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1.
Sci Adv ; 5(8): eaaw3538, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31453325

RESUMO

Genotype-by-environment interaction (GEI) is a fundamental component in understanding complex trait variation. However, it remains challenging to identify genetic variants with GEI effects in humans largely because of the small effect sizes and the difficulty of monitoring environmental fluctuations. Here, we demonstrate that GEI can be inferred from genetic variants associated with phenotypic variability in a large sample without the need of measuring environmental factors. We performed a genome-wide variance quantitative trait locus (vQTL) analysis of ~5.6 million variants on 348,501 unrelated individuals of European ancestry for 13 quantitative traits in the UK Biobank and identified 75 significant vQTLs with P < 2.0 × 10-9 for 9 traits, especially for those related to obesity. Direct GEI analysis with five environmental factors showed that the vQTLs were strongly enriched with GEI effects. Our results indicate pervasive GEI effects for obesity-related traits and demonstrate the detection of GEI without environmental data.

2.
Genome Biol ; 20(1): 107, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138268

RESUMO

The rapid increase of omic data has greatly facilitated the investigation of associations between omic profiles such as DNA methylation (DNAm) and complex traits in large cohorts. Here, we propose a mixed-linear-model-based method called MOMENT that tests for association between a DNAm probe and trait with all other distal probes fitted in multiple random-effect components to account for unobserved confounders. We demonstrate by simulations that MOMENT shows a lower false positive rate and more robustness than existing methods. MOMENT has been implemented in a versatile software package called OSCA together with a number of other implementations for omic-data-based analyses.


Assuntos
Técnicas Genéticas , Metabolômica/métodos , Software , Idoso , Simulação por Computador , Metilação de DNA , Humanos , Modelos Lineares , Fenótipo
3.
Toxicology ; 422: 53-59, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31005593

RESUMO

Quinolones (QNs)-induced cartilaginous lesions in juvenile animals by chondrocyte apoptosis is an important toxic effect, which results in the restriction of their use in pediatrics. However, limited data about QNs chondrotoxicity are available for evaluation of the potential toxicity in both animals and human cartilage. To explore whether tumor necrosis factor/its receptor (TNF/TNFR1) signaling pathway is involved in the early apoptosis of marbofloxacin-induced chondrocytes, canine juvenile chondrocytes were treated with 0, 20, 50 and 100 µg/mL marbofloxacin. Results showed that the apoptosis rates of the chondrocytes at 2, 8 and 24 h were significantly increased in a concentration- and time-dependent manner (P < 0.05). The mRNA levels of apoptosis-related factors in TNF/TNFR1 signaling pathways and the protein levels of TNFα and TNFR1 were increased in canine chondrocytes treated with 20-100 µg/mL marbofloxacin (P < 0.05) while TNFR1 gene silencing significantly decreased the chondrocyte apoptosis and inhibited the mRNA expression of TNF/TNFR1 downstream signaling molecules after 100 µg/mL marbofloxacin treatment at 8 h (P < 0.01). It was confirmed that activated TNF/TNFR1 signaling pathway may play a leading role in the early apoptosis of marbofloxacin-induced canine juvenile chondrocytes, which is helpful for clinical estimation or prevention of the risk of QNs.

4.
Nat Genet ; 51(2): 245-257, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30643258

RESUMO

Humans vary substantially in their willingness to take risks. In a combined sample of over 1 million individuals, we conducted genome-wide association studies (GWAS) of general risk tolerance, adventurousness, and risky behaviors in the driving, drinking, smoking, and sexual domains. Across all GWAS, we identified hundreds of associated loci, including 99 loci associated with general risk tolerance. We report evidence of substantial shared genetic influences across risk tolerance and the risky behaviors: 46 of the 99 general risk tolerance loci contain a lead SNP for at least one of our other GWAS, and general risk tolerance is genetically correlated ([Formula: see text] ~ 0.25 to 0.50) with a range of risky behaviors. Bioinformatics analyses imply that genes near SNPs associated with general risk tolerance are highly expressed in brain tissues and point to a role for glutamatergic and GABAergic neurotransmission. We found no evidence of enrichment for genes previously hypothesized to relate to risk tolerance.


