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1.
Sleep ; 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33823024

RESUMO

STUDY OBJECTIVES: To prospectively investigate the association between sleep traits and lung cancer risk, accounting for the interactions with genetic predisposition of lung cancer. METHODS: We included 469,691 individuals free of lung cancer at recruitment from UK Biobank, measuring sleep behaviors with a standardized questionnaire and identifying incident lung cancer cases through linkage to national cancer and death registries. We estimated multivariable adjusted hazard ratios (HR) for lung cancer (2,177 incident cases) across four sleep traits (sleep duration, chronotype, insomnia and snoring), and examined the interaction and joint effects with a lung cancer polygenic risk score. RESULTS: A U-shaped association was observed for sleep duration and lung cancer risk, with a 18% higher risk (95% confidence interval (CI): 1.07-1.30) for short sleepers and a 17% higher risk (95%CI: 1.02-1.34) for long sleepers compared with normal sleepers (7-8 h/day). Evening preference was associated with elevated lung cancer risk compared with morning preference (HR: 1.25; 95%CI: 1.07-1.46), but no association was found for insomnia or snoring. Compared to participants with favorable sleep traits and low genetic risk, those with both unfavorable sleep duration (<7 hours or >8 hours) or evening preference and high genetic risk showed the greatest lung cancer risk (HRsleep duration: 1.83; 95%CI: 1.47-2.27; HRchronotype: 1.85; 95%CI: 1.34-2.56). CONCLUSIONS: Both unfavorable sleep duration and evening chronotype were associated with increased lung cancer incidence, especially for those with low to moderate genetic risk. These results indicate that sleep behaviors as modifiable risk factors may have potential implications for lung cancer risk.

2.
Biomed Res Int ; 2021: 7413605, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33506033

RESUMO

Inflammation is an important biological process for eliciting immune responses against physiological and pathological stimuli. Inflammation must be efficiently regulated to ensure homeostasis in the body. Nuclear factor-kappa B (NF-κB) signaling is crucial for inflammatory and immune responses. Aberrant activation of NF-κB signaling leads to development of numerous human diseases. In this study, we investigated the function of chromosome 7 open reading frame 41 (C7ORF41) in NF-κB signaling during inflammation. C7ORF41 was upregulated in cells stimulated with tumor necrosis factor-alpha or lipopolysaccharide. Moreover, overexpression of C7ORF41 inhibited the activation of NF-κB and decreased the expression of its downstream target genes. Notably, small hairpin RNA-mediated depletion of C7ORF41 increased the levels of downstream genes and enabled the activation of NF-κB. In conclusion, C7ORF41 negatively regulated inflammation via NF-κB signaling and p65 phosphorylation in vitro. These findings may help to diagnose and prognosticate inflammatory conditions and may help develop new strategies for the management of inflammation-related diseases.

3.
Gene ; 767: 145287, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-33181258

RESUMO

BACKGROUND: Chronic respiratory diseases have become a non-negligible cause of death globally. Although smoking and environmental exposures are primary risk factors for chronic respiratory diseases, genetic factors also play an important role in determining individual's susceptibility to diseases. Here we performed integrated gene-based and pathway analyses to systematically illuminate the heritable characteristics of chronic respiratory diseases. METHODS: UK (United Kingdom) Biobank is a very large, population-based prospective study with over 500,000 participants, established to allow detailed investigations of the genetic and nongenetic determinants of the diseases. Utilizing the GWAS-summarized data downloaded from UK Biobank, we conducted gene-based analysis to obtain associations of susceptibility genes with asthma, chronic obstructive pulmonary disease(COPD) and pneumonia using FUSION and MAGMA software. Across the identified susceptibility regions, functional annotation integrating multiple functional data sources was performed to explore potential regulatory mechanisms with INQUISIT algorithm. To further detect the biological process involved in the development of chronic respiratory diseases, we undertook pathway enrichment analysis with the R package (clusterProfiler). RESULTS: A total of 195 susceptibility genes were identified significantly associated with chronic respiratory diseases (Pbonferroni < 0.05), and 24/195 located out of known susceptibility regions (e.g. WDPCP in 2p15). Within the identified susceptibility regions, functional annotation revealed an aggregation of credible variants in promoter-like and enhancer-like histone modification regions and such regulatory mechanisms were specific to lung tissues. Furthermore, 110 genes with INQUISIT score ≥1 may influence diseases susceptibility through exerting effects on coding sequences, proximal promoter and distal enhancer regulations. Pathway enrichment results showed that these genes were enriched in immune-related processes and nicotinic acetylcholine receptors pathways. CONCLUSIONS: This study implemented an integrated gene-based and pathway strategy to explore the underlying biological mechanisms and our findings may serve as promising targets for future clinical treatments of chronic respiratory diseases.


Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Transtornos Respiratórios/genética , Asma/genética , Bancos de Espécimes Biológicos , Doença Crônica/epidemiologia , Bases de Dados Genéticas , Feminino , Humanos , Pulmão/fisiopatologia , Masculino , Polimorfismo de Nucleotídeo Único/genética , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/genética , Fumar/genética , Reino Unido
4.
Brief Bioinform ; 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33212483

RESUMO

NLRP3 inflammasome was introduced as a double-edged sword in tumorigenesis and influenced immunotherapy response by modulating host immunity. However, a systematic assessment of the NLRP3-inflammasome-related genes across human cancers is lacking, and the predictive role of NLRP3 inflammasome in cancer immunotherapy (CIT) response remains unexplored. Thus, in this study, we performed a pan-cancer analysis of NLRP3-inflammasome-related genes across 24 human cancers. Out of these 24 cancers, 15 cancers had significantly different expression of NLRP3-inflammasome-related genes between normal and tumor samples. Meanwhile, Cox regression analysis showed that the NLRP3 inflammasome score could be served as an independent prognostic factor in skin cutaneous melanoma. Further analysis indicated that NLRP3 inflammasome may influence tumor immunity mainly by mediating tumor-infiltrating lymphocytes and macrophages, and the effect of NLRP3 inflammasome on immunity is diverse across tumor types in tumor microenvironment. We also found that the NLRP3 inflammasome score could be a stronger predictor for immune signatures compared with tumor mutation burden (TMB) and glycolytic activity, which have been reported as immune predictors. Furthermore, analysis of the association between NLRP3 inflammasome and CIT response using six CIT response datasets revealed the predictive value of NLRP3 inflammasome for immunotherapy response of patients in diverse cancers. Our study illustrates the characterization of NLRP3 inflammasome in multiple cancer types and highlights its potential value as a predictive biomarker of CIT response, which can pave the way for further investigation of the prognostic and therapeutic potentials of NLRP3 inflammasome.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33038193

RESUMO

STUDY DESIGN: Questionnaire translation and validation. OBJECTIVE: The aim of this study was to translate the Early-Onset Scoliosis 24-Item Questionnaire (EOSQ-24) into simplified Chinese and to evaluate the reliability and validity of this questionnaire in children with early-onset scoliosis (EOS) in mainland China. SUMMARY OF BACKGROUND DATA: The EOSQ-24 is a validated quality of life questionnaire in children with EOS and has been translated into multiple languages and used worldwide. However, there is currently no simplified Chinese version available for use in mainland China. METHODS: The English version of the EOSQ-24 questionnaire was translated into simplified Chinese based on the recommendations of the International Quality of Life Assessment (IQoLA) group. The reliability of the scale was evaluated using test-retest reliability and internal consistency, and construct validity was examined through factor analysis. Hundred childrenwith EOS were enrolled in the study. To assess the test-retest reliability of the scale, the parents or caregivers of 38 of participants repeated the questionnaire after 2 weeks. RESULTS: Test-retest reliability was excellent overall (intraclass correlation coefficient [ICC] = 0.935) and ranged from moderate to excellent for each domain (ICC = 0.681-0.945). The overall internal consistency was excellent (Cronbach α = 0.893) and had a variable range for each domain (Cronbach α = 0.560-0.889). Factor analysis was performed, and seven principal components were extracted that accounted for 70.1% of the variance. CONCLUSION: The simplified Chinese version of the EOSQ-24 scale has acceptable reliability and construct validity, and it can be used for the assessment of health-related quality of life (HRQL), caretaker burden, and satisfaction for children with EOS in mainland China. LEVEL OF EVIDENCE: 3.

6.
Theranostics ; 10(24): 11264-11277, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042282

RESUMO

Rationale: As the transcriptional products of active enhancers, enhancer RNAs (eRNAs) are essential for the initiation of tumorigenesis. However, the landscape and functional characteristics of eRNAs