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1.
Pathologe ; 42(1): 78-82, 2021 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-33475809

RESUMO

In the diagnosis of mycobacterioses, microbiological examination with culture and antibiogram, possibly in combination with molecular biological testing of the fresh material, still represents the gold standard. However, these methods are not available for formalin-fixed paraffin-embedded (FFPE) material or other fixed samples. For this reason, the first step in pathology is to attempt microscopic pathogen detection (ZN/Fite/rhodamine-auramine). Subsequently, molecular pathological examination for the detection of mycobacterial gene sequences should also be considered mandatory today. Although this has clear limits due to the material, it is nevertheless well suited, if carried out correctly, to detect a mycobacterial infection or make it unlikely. A negative result may favor an alternative diagnosis but does not completely rule out mycobacteriosis.For the therapy of tuberculosis or nontuberculous mycobacterial (NTM) disease, the reliable detection of the species and the determination of resistance is of utmost importance. With regard to therapy, the clinician cannot afford to make a false diagnosis. In case of doubt, a rebiopsy for sampling native material, particularly for microbiological testing, should be discussed.


Assuntos
Mycobacterium tuberculosis , Mycobacterium , Tuberculose , DNA Bacteriano/genética , Humanos , Mycobacterium/genética , Mycobacterium tuberculosis/genética , Inclusão em Parafina , Patologia Molecular , Reação em Cadeia da Polimerase , Tuberculose/diagnóstico , Tuberculose/genética
2.
BMC Infect Dis ; 21(1): 106, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33482742

RESUMO

BACKGROUND: Gene expression signatures have been used as biomarkers of tuberculosis (TB) risk and outcomes. Platforms are needed to simplify access to these signatures and determine their validity in the setting of comorbidities. We developed a computational profiling platform of TB signature gene sets and characterized the diagnostic ability of existing signature gene sets to differentiate active TB from LTBI in the setting of malnutrition. METHODS: We curated 45 existing TB-related signature gene sets and developed our TBSignatureProfiler software toolkit that estimates gene set activity using multiple enrichment methods and allows visualization of single- and multi-pathway results. The TBSignatureProfiler software is available through Bioconductor and on GitHub. For evaluation in malnutrition, we used whole blood gene expression profiling from 23 severely malnourished Indian individuals with TB and 15 severely malnourished household contacts with latent TB infection (LTBI). Severe malnutrition was defined as body mass index (BMI) < 16 kg/m2 in adults and based on weight-for-height Z scores in children < 18 years. Gene expression was measured using RNA-sequencing. RESULTS: The comparison and visualization functions from the TBSignatureProfiler showed that TB gene sets performed well in malnourished individuals; 40 gene sets had statistically significant discriminative power for differentiating TB from LTBI, with area under the curve ranging from 0.662-0.989. Three gene sets were not significantly predictive. CONCLUSION: Our TBSignatureProfiler is a highly effective and user-friendly platform for applying and comparing published TB signature gene sets. Using this platform, we found that existing gene sets for TB function effectively in the setting of malnutrition, although differences in gene set applicability exist. RNA-sequencing gene sets should consider comorbidities and potential effects on diagnostic performance.


Assuntos
Perfilação da Expressão Gênica/métodos , Desnutrição/genética , Software , Tuberculose/genética , Adolescente , Adulto , Idoso , Área Sob a Curva , Biomarcadores/sangue , Criança , Comorbidade , Feminino , Humanos , Tuberculose Latente/diagnóstico , Tuberculose Latente/epidemiologia , Tuberculose Latente/genética , Masculino , Desnutrição/diagnóstico , Desnutrição/epidemiologia , Pessoa de Meia-Idade , Mycobacterium tuberculosis , Transcriptoma , Tuberculose/diagnóstico , Tuberculose/epidemiologia , Adulto Jovem
3.
Respir Res ; 22(1): 23, 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33472618

RESUMO

BACKGROUND: When infected with Mycobacterium tuberculosis, only a small proportion of the population will develop active TB, and the role of host genetic factors in different TB infection status was not fully understood. METHODS: Forty-three patients with active tuberculosis and 49 with latent tuberculosis were enrolled in the prospective cohort. Expressing levels of 27 candidate mRNAs, which were previously demonstrated to differentially expressed in latent and active TB, were measured by dual color reverse transcription multiplex ligation dependent probe amplification assay (dcRT-MLPA). Using expression levels of these mRNAs as quantitative traits, associations between expression abundance and genome-wild single nucleotide polymorphisms (SNPs) were calculated. Finally, identified candidate SNPs were further assessed for their associations with TB infection status in a validation cohort with 313 Chinese Han cases. RESULTS: We identified 9 differentially expressed mRNAs including il7r, il4, il8, tnfrsf1b, pgm5, ccl19, il2ra, marco and fpr1 in the prospective cohort. Through expression quantitative trait loci mapping, we screened out 8 SNPs associated with these mRNAs. Then, CG genotype of the SNP rs62292160 was finally verified to be significantly associated with higher transcription levels of IL4 in LTBI than in TB patients. CONCLUSION: We reported that the SNP rs62292160 in Chinese Han population may link to higher expression of il4 in latent tuberculosis. Our findings provided a new genetic variation locus for further exploration of the mechanisms of TB and a possible target for TB genetic susceptibility studies, which might aid the clinical decision to precision treatment of TB.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Locos de Características Quantitativas/genética , DNA Polimerase Dirigida por RNA/genética , Tuberculose/genética , Adulto , China/epidemiologia , Estudos de Coortes , Feminino , Expressão Gênica , Redes Reguladoras de Genes/genética , Predisposição Genética para Doença/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Estudos Prospectivos , Tuberculose/diagnóstico , Tuberculose/epidemiologia
5.
PLoS Pathog ; 16(9): e1008357, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32997707

RESUMO

In genome evolution, genetic variants are the source of diversity, which natural selection acts upon. Treatment of human tuberculosis (TB) induces a strong selection pressure for the emergence of antibiotic resistance-conferring variants in the infecting Mycobacterium tuberculosis (MTB) strains. MTB evolution in response to treatment has been intensively studied and mainly attributed to point substitutions. However, the frequency and contribution of insertions and deletions (indels) to MTB genome evolution remains poorly understood. Here, we analyzed a multi-drug resistant MTB outbreak for the presence of high-quality indels and substitutions. We find that indels are significantly enriched in genes conferring antibiotic resistance. Furthermore, we show that indels are inherited during the outbreak and follow a molecular clock with an evolutionary rate of 5.37e-9 indels/site/year, which is 23 times lower than the substitution rate. Inherited indels may co-occur with substitutions in genes along related biological pathways; examples are iron storage and resistance to second-line antibiotics. This suggests that epistatic interactions between indels and substitutions affect antibiotic resistance and compensatory evolution in MTB.


Assuntos
Antibacterianos/farmacologia , Antituberculosos/farmacologia , Evolução Molecular , Genoma/genética , Mycobacterium tuberculosis/genética , Surtos de Doenças/prevenção & controle , Humanos , Mycobacterium tuberculosis/patogenicidade , Seleção Genética , Tuberculose/genética
6.
BMC Bioinformatics ; 21(1): 375, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32859148

RESUMO

BACKGROUND: As the barriers to incorporating RNA sequencing (RNA-Seq) into biomedical studies continue to decrease, the complexity and size of RNA-Seq experiments are rapidly growing. Paired, longitudinal, and other correlated designs are becoming commonplace, and these studies offer immense potential for understanding how transcriptional changes within an individual over time differ depending on treatment or environmental conditions. While several methods have been proposed for dealing with repeated measures within RNA-Seq analyses, they are either restricted to handling only paired measurements, can only test for differences between two groups, and/or have issues with maintaining nominal false positive and false discovery rates. In this work, we propose a Bayesian hierarchical negative binomial generalized linear mixed model framework that can flexibly model RNA-Seq counts from studies with arbitrarily many repeated observations, can include covariates, and also maintains nominal false positive and false discovery rates in its posterior inference. RESULTS: In simulation studies, we showed that our proposed method (MCMSeq) best combines high statistical power (i.e. sensitivity or recall) with maintenance of nominal false positive and false discovery rates compared the other available strategies, especially at the smaller sample sizes investigated. This behavior was then replicated in an application to real RNA-Seq data where MCMSeq was able to find previously reported genes associated with tuberculosis infection in a cohort with longitudinal measurements. CONCLUSIONS: Failing to account for repeated measurements when analyzing RNA-Seq experiments can result in significantly inflated false positive and false discovery rates. Of the methods we investigated, whether they model RNA-Seq counts directly or worked on transformed values, the Bayesian hierarchical model implemented in the mcmseq R package (available at https://github.com/stop-pre16/mcmseq ) best combined sensitivity and nominal error rate control.


Assuntos
RNA/química , Análise de Sequência de RNA/métodos , Interface Usuário-Computador , Teorema de Bayes , Humanos , Método de Monte Carlo , RNA/genética , RNA/metabolismo , Tuberculose/genética , Tuberculose/patologia
7.
Int J Infect Dis ; 98: 447-453, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32619758

RESUMO

OBJECTIVES: Tuberculosis (TB) is an infectious and contagious disease that has been very influential in human history and presents high rates of mortality. The objective of this study was to investigate the association of VDR, IL10, and SLC11A1 gene polymorphisms with susceptibility to the presence of Mycobacterium tuberculosis infection. METHODS: A total of 135 patients with confirmed TB and 141 healthy individuals were included in the analysis. Blood samples were collected for DNA extraction. Genotyping of the polymorphisms in the VDR and IL10 genes was performed by real-time PCR, and genotyping of the polymorphisms in the SLC11A1 gene by conventional PCR, followed by visualization in polyacrylamide gel. The genomic ancestry was obtained using an autosomal panel with 48 insertion/deletion ancestry-informative markers. RESULTS: Polymorphisms TaqI (TT, p=0.004), FokI (CC and CC+CT, p=0.012 and p=0.003, respectively), and BsmI (GG, p=0.008) in the VDR gene, as well as A-592C (GC+AG, p=0.001) in the IL10 gene, were significantly associated with susceptibility to TB In addition, high production of VDR combined with low production of IL10 showed protection for the TB group (p=0.035). CONCLUSIONS: The VDR polymorphisms may confer an increased risk and the IL10 haplotype may be a protection factor for the presence of M. tuberculosis infection in the Brazilian population.


Assuntos
Interleucina-10/genética , Receptores de Calcitriol/genética , Tuberculose/genética , Adulto , Brasil/epidemiologia , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Mycobacterium tuberculosis/fisiologia , Polimorfismo Genético , Tuberculose/epidemiologia , Tuberculose/microbiologia , Adulto Jovem
8.
PLoS One ; 15(7): e0236033, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32673332

RESUMO

In recent years, the incidence of tuberculosis (TB) has declined worldwide, although this disease still occurs at relatively high rates in Amerindian populations. This suggests that the genetic ancestry of Amerindians may be an important factor in the development of infections, and may account for at least some of the variation in infection rates in the different populations. The present study investigated the potential influence of Amerindian genetic ancestry on susceptibility to tuberculosis in an Amazon population. The study included 280 patients diagnosed with tuberculosis and 138 asymptomatic hospital employees with no history of TB, but who were in contact with bacterially active TB patients. Ancestry analysis was run on a set of 61 Ancestry-Informative Markers to estimate European, African, and Amerindian genetic ancestry using STRUCTURE v2.2. The TB group had significantly higher Amerindian ancestry in comparison with the control group, and significantly lower European ancestry. Amerindian ancestry in the 20-60% range was found to be the principal risk factor for increased susceptibility to TB. The results of the study indicate that Amerindian ancestry is an important risk factor for susceptibility to TB in the admixed population of the Brazilian Amazon region.


Assuntos
Grupo com Ancestrais do Continente Africano/estatística & dados numéricos , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Variação Genética , Genética Populacional , Índios Sul-Americanos/estatística & dados numéricos , Mycobacterium tuberculosis/genética , Tuberculose/epidemiologia , Brasil/epidemiologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tuberculose/genética , Tuberculose/microbiologia
9.
DNA Cell Biol ; 39(7): 1356-1367, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32522041

RESUMO

Tuberculosis (TB) is an intricate infectious disease that causes a large number of deaths in the population. Interleukin (IL)-6 and IL-13 play functional roles in host resistance to Mycobacterium tuberculosis infection. Our aim in this study was to explore the association of IL-6 and IL-13 polymorphisms with TB susceptibility in the Western Chinese Han population. The case and control groups comprised 900 TB patients and 1534 healthy controls, respectively, and four single-nucleotide polymorphisms (SNPs) were genotyped in IL-6 and five SNPs in IL-13 through the improved multiplex ligation detection reaction method. We found no genetic variants in the IL-6 or IL-13 genes that were related to TB susceptibility in the analysis of alleles, genotypes, genetic models, and TB clinical subtypes, except for a trend toward low pulmonary tuberculosis and extrapulmonary tuberculosis susceptibility for the SNPs rs1295686 and rs20541. Our study did not find a link between IL-6 and IL-13 polymorphisms and TB susceptibility in the Western Chinese Han population. Therefore, our present data revealed the challenge of applying IL-6 and IL-13 SNPs as genetic markers for TB and that increased sample sizes and additional races are needed for further studies.


Assuntos
Predisposição Genética para Doença/genética , Interleucina-13/genética , Interleucina-6/genética , Polimorfismo de Nucleotídeo Único , Tuberculose/genética , Estudos de Casos e Controles , China/epidemiologia , Haplótipos/genética , Humanos , Tuberculose/epidemiologia
10.
Proc Natl Acad Sci U S A ; 117(24): 13659-13669, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32482872

RESUMO

T cell maturation and activation depend upon T cell receptor (TCR) interactions with a wide variety of antigenic peptides displayed in a given major histocompatibility complex (MHC) context. Complementarity-determining region 3 (CDR3) is the most variable part of the TCRα and -ß chains, which govern interactions with peptide-MHC complexes. However, it remains unclear how the CDR3 landscape is shaped by individual MHC context during thymic selection of naïve T cells. We established two mouse strains carrying distinct allelic variants of H2-A and analyzed thymic and peripheral production and TCR repertoires of naïve conventional CD4+ T (Tconv) and naïve regulatory CD4+ T (Treg) cells. Compared with tuberculosis-resistant C57BL/6 (H2-Ab) mice, the tuberculosis-susceptible H2-Aj mice had fewer CD4+ T cells of both subsets in the thymus. In the periphery, this deficiency was only apparent for Tconv and was compensated for by peripheral reconstitution for Treg We show that H2-Aj favors selection of a narrower and more convergent repertoire with more hydrophobic and strongly interacting amino acid residues in the middle of CDR3α and CDR3ß, suggesting more stringent selection against a narrower peptide-MHC-II context. H2-Aj and H2-Ab mice have prominent reciprocal differences in CDR3α and CDR3ß features, probably reflecting distinct modes of TCR fitting to MHC-II variants. These data reveal the mechanics and extent of how MHC-II shapes the naïve CD4+ T cell CDR3 landscape, which essentially defines adaptive response to infections and self-antigens.


Assuntos
Regiões Determinantes de Complementaridade/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Tuberculose/genética , Alelos , Animais , Linfócitos T CD4-Positivos/imunologia , Regiões Determinantes de Complementaridade/química , Regiões Determinantes de Complementaridade/genética , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/genética , Baço/imunologia , Linfócitos T Reguladores/química , Tuberculose/imunologia
11.
PLoS Pathog ; 16(6): e1008621, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32544188

RESUMO

During tuberculosis, lung myeloid cells have two opposing roles: they are an intracellular niche occupied by Mycobacterium tuberculosis, and they restrict bacterial replication. Lung myeloid cells from mice infected with yellow-fluorescent protein expressing M. tuberculosis were analyzed by flow cytometry and transcriptional profiling to identify the cell types infected and their response to infection. CD14, CD38, and Abca1 were expressed more highly by infected alveolar macrophages and CD11cHi monocyte-derived cells compared to uninfected cells. CD14, CD38, and Abca1 "triple positive" (TP) cells had not only the highest infection rates and bacterial loads, but also a strong interferon-γ signature and nitric oxide synthetase-2 production indicating recognition by T cells. Despite evidence of T cell recognition and appropriate activation, these TP macrophages are a cellular compartment occupied by M. tuberculosis long-term. Defining the niche where M. tuberculosis resists elimination promises to provide insight into why inducing sterilizing immunity is a formidable challenge.


Assuntos
Antígenos CD11/imunologia , Macrófagos Alveolares , Monócitos , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , ADP-Ribosil Ciclase 1/genética , ADP-Ribosil Ciclase 1/imunologia , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/imunologia , Animais , Antígenos CD11/genética , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/microbiologia , Macrófagos Alveolares/patologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , Monócitos/imunologia , Monócitos/microbiologia , Monócitos/patologia , Mycobacterium tuberculosis/genética , Linfócitos T/imunologia , Linfócitos T/microbiologia , Linfócitos T/patologia , Tuberculose/genética , Tuberculose/patologia
12.
Immunogenetics ; 72(5): 305-314, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32556499

RESUMO

Several genetic studies have implicated genes that encode for components of the innate immune response in tuberculosis (TB) susceptibility. The complement system is an early player in the innate immune response and provides the host with initial protection by promoting phagocytosis of apoptotic or necrotic cells. The C1q molecule is the first component of the classical pathway that leads to the activation of complement by binding to immune complexes and is encoded by the C1Q gene cluster. We investigated variants in this region to determine its association with TB susceptibility. Five single nucleotide polymorphisms (SNPs) (rs12033074, rs631090, rs172378, rs587585, and rs665691) were genotyped using TaqMan® SNP assays in 456 TB cases and 448 healthy controls and analysed by logistic regression models. The rs587585 variant showed a significant additive allelic association where the minor G allele was found more frequently in TB cases than in controls in both the discovery (p = 0.023; OR = 1.30; 95% CI, 1.04-1.64) and validation cohort (p = 0.038; OR = 1.31; 95% CI, 1.22-1.40). In addition, we detected increased C1qA expression when comparing cases and controls (p = 0.037) and linked this to a dosage effect of the G allele, which increased C1qA expression in TB cases. This is the first study to report the association of C1Q gene polymorphisms with progression to tuberculosis.


Assuntos
Complemento C1q/genética , Complemento C1q/metabolismo , Predisposição Genética para Doença/genética , Tuberculose/genética , Adulto , Grupo com Ancestrais do Continente Africano/genética , Alelos , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Família Multigênica , Polimorfismo de Nucleotídeo Único , Tuberculose/imunologia , Adulto Jovem
13.
PLoS Genet ; 16(5): e1008766, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32365090

RESUMO

Complex traits are known to be influenced by a combination of environmental factors and rare and common genetic variants. However, detection of such multivariate associations can be compromised by low statistical power and confounding by population structure. Linear mixed effects models (LMM) can account for correlations due to relatedness but have not been applicable in high-dimensional (HD) settings where the number of fixed effect predictors greatly exceeds the number of samples. False positives or false negatives can result from two-stage approaches, where the residuals estimated from a null model adjusted for the subjects' relationship structure are subsequently used as the response in a standard penalized regression model. To overcome these challenges, we develop a general penalized LMM with a single random effect called ggmix for simultaneous SNP selection and adjustment for population structure in high dimensional prediction models. We develop a blockwise coordinate descent algorithm with automatic tuning parameter selection which is highly scalable, computationally efficient and has theoretical guarantees of convergence. Through simulations and three real data examples, we show that ggmix leads to more parsimonious models compared to the two-stage approach or principal component adjustment with better prediction accuracy. Our method performs well even in the presence of highly correlated markers, and when the causal SNPs are included in the kinship matrix. ggmix can be used to construct polygenic risk scores and select instrumental variables in Mendelian randomization studies. Our algorithms are available in an R package available on CRAN (https://cran.r-project.org/package=ggmix).


Assuntos
Algoritmos , Estudo de Associação Genômica Ampla/métodos , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Animais , Simulação por Computador , Cruzamentos Genéticos , Genética Populacional/métodos , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Leishmania tropica/genética , Leishmaniose Cutânea/genética , Modelos Lineares , Camundongos , Camundongos Endogâmicos , Herança Multifatorial/genética , Mycobacterium bovis , Dinâmica Populacional , Tamanho da Amostra , Software , Tuberculose/genética , Tuberculose/patologia
14.
PLoS Genet ; 16(4): e1008728, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32352966

RESUMO

Genetic studies of both the human host and Mycobacterium tuberculosis (MTB) demonstrate independent association with tuberculosis (TB) risk. However, neither explains a large portion of disease risk or severity. Based on studies in other infectious diseases and animal models of TB, we hypothesized that the genomes of the two interact to modulate risk of developing active TB or increasing the severity of disease, when present. We examined this hypothesis in our TB household contact study in Kampala, Uganda, in which there were 3 MTB lineages of which L4-Ugandan (L4.6) is the most recent. TB severity, measured using the Bandim TBscore, was modeled as a function of host SNP genotype, MTB lineage, and their interaction, within two independent cohorts of TB cases, N = 113 and 121. No association was found between lineage and severity, but association between multiple polymorphisms in IL12B and TBscore was replicated in two independent cohorts (most significant rs3212227, combined p = 0.0006), supporting previous associations of IL12B with TB susceptibility. We also observed significant interaction between a single nucleotide polymorphism (SNP) in SLC11A1 and the L4-Ugandan lineage in both cohorts (rs17235409, meta p = 0.0002). Interestingly, the presence of the L4-Uganda lineage in the presence of the ancestral human allele associated with more severe disease. These findings demonstrate that IL12B is associated with severity of TB in addition to susceptibility, and that the association between TB severity and human genetics can be due to an interaction between genes in the two species, consistent with host-pathogen coevolution in TB.


Assuntos
Coevolução Biológica , Mycobacterium tuberculosis/genética , Polimorfismo de Nucleotídeo Único , Tuberculose/genética , Adolescente , Adulto , Idoso , Proteínas de Transporte de Cátions/genética , Evolução Molecular , Feminino , Genoma Bacteriano , Interações Hospedeiro-Patógeno , Humanos , Subunidade p40 da Interleucina-12/genética , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/patogenicidade , Tuberculose/microbiologia , Tuberculose/patologia
16.
Mol Genet Genomics ; 295(5): 1155-1162, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32462533

RESUMO

Tuberculosis (TB) is a complex infectious disease caused by the pathogen Mycobacterium tuberculosis (Mtb) which has coexisted with humanity since the Neolithic. Recent research indicated that SIRT3 plays a pivotal role in promoting the antimycobacterial response of mitochondria and autophagy during Mtb infection. A case-control study comprised 900 TB patients and 1534 healthy controls who were retrospectively enrolled to assess the association between Sirt3 gene polymorphisms and TB susceptibility. In total, five single-nucleotide polymorphisms (SNPs) (rs511744, rs3782118, rs7104764, rs536715 and rs28365927) were selected through database 1000 Genomes Project and offline software Haploview V4.2 and genotyped by a customized 2 × 48-Plex SNPscan™ Kit. Our results suggested that the minor allele genotypes (A carriers) of rs3782118 confers the decreased risk of TB susceptibility (pBonferroni = 0.032), and a similar but more significant effect was observed under the dominant model analysis (OR 0.787, 95% CI 0.666-0.931, pBonferroni = 0.026). Haplotype analysis showed that haplotype AGAAG (rs511744/rs3782118/rs7104764/rs536715/rs28365927) was associated with an increased risk of TB (p = 0.023, OR 1.159, 95% CI 1.019-1.317). In stratification analysis, we found that rs3782118 was associated with decreased risk of TB in female subgroup under the dominant model analysis (pBonferroni = 0.016, OR 0.678, 95% CI 0.523-0.878). Moreover, functional annotations for three loci (rs7930823, rs3782116 and rs3782115) which are strongly linked to rs3782118 indicated that they may be responsible for the changes in some motifs. In conclusion, our study suggested that the SNP rs3782118 was associated with a lower susceptibility to TB, especially under the dominant model analysis and that the haplotype AGAAG (containing the major allele G of rs3782118) was associated with an increased risk of TB. Further independent cohort studies are necessary to validate the protective effect of Sirt3 genetic variants on the risk of TB.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Polimorfismo de Nucleotídeo Único , Sirtuína 3/genética , Tuberculose/genética , Adulto , Grupo com Ancestrais do Continente Asiático/etnologia , Estudos de Casos e Controles , China/etnologia , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
17.
Infect Dis Poverty ; 9(1): 46, 2020 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-32349793

RESUMO

BACKGROUND: Immune- and inflammation-related genes (IIRGs) play an important role in the pathogenesis of tuberculosis (TB). However, the relationship between IIRG polymorphisms and TB risk remains unknown. In this study, the gene polymorphisms and their association with tuberculosis were determined in a Chinese population. METHODS: We performed a case-control study involving 1016 patients with TB and 507 healthy controls of Han Chinese origin. Sixty-four single-nucleotide polymorphisms (SNPs) belonging to 18 IIRGs were genotyped by the PCR-MassArray assay, and the obtained data was analyzed with χ2-test, Bonferroni correction, and unconditional logistic regression analysis. RESULTS: We observed significant differences in the allele frequency of LTA rs2229094*C (P = 0.015), MBL2 rs2099902*C (P = 0.001), MBL2 rs930507*G (P = 0.004), MBL2 rs10824793*G (P = 0.004), and IL12RB1 rs2305740*G (P = 0.040) between the TB and healthy groups. Increased TB risk was identified in the rs930507 G/G genotype (Padjusted = 0.027) under a codominant genetic model as well as in the rs2099902 (C/T + C/C) vs T/T genotype (Padjusted = 0.020), rs930507 (C/G + G/G) vs C/C genotype (Padjusted = 0.027), and rs10824793 (G/A + G/G) vs A/A genotype (Padjusted = 0.017) under a dominant genetic model after Bonferroni correction in the analysis of the overall TB group rather than the TB subgroups. Furthermore, the rs10824793_rs7916582*GT and rs10824793_rs7916582*GC haplotypes were significantly associated with increased TB risk (P = 0.001, odds ratio [OR] = 1.421, 95% confidence interval [CI]: 1.152-1.753; and P = 0.018, OR = 1.364, 95% CI: 1.055-1.765, respectively). Moreover, the rs10824793_rs7916582*AT/AT or rs10824793_rs7916582*GT/GT diplotype showed a protective (P = 0.003, OR = 0.530, 95% CI: 0.349-0.805) or harmful (P = 0.009, OR = 1.396, 95% CI: 1.087-1.793) effect against the development of TB. CONCLUSIONS: This study indicated that MBL2 polymorphisms, haplotypes, and diplotypes were associated with TB susceptibility in the Han Chinese population. Additionally, larger sample size studies are needed to further confirm these findings in the future.


Assuntos
Lectina de Ligação a Manose/genética , Polimorfismo de Nucleotídeo Único , Tuberculose/genética , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China , Feminino , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
18.
Zhonghua Jie He He Hu Xi Za Zhi ; 43(5): 444-449, 2020 May 12.
Artigo em Chinês | MEDLINE | ID: mdl-32450633

RESUMO

Objective: To investigate the relationship between single nucleotide polymorphism (SNP) of IL-1ß gene and susceptibility to tuberculosis. Methods: A case-control study was conducted in Shenzhen Third People's Hospital from January 2012 to December 2014. A total of 1 533 patients with active tuberculosis were enrolled, including 1 432 cases of pulmonary tuberculosis[920 males and 512 females, mean age (37±14) years] and 101 cases of extrapulmonary tuberculosis [60 males and 41 females, mean age (35±13) years]. At the same time, 1 445 healthy controls (882 males and 563 females, mean age (37±20) years) were selected. The genotypes of rs1143627, rs1143623, rs16944 and rs2853550 of IL-1ß gene were detected by time-of-flight mass spectrometry. The allele frequencies of rs1143627 T>C (-31) were compared between patients with pulmonary tuberculosis and those with extrapulmonary tuberculosis. Fifty-three patients with active tuberculosis [male 32, female 21, mean age (37±15) years] were randomly selected, and the correlation between SNP alleles and tuberculosis severity was analyzed before and after treatment. Results: Time-of-flight mass spectrometry effectively detected the genotypes of 4 SNP loci. Among the 4 SNP loci, only the allele frequency of -31 locus was significantly different between the active tuberculosis group and the control group. The allele frequency of rs1143627 T locus in active tuberculosis group was 53.3%(1 634/3 066), which was significantly higher than that in the healthy control group 48.7%(1 407/2 890; OR=1.20, 95%CI=1.09-1.33, P=0.001 6) .The frequencies of the other 3 SNP alleles were not significantly different between the active tuberculosis group and the control group. The frequencies of the other 3 SNP alleles were 59% (1 821/3 066) and 60% (1 732/2 890) for rs1143623 G allele, 51% (1 574/3 066) and 52% (1 499/2 890) for rs16944 G allele, and 64% (1 964/3 066) and 65% (1 875/2 890) for rs2853550 T allele respectively. Stratified analysis showed that the frequency of the -31 T allele in patients with extrapulmonary tuberculosis (62.9%, 127/202) was significantly higher than that in patients with pulmonary tuberculosis (52.6%,1 507/2 864) (OR=1.53; 95% CI=1.13-2.05; P=0.005).The HRCT scores of patients with rs1143627 TT, TC and CC genotypes were 26.6, 13.9 and 13.3 respectively before anti-tuberculosis treatment, and after 2 years of anti-tuberculosis treatment, the HRCT scores of patients with rs1143627 TT, TC and CC genotypes were 14.7, 6.6 and 5.4 respectively, which indicated that TB patients with rs1143627T allele were associated with more severe pulmonary disease. Conclusion: The SNP of IL-1ß-31T>C was associated with susceptibility to active tuberculosis, and T allele was the susceptible gene and individuals carrying T allele were more likely to develop extrapulmonary tuberculosis.


Assuntos
Predisposição Genética para Doença , Interleucina-1beta/genética , Tuberculose/genética , Adolescente , Adulto , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
19.
PLoS Pathog ; 16(5): e1008569, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32463840

RESUMO

Mycobacterial infection leads to activation of the RIG-I/MAVS/TBK1 RNA sensing pathway in macrophages but the consequences of this activation remains poorly defined. In this study, we determined that activation of this RNA sensing pathway stimulates ICAM-1 expression in M.avium-infected macrophage through the inhibition of the E3 ubiquitin ligase CRL4COP1/DET1. CRL4 when active targets the transcription factor ETV5 for degradation by the ubiquitin-proteasome system. In the absence of the ETV5 transcription factor, ICAM-1 expression is significantly decreased. The M.avium-induced ICAM-1 production is required for the formation of immune synapse between infected macrophages and antigen-specific CD4+ T lymphocytes, and is essential for CD4+ T lymphocyte-mediated mycobacterial killing in vitro and in mice. This study demonstrates a previously undefined mechanism by which a host cytosolic RNA sensing pathway contributes to the interplay between mycobacteria infected macrophages and antigen-specific T lymphocytes.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/imunologia , Linfócitos T CD4-Positivos/imunologia , Proteína DEAD-box 58/imunologia , Macrófagos , Mycobacterium avium/imunologia , Proteínas Serina-Treonina Quinases/imunologia , Tuberculose/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Linfócitos T CD4-Positivos/microbiologia , Linfócitos T CD4-Positivos/patologia , Proteína DEAD-box 58/genética , Macrófagos/imunologia , Macrófagos/microbiologia , Macrófagos/patologia , Camundongos , Camundongos Knockout , Proteínas Serina-Treonina Quinases/genética , Tuberculose/genética , Tuberculose/patologia
20.
Proc Natl Acad Sci U S A ; 117(15): 8494-8502, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32229570

RESUMO

Human tuberculosis is caused by members of the Mycobacterium tuberculosis complex (MTBC) that vary in virulence and transmissibility. While genome-wide association studies have uncovered several mutations conferring drug resistance, much less is known about the factors underlying other bacterial phenotypes. Variation in the outcome of tuberculosis infection and diseases has been attributed primarily to patient and environmental factors, but recent evidence indicates an additional role for the genetic diversity among MTBC clinical strains. Here, we used metabolomics to unravel the effect of genetic variation on the strain-specific metabolic adaptive capacity and vulnerability. To define the functionality of single-nucleotide polymorphisms (SNPs) systematically, we developed a constraint-based approach that integrates metabolomic and genomic data. Our model-based predictions correctly classify SNP effects in pyruvate kinase and suggest a genetic basis for strain-specific inherent baseline susceptibility to the antibiotic para-aminosalicylic acid. Our method is broadly applicable across microbial life, opening possibilities for the development of more selective treatment strategies.


Assuntos
Antituberculosos/farmacologia , Genômica/métodos , Interações Hospedeiro-Patógeno , Metaboloma , Mycobacterium tuberculosis/genética , Polimorfismo de Nucleotídeo Único , Tuberculose/genética , Ácido Aminossalicílico/farmacologia , Genoma Bacteriano , Estudo de Associação Genômica Ampla , Humanos , Modelos Moleculares , Mycobacterium tuberculosis/classificação , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/metabolismo , Fenótipo , Filogenia , Piruvato Quinase/metabolismo , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Virulência
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