Assuntos
Comportamento/fisiologia , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Estudos de Casos e Controles , Feminino , Genética Comportamental/métodos , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética
5.
Nat Commun ; 9(1): 2941, 2018 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-30054458

RESUMO

Type 2 diabetes (T2D) is a very common disease in humans. Here we conduct a meta-analysis of genome-wide association studies (GWAS) with ~16 million genetic variants in 62,892 T2D cases and 596,424 controls of European ancestry. We identify 139 common and 4 rare variants associated with T2D, 42 of which (39 common and 3 rare variants) are independent of the known variants. Integration of the gene expression data from blood (n = 14,115 and 2765) with the GWAS results identifies 33 putative functional genes for T2D, 3 of which were targeted by approved drugs. A further integration of DNA methylation (n = 1980) and epigenomic annotation data highlight 3 genes (CAMK1D, TP53INP1, and ATP5G1) with plausible regulatory mechanisms, whereby a genetic variant exerts an effect on T2D through epigenetic regulation of gene expression. Our study uncovers additional loci, proposes putative genetic regulatory mechanisms for T2D, and provides evidence of purifying selection for T2D-associated variants.

6.
Nat Commun ; 9(1): 2282, 2018 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-29891976

RESUMO

Understanding the difference in genetic regulation of gene expression between brain and blood is important for discovering genes for brain-related traits and disorders. Here, we estimate the correlation of genetic effects at the top-associated cis-expression or -DNA methylation (DNAm) quantitative trait loci (cis-eQTLs or cis-mQTLs) between brain and blood (r b ). Using publicly available data, we find that genetic effects at the top cis-eQTLs or mQTLs are highly correlated between independent brain and blood samples ([Formula: see text] for cis-eQTLs and [Formula: see text] for cis-mQTLs). Using meta-analyzed brain cis-eQTL/mQTL data (n = 526 to 1194), we identify 61 genes and 167 DNAm sites associated with four brain-related phenotypes, most of which are a subset of the discoveries (97 genes and 295 DNAm sites) using data from blood with larger sample sizes (n = 1980 to 14,115). Our results demonstrate the gain of power in gene discovery for brain-related phenotypes using blood cis-eQTL/mQTL data with large sample sizes.

7.
Nat Commun ; 9(1): 918, 2018 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-29500431

RESUMO

The identification of genes and regulatory elements underlying the associations discovered by GWAS is essential to understanding the aetiology of complex traits (including diseases). Here, we demonstrate an analytical paradigm of prioritizing genes and regulatory elements at GWAS loci for follow-up functional studies. We perform an integrative analysis that uses summary-level SNP data from multi-omics studies to detect DNA methylation (DNAm) sites associated with gene expression and phenotype through shared genetic effects (i.e., pleiotropy). We identify pleiotropic associations between 7858 DNAm sites and 2733 genes. These DNAm sites are enriched in enhancers and promoters, and >40% of them are mapped to distal genes. Further pleiotropic association analyses, which link both the methylome and transcriptome to 12 complex traits, identify 149 DNAm sites and 66 genes, indicating a plausible mechanism whereby the effect of a genetic variant on phenotype is mediated by genetic regulation of transcription through DNAm.


Assuntos
Genômica/métodos , Característica Quantitativa Herdável , Metilação de DNA/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Especificidade de Órgãos , Locos de Características Quantitativas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sequências Reguladoras de Ácido Nucleico/genética , Esquizofrenia/genética , Transcriptoma/genética
8.
Chin Med J (Engl) ; 131(7): 804-812, 2018 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-29578124

RESUMO

Background: Ventilator-induced lung injury (VILI) is commonly associated with barrier dysfunction and inflammation reaction. Glutamine could ameliorate VILI, but its role has not been fully elucidated. This study examined the relationship between inflammatory cytokines (interleukin [IL]-6, tumor necrosis factor [TNF]-α, and IL-10) and adherens junctions (E-cadherin, p120-catenin), which were ameliorated by glutamine in VILI, both in vitro and in vivo. Methods: For the in vivo study, 30 healthy C57BL/6 mice weighing 25-30 g were randomly divided into five groups with random number table (n = 6 in each group): control (Group C); low tidal volume (Group L); low tidal volume + glutamine (Group L + G); high tidal volume (Group H); and high tidal volume + glutamine (Group H + G). Mice in all groups, except Group C, underwent mechanical ventilation for 4 h. For the in vitro study, mouse lung epithelial 12 (MLE-12) cells pretreated with glutamine underwent cyclic stretching at 20% for 4 h. Cell lysate and lung tissue were obtained to detect the junction proteins, inflammatory cytokines, and lung pathological changes by the Western blotting, cytokine assay, hematoxylin and eosin staining, and immunofluorescence. Results: In vivo, compared with Group C, total cell counts (t = -28.182, P < 0.01), the percentage of neutrophils (t = -28.095, P < 0.01), IL-6 (t = -28.296, P < 0.01), and TNF-α (t = -19.812, P < 0.01) in bronchoalveolar lavage (BAL) fluid, lung injury scores (t = -6.708, P < 0.01), and the wet-to-dry ratio (t = -15.595, P < 0.01) were increased in Group H; IL-10 in BAL fluid (t = 9.093, P < 0.01) and the expression of E-cadherin (t = 10.044, P < 0.01) and p120-catenin (t = 13.218, P < 0.01) were decreased in Group H. Compared with Group H, total cell counts (t = 14.844, P < 0.01), the percentage of neutrophils (t = 18.077, P < 0.01), IL-6 (t = 18.007, P < 0.01), and TNF-α (t = 10.171, P < 0.01) in BAL fluid were decreased in Group H + G; IL-10 in BAL fluid (t = -7.531, P < 0.01) and the expression of E-cadherin (t = -14.814, P < 0.01) and p120-catenin (t = -9.114, P < 0.01) were increased in Group H + G. In vitro, compared with the nonstretching group, the levels of IL-6 (t = -21.111, P < 0.01) and TNF-α (t = -15.270, P < 0.01) were increased in the 20% cyclic stretching group; the levels of IL-10 (t = 5.450, P < 0.01) and the expression of E-cadherin (t = 17.736, P < 0.01) and p120-catenin (t = 16.136, P < 0.01) were decreased in the 20% cyclic stretching group. Compared with the stretching group, the levels of IL-6 (t = 11.818, P < 0.01) and TNF-α (t = 8.631, P < 0.01) decreased in the glutamine group; the levels of IL-10 (t = -3.203, P < 0.05) and the expression of E-cadherin (t = -13.567, P < 0.01) and p120-catenin (t = -10.013, P < 0.01) were increased in the glutamine group. Conclusions: High tidal volume mechanical ventilation and 20% cyclic stretching could cause VILI. Glutamine regulates VILI by improving cytokines and increasing the adherens junctions, protein E-cadherin and p120-catenin, to enhance the epithelial barrier function.


Assuntos
Caderinas/metabolismo , Glutamina/metabolismo , Pulmão/metabolismo , Lesão Pulmonar Induzida por Ventilação Mecânica/metabolismo , Animais , Cateninas/metabolismo , Inflamação/metabolismo , Interleucina-6/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Lesão Pulmonar Induzida por Ventilação Mecânica/imunologia
9.
Nat Commun ; 9(1): 224, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29335400

RESUMO

Health risk factors such as body mass index (BMI) and serum cholesterol are associated with many common diseases. It often remains unclear whether the risk factors are cause or consequence of disease, or whether the associations are the result of confounding. We develop and apply a method (called GSMR) that performs a multi-SNP Mendelian randomization analysis using summary-level data from genome-wide association studies to test the causal associations of BMI, waist-to-hip ratio, serum cholesterols, blood pressures, height, and years of schooling (EduYears) with common diseases (sample sizes of up to 405,072). We identify a number of causal associations including a protective effect of LDL-cholesterol against type-2 diabetes (T2D) that might explain the side effects of statins on T2D, a protective effect of EduYears against Alzheimer's disease, and bidirectional associations with opposite effects (e.g., higher BMI increases the risk of T2D but the effect of T2D on BMI is negative).


Assuntos
Índice de Massa Corporal , Colesterol/sangue , Doença/genética , Estudo de Associação Genômica Ampla/métodos , Doença de Alzheimer/sangue , Doença de Alzheimer/genética , LDL-Colesterol/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Doença/etiologia , Humanos , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Fatores de Risco
10.
ACS Appl Mater Interfaces ; 10(2): 2075-2082, 2018 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-29253331

RESUMO

A new surface modification method is developed for electroless deposition of robust metal (copper, nickel, silver) layers on poly(dimethylsiloxane) (PDMS) substrate with strong adhesion. Under the synergies of the polydopamine (PDA), the plasma process enhances Ag+ reduction, and a thin Ag film is capable of tightly attaching to the PDMS surface, which catalyzes electroless deposition (ELD) to form robust metal layers on the PDMS surface with strong adhesion. Subsequently, a flexible and stretchable Cu-PDMS conductor is obtained through this method, showing excellent metallic conductivity of 1.2 × 107 S m-1, even at the longest stretch strain (700%). This process provides a successful strategy for obtaining good robust metal layers on PDMS and other polymer substrate surfaces with strong adhesion and conductivity.

11.
Nat Commun ; 8: 15539, 2017 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-28537267

RESUMO

Endometriosis is a heritable hormone-dependent gynecological disorder, associated with severe pelvic pain and reduced fertility; however, its molecular mechanisms remain largely unknown. Here we perform a meta-analysis of 11 genome-wide association case-control data sets, totalling 17,045 endometriosis cases and 191,596 controls. In addition to replicating previously reported loci, we identify five novel loci significantly associated with endometriosis risk (P<5 × 10-8), implicating genes involved in sex steroid hormone pathways (FN1, CCDC170, ESR1, SYNE1 and FSHB). Conditional analysis identified five secondary association signals, including two at the ESR1 locus, resulting in 19 independent single nucleotide polymorphisms (SNPs) robustly associated with endometriosis, which together explain up to 5.19% of variance in endometriosis. These results highlight novel variants in or near specific genes with important roles in sex steroid hormone signalling and function, and offer unique opportunities for more targeted functional research efforts.


Assuntos
Endometriose/genética , Loci Gênicos/genética , Predisposição Genética para Doença , Hormônios Esteroides Gonadais/metabolismo , Redes e Vias Metabólicas/genética , Adulto , Idoso , Endometriose/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
12.
Addict Biol ; 22(6): 1475-1485, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27151647

RESUMO

Alcohol dependence is a complex disease involving polygenes, environment and their interactions. Inadequate consideration of these interactions may have hampered the progress on genome-wide association studies of alcohol dependence. By using the dataset of the Study of Addiction: Genetics and Environment with 3838 subjects, we conducted a genome-wide association studies of alcohol dependence symptom count (ADSC) with a full genetic model considering additive, dominance, epistasis and their interactions with ethnicity, as well as conditions of co-morbid substance dependence. Twenty quantitative trait single nucleotide polymorphisms (QTSs) showed highly significant associations with ADSC, including four previously reported genes (ADH1C, PKNOX2, CPE and KCNB2) and the reported intergenic rs1363605, supporting the overall validity of the analysis. Two QTSs within or near ADH1C showed very strong association in a dominance inheritance mode and increased the phenotype value of ADSC when the effect of co-morbid opiate or marijuana dependence was controlled. Highly significant association was also identified in variants within four novel genes (RGS6, FMN1, NRM and BPTF), two non-coding RNA and two epistasis loci. QTS rs7616413, located near PTPRG encoding a protein tyrosine phosphatase receptor, interacted with rs10090742 within ANGPT1 encoding a protein tyrosine phosphatase in an additive × additive or dominance × additive manner. The detected QTSs contributed to about 20 percent of total heritability, in which dominance and epistasis effects accounted for over 50 percent. These results demonstrated that perturbations arising from gene-gene interaction and conditions of co-morbidity substantially influence the genetic architecture of complex trait.


Assuntos
Alcoolismo/epidemiologia , Epistasia Genética/genética , Estudo de Associação Genômica Ampla/métodos , Adolescente , Adulto , Alcoolismo/genética , Comorbidade , Feminino , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/genética , Estados Unidos/epidemiologia , Adulto Jovem
13.
PLoS Genet ; 12(4): e1005965, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27104857

RESUMO

To date, most genetic analyses of phenotypes have focused on analyzing single traits or analyzing each phenotype independently. However, joint epistasis analysis of multiple complementary traits will increase statistical power and improve our understanding of the complicated genetic structure of the complex diseases. Despite their importance in uncovering the genetic structure of complex traits, the statistical methods for identifying epistasis in multiple phenotypes remains fundamentally unexplored. To fill this gap, we formulate a test for interaction between two genes in multiple quantitative trait analysis as a multiple functional regression (MFRG) in which the genotype functions (genetic variant profiles) are defined as a function of the genomic position of the genetic variants. We use large-scale simulations to calculate Type I error rates for testing interaction between two genes with multiple phenotypes and to compare the power with multivariate pairwise interaction analysis and single trait interaction analysis by a single variate functional regression model. To further evaluate performance, the MFRG for epistasis analysis is applied to five phenotypes of exome sequence data from the NHLBI's Exome Sequencing Project (ESP) to detect pleiotropic epistasis. A total of 267 pairs of genes that formed a genetic interaction network showed significant evidence of epistasis influencing five traits. The results demonstrate that the joint interaction analysis of multiple phenotypes has a much higher power to detect interaction than the interaction analysis of a single trait and may open a new direction to fully uncovering the genetic structure of multiple phenotypes.


Assuntos
Epistasia Genética , Modelos Genéticos , Locos de Características Quantitativas , Exoma , Humanos , Polimorfismo de Nucleotídeo Único
14.
Nat Genet ; 48(5): 481-7, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27019110

RESUMO

Genome-wide association studies (GWAS) have identified thousands of genetic variants associated with human complex traits. However, the genes or functional DNA elements through which these variants exert their effects on the traits are often unknown. We propose a method (called SMR) that integrates summary-level data from GWAS with data from expression quantitative trait locus (eQTL) studies to identify genes whose expression levels are associated with a complex trait because of pleiotropy. We apply the method to five human complex traits using GWAS data on up to 339,224 individuals and eQTL data on 5,311 individuals, and we prioritize 126 genes (for example, TRAF1 and ANKRD55 for rheumatoid arthritis and SNX19 and NMRAL1 for schizophrenia), of which 25 genes are new candidates; 77 genes are not the nearest annotated gene to the top associated GWAS SNP. These genes provide important leads to design future functional studies to understand the mechanism whereby DNA variation leads to complex trait variation.


Assuntos
Pleiotropia Genética , Técnicas Genéticas , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas , Interpretação Estatística de Dados , Regulação da Expressão Gênica , Ligação Genética , Variação Genética , Humanos , Transcriptoma
15.
Sci Rep ; 5: 10298, 2015 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-26223539

RESUMO

Precise prediction for genetic architecture of complex traits is impeded by the limited understanding on genetic effects of complex traits, especially on gene-by-gene (GxG) and gene-by-environment (GxE) interaction. In the past decades, an explosion of high throughput technologies enables omics studies at multiple levels (such as genomics, transcriptomics, proteomics, and metabolomics). The analyses of large omics data, especially two-loci interaction analysis, are very time intensive. Integrating the diverse omics data and environmental effects in the analyses also remain challenges. We proposed mixed linear model approaches using GPU (Graphic Processing Unit) computation to simultaneously dissect various genetic effects. Analyses can be performed for estimating genetic main effects, GxG epistasis effects, and GxE environment interaction effects on large-scale omics data for complex traits, and for estimating heritability of specific genetic effects. Both mouse data analyses and Monte Carlo simulations demonstrated that genetic effects and environment interaction effects could be unbiasedly estimated with high statistical power by using the proposed approaches.


Assuntos
Mapeamento Cromossômico , Interação Gene-Ambiente , Genômica , Metabolômica , Modelos Genéticos , Característica Quantitativa Herdável , Animais , Epistasia Genética/fisiologia , Camundongos
16.
PLoS One ; 10(1): e0116776, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25602758

RESUMO

Gene co-expression networks comprise one type of valuable biological networks. Many methods and tools have been published to construct gene co-expression networks; however, most of these tools and methods are inconvenient and time consuming for large datasets. We have developed a user-friendly, accelerated and optimized tool for constructing gene co-expression networks that can fully harness the parallel nature of GPU (Graphic Processing Unit) architectures. Genetic entropies were exploited to filter out genes with no or small expression changes in the raw data preprocessing step. Pearson correlation coefficients were then calculated. After that, we normalized these coefficients and employed the False Discovery Rate to control the multiple tests. At last, modules identification was conducted to construct the co-expression networks. All of these calculations were implemented on a GPU. We also compressed the coefficient matrix to save space. We compared the performance of the GPU implementation with those of multi-core CPU implementations with 16 CPU threads, single-thread C/C++ implementation and single-thread R implementation. Our results show that GPU implementation largely outperforms single-thread C/C++ implementation and single-thread R implementation, and GPU implementation outperforms multi-core CPU implementation when the number of genes increases. With the test dataset containing 16,000 genes and 590 individuals, we can achieve greater than 63 times the speed using a GPU implementation compared with a single-thread R implementation when 50 percent of genes were filtered out and about 80 times the speed when no genes were filtered out.


Assuntos
Gráficos por Computador , Algoritmos , Software
17.
Genome Res ; 24(6): 989-98, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24803592

RESUMO

The critical barrier in interaction analysis for rare variants is that most traditional statistical methods for testing interactions were originally designed for testing the interaction between common variants and are difficult to apply to rare variants because of their prohibitive computational time and poor ability. The great challenges for successful detection of interactions with next-generation sequencing (NGS) data are (1) lack of methods for interaction analysis with rare variants, (2) severe multiple testing, and (3) time-consuming computations. To meet these challenges, we shift the paradigm of interaction analysis between two loci to interaction analysis between two sets of loci or genomic regions and collectively test interactions between all possible pairs of SNPs within two genomic regions. In other words, we take a genome region as a basic unit of interaction analysis and use high-dimensional data reduction and functional data analysis techniques to develop a novel functional regression model to collectively test interactions between all possible pairs of single nucleotide polymorphisms (SNPs) within two genome regions. By intensive simulations, we demonstrate that the functional regression models for interaction analysis of the quantitative trait have the correct type 1 error rates and a much better ability to detect interactions than the current pairwise interaction analysis. The proposed method was applied to exome sequence data from the NHLBI's Exome Sequencing Project (ESP) and CHARGE-S study. We discovered 27 pairs of genes showing significant interactions after applying the Bonferroni correction (P-values < 4.58 × 10(-10)) in the ESP, and 11 were replicated in the CHARGE-S study.


Assuntos
Epistasia Genética , Modelos Genéticos , Característica Quantitativa Herdável , Genoma Humano , Humanos , Polimorfismo de Nucleotídeo Único , Análise de Regressão
18.
Toxicol Appl Pharmacol ; 276(2): 121-8, 2014 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-24582689

RESUMO

BACKGROUND AND PURPOSE: Quinolones cause obvious cartilaginous lesions in juvenile animals by chondrocyte apoptosis, which results in the restriction of their use in pediatric and adolescent patients. Studies showed that chondrocytes can be induced to produce TNFα, and the cisternae of the endoplasmic reticulum in quinolone-treated chondrocytes become dilated. We investigated whether TNF/TNFR1 pathway and endoplasmic reticulum stress (ERs) are involved in ofloxacin (a typical quinolone)-induced apoptosis of juvenile canine chondrocytes. EXPERIMENTAL APPROACH: Canine juvenile chondrocytes were treated with ofloxacin. Cell survival and apoptosis rates were determined with MTT method and flow cytometry, respectively. The gene expression levels of the related signaling molecules (TNFα, TNFR1, TRADD, FADD and caspase-8) in death receptor pathways and main apoptosis-related molecules (calpain, caspase-12, GADD153 and GRP78) in ERs were measured by qRT-PCR. The gene expression of TNFR1 was suppressed with its siRNA. The protein levels of TNFα, TNFR1 and caspase-12 were assayed using Western blotting. KEY RESULTS: The survival rates decreased while apoptosis rates increased after the chondrocytes were treated with ofloxacin. The mRNA levels of the measured apoptosis-related molecules in death receptor pathways and ERs, and the protein levels of TNFα, TNFR1 and caspase-12 increased after the chondrocytes were exposed to ofloxacin. The downregulated mRNA expressions of TNFR1, Caspase-8 and TRADD, and the decreased apoptosis rates of the ofloxacin-treated chondrocytes occurred after TNFR1-siRNA interference. CONCLUSIONS AND IMPLICATIONS: Ofloxacin-induced chondrocyte apoptosis in a time- and concentration-dependent fashion. TNF/TNFR1 pathway and ERs are involved in ofloxacin-induced apoptosis of juvenile canine chondrocytes in the early stage.


Assuntos
Antibacterianos/toxicidade , Apoptose/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Estresse do Retículo Endoplasmático/fisiologia , Ofloxacino/toxicidade , Receptores Tipo I de Fatores de Necrose Tumoral/fisiologia , Transdução de Sinais/fisiologia , Fator de Necrose Tumoral alfa/fisiologia , Envelhecimento , Animais , Caspase 12/análise , Células Cultivadas , Condrócitos/patologia , Cães , Relação Dose-Resposta a Droga , RNA Mensageiro/análise , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Fator de Necrose Tumoral alfa/genética
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