate an exaggerated pressor response to angiotensin II infusion. Our findings may help to identify novel targets for the prevention or treatment of hypertension.


Assuntos
Pressão Sanguínea/genética , Hipertensão/genética , Adulto , Idoso , Angiotensina II/metabolismo , Animais , Índice de Massa Corporal , Estudos de Coortes , Modelos Animais de Doenças , Feminino , Redes Reguladoras de Genes , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Modelos Lineares , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Domínios e Motivos de Interação entre Proteínas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Análise de Sequência de RNA , Biologia de Sistemas , Transcriptoma , Adulto Jovem
14.
Nat Commun ; 6: 6601, 2015 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-25791433

RESUMO

Identification of microRNA expression quantitative trait loci (miR-eQTL) can yield insights into regulatory mechanisms of microRNA transcription, and can help elucidate the role of microRNA as mediators of complex traits. Here we present a miR-eQTL mapping study of whole blood from 5,239 individuals, and identify 5,269 cis-miR-eQTLs for 76 mature microRNAs. Forty-nine per cent of cis-miR-eQTLs are located 300-500 kb upstream of their associated intergenic microRNAs, suggesting that distal regulatory elements may affect the interindividual variability in microRNA expression levels. We find that cis-miR-eQTLs are highly enriched for cis-mRNA-eQTLs and regulatory single nucleotide polymorphisms. Among 243 cis-miR-eQTLs that were reported to be associated with complex traits in prior genome-wide association studies, many cis-miR-eQTLs miRNAs display differential expression in relation to the corresponding trait (for example, rs7115089, miR-125b-5p and high-density lipoprotein cholesterol). Our study provides a roadmap for understanding the genetic basis of miRNA expression, and sheds light on miRNA involvement in a variety of complex traits.


Assuntos
MicroRNAs/genética , Locos de Características Quantitativas/genética , Adulto , Idoso , Mapeamento Cromossômico , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Sequências Reguladoras de Ácido Nucleico , Reação em Cadeia da Polimerase Via Transcriptase Reversa
15.
PLoS Genet ; 11(3): e1005035, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25785607

RESUMO

Genome-wide association studies (GWAS) have uncovered numerous genetic variants (SNPs) that are associated with blood pressure (BP). Genetic variants may lead to BP changes by acting on intermediate molecular phenotypes such as coded protein sequence or gene expression, which in turn affect BP variability. Therefore, characterizing genes whose expression is associated with BP may reveal cellular processes involved in BP regulation and uncover how transcripts mediate genetic and environmental effects on BP variability. A meta-analysis of results from six studies of global gene expression profiles of BP and hypertension in whole blood was performed in 7017 individuals who were not receiving antihypertensive drug treatment. We identified 34 genes that were differentially expressed in relation to BP (Bonferroni-corrected p<0.05). Among these genes, FOS and PTGS2 have been previously reported to be involved in BP-related processes; the others are novel. The top BP signature genes in aggregate explain 5%-9% of inter-individual variance in BP. Of note, rs3184504 in SH2B3, which was also reported in GWAS to be associated with BP, was found to be a trans regulator of the expression of 6 of the transcripts we found to be associated with BP (FOS, MYADM, PP1R15A, TAGAP, S100A10, and FGBP2). Gene set enrichment analysis suggested that the BP-related global gene expression changes include genes involved in inflammatory response and apoptosis pathways. Our study provides new insights into molecular mechanisms underlying BP regulation, and suggests novel transcriptomic markers for the treatment and prevention of hypertension.


Assuntos
Pressão Sanguínea/genética , Estudo de Associação Genômica Ampla , Hipertensão/genética , Transcriptoma/genética , Regulação da Expressão Gênica , Predisposição Genética para Doença , Genótipo , Humanos , Hipertensão/patologia , Polimorfismo de Nucleotídeo Único
16.
PLoS Pathog ; 11(3): e1004698, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25741691

RESUMO

Leukocyte Adhesion Deficiency I (LAD-I) is a primary immunodeficiency caused by single gene mutations in the CD18 subunit of ß2 integrins which result in defective transmigration of neutrophils into the tissues. Affected patients suffer from recurrent life threatening infections and severe oral disease (periodontitis). Microbial communities in the local environment (subgingival plaque) are thought to be the triggers for inflammatory periodontitis, yet little is known regarding the microbial communities associated with LAD-I periodontitis. Here we present the first comprehensive characterization of the subgingival communities in LAD-I, using a 16S rRNA gene-based microarray, and investigate the relationship of this tooth adherent microbiome to the local immunopathology of periodontitis. We show that the LAD subgingival microbiome is distinct from that of health and Localized Aggressive Periodontitits. Select periodontitis-associated species in the LAD microbiome included Parvimonas micra, Porphyromonas endodontalis, Eubacterium brachy and Treponema species. Pseudomonas aeruginosa, a bacterium not typically found in subgingival plaque is detected in LAD-I. We suggest that microbial products from LAD-associated communities may have a role in stimulating the local inflammatory response. We demonstrate that bacterial LPS translocates into the lesions of LAD-periodontitis potentially triggering immunopathology. We also show in in vitro assays with human macrophages and in vivo in animal models that microbial products from LAD-associated subgingival plaque trigger IL-23-related immune responses, which have been shown to dominate in patient lesions. In conclusion, our current study characterizes the subgingival microbial communities in LAD-periodontitis and supports their role as triggers of disease pathogenesis.


Assuntos
Síndrome da Aderência Leucocítica Deficitária/imunologia , Leucócitos/imunologia , Periodontite/microbiologia , Porphyromonas gingivalis , Animais , DNA Bacteriano/genética , DNA Bacteriano/imunologia , Placa Dentária/genética , Humanos , Interleucina-23/metabolismo , Síndrome da Aderência Leucocítica Deficitária/metabolismo , Síndrome da Aderência Leucocítica Deficitária/terapia , Camundongos , Microbiota/imunologia , RNA Ribossômico 16S/genética
17.
Nat Genet ; 47(4): 345-52, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25685889

RESUMO

An understanding of the genetic variation underlying transcript splicing is essential to dissect the molecular mechanisms of common disease. The available evidence from splicing quantitative trait locus (sQTL) studies has been limited to small samples. We performed genome-wide screening to identify SNPs that might control mRNA splicing in whole blood collected from 5,257 Framingham Heart Study participants. We identified 572,333 cis sQTLs involving 2,650 unique genes. Many sQTL-associated genes (40%) undergo alternative splicing. Using the National Human Genome Research Institute (NHGRI) genome-wide association study (GWAS) catalog, we determined that 528 unique sQTLs were significantly enriched for 8,845 SNPs associated with traits in previous GWAS. In particular, we found 395 (4.5%) GWAS SNPs with evidence of cis sQTLs but not gene-level cis expression quantitative trait loci (eQTLs), suggesting that sQTL analysis could provide additional insights into the functional mechanism underlying GWAS results. Our findings provide an informative sQTL resource for further characterizing the potential functional roles of SNPs that control transcript isoforms relevant to common diseases.


Assuntos
Processamento Alternativo/genética , Células Sanguíneas/metabolismo , Polimorfismo de Nucleotídeo Único , Isoformas de Proteínas/genética , Locos de Características Quantitativas/genética , Sequência de Bases , Análise Mutacional de DNA , Doença/genética , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Sítios de Splice de RNA/genética , Transcriptoma
18.
Arterioscler Thromb Vasc Biol ; 35(4): 1011-21, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25657313

RESUMO

OBJECTIVE: The roles of microRNAs (miRNAs) in coronary heart disease (CHD) have not been well characterized. This study sought to systematically characterize the complex genomic architecture of CHD by integrating whole blood miRNA and mRNA expression with genetic variation in 186 CHD cases and 186 controls. APPROACH AND RESULTS: At false discovery rate <0.2, 15 miRNAs were differentially expressed between CHD cases and controls. To explore regulatory mechanisms, we integrated miRNA and mRNA expression with genome-wide genotype data to investigate miRNA and mRNA associations and relationships of genetic variation with miRNAs. We identified a large number of correlated miRNA-mRNA pairs and genetic loci that seem to regulate miRNA levels. Subsequently, we explored the relationships of these complex molecular associations with CHD status. We identified a large difference in miRNA-mRNA associations between CHD cases and controls, as demonstrated by a significantly higher proportion of inversely correlated miRNA-mRNA pairs in cases versus controls (80% versus 30%; P<1×10(-16)), suggesting a genome-wide shift in the regulatory structure of the transcriptome in CHD. The differentially coexpressed miRNA-mRNA pairs showed enrichment for CHD risk genetic variants affecting both miRNA and mRNA expression levels, implicating a putatively causal role in CHD. Furthermore, 3 miRNAs (miR-1275, miR-365a-3p, and miR-150-5p) were associated with an mRNA coexpression module that was causally linked to CHD and reflected the dysregulation of B-cell centered immune function. CONCLUSIONS: Our results provide novel evidence that miRNAs are important regulators of biological processes involved in CHD via genetic control and via their tight coexpression with mRNAs.


Assuntos
Doença das Coronárias/genética , Genômica , MicroRNAs/genética , Idoso , Estudos de Casos e Controles , Doença das Coronárias/sangue , Doença das Coronárias/diagnóstico , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Estudos de Associação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Genômica/métodos , Humanos , Modelos Lineares , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/sangue , RNA Mensageiro/genética , Reprodutibilidade dos Testes , Biologia de Sistemas
19.
Hum Genet ; 134(3): 343-58, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25585846

RESUMO

Genome-wide expression quantitative trait locus (eQTL) mapping may reveal common genetic variants regulating gene expression. In addition to mapping eQTLs, we systematically evaluated the heritability of the whole blood transcriptome in 5,626 participants from the Framingham Heart Study. Of all gene expression measurements, about 40 % exhibit evidence of being heritable [hgeneExp(2) > 0, (p < 0.05)], the average heritability was estimated to be 0.13, and 10 % display hgeneExp(2) > 0.2. To identify the role of eQTLs in promoting phenotype differences and disease susceptibility, we investigated the proportion of cis/trans eQTLs in different heritability categories and discovered that genes with higher heritability are more likely to have cis eQTLs that explain large proportions of variance in the expression of the corresponding genes. Single cis eQTLs explain 0.33-0.53 of variance in transcripts on average, whereas single trans eQTLs only explain 0.02-0.07. The top cis eQTLs tend to explain more variance in the corresponding gene when its hgeneExp(2) is greater. Taking body mass index (BMI) as a case study, we cross-linked cis/trans eQTLs with both GWAS SNPs and differentially expressed genes for BMI. We discovered that BMI GWAS SNPs in 16p11.2 (e.g., rs7359397) are associated with several BMI differentially expressed genes in a cis manner (e.g. SULT1A1, SPNS1, and TUFM). These BMI signature genes explain a much larger proportion of variance in BMI than do the GWAS SNPs. Our results shed light on the impact of eQTLs on the heritability of the human whole blood transcriptome and its relations to phenotype differences.


Assuntos
Transcriptoma , Adulto , Idoso , Índice de Massa Corporal , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , RNA Mensageiro/sangue , RNA Mensageiro/genética
20.
Circulation ; 131(6): 536-49, 2015 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-25533967

RESUMO

BACKGROUND: Cardiovascular disease (CVD) reflects a highly coordinated complex of traits. Although genome-wide association studies have reported numerous single nucleotide polymorphisms (SNPs) to be associated with CVD, the role of most of these variants in disease processes remains unknown. METHODS AND RESULTS: We built a CVD network using 1512 SNPs associated with 21 CVD traits in genome-wide association studies (at P≤5×10(-8)) and cross-linked different traits by virtue of their shared SNP associations. We then explored whole blood gene expression in relation to these SNPs in 5257 participants in the Framingham Heart Study. At a false discovery rate <0.05, we identified 370 cis-expression quantitative trait loci (eQTLs; SNPs associated with altered expression of nearby genes) and 44 trans-eQTLs (SNPs associated with altered expression of remote genes). The eQTL network revealed 13 CVD-related modules. Searching for association of eQTL genes with CVD risk factors (lipids, blood pressure, fasting blood glucose, and body mass index) in the same individuals, we found examples in which the expression of eQTL genes was significantly associated with these CVD phenotypes. In addition, mediation tests suggested that a subset of SNPs previously associated with CVD phenotypes in genome-wide association studies may exert their function by altering expression of eQTL genes (eg, LDLR and PCSK7), which in turn may promote interindividual variation in phenotypes. CONCLUSIONS: Using a network approach to analyze CVD traits, we identified complex networks of SNP-phenotype and SNP-transcript connections. Integrating the CVD network with phenotypic data, we identified biological pathways that may provide insights into potential drug targets for treatment or prevention of CVD.


Assuntos
Doenças Cardiovasculares/genética , Redes Reguladoras de Genes/genética , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Adulto , Mapeamento Cromossômico , Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 1/genética , Feminino , Expressão Gênica , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Proteína Associada a Proteínas Relacionadas a Receptor de LDL/genética , Lipoproteínas HDL/genética , Lipoproteínas LDL/genética , Masculino , Fenótipo , Fatores de Risco , Fumar/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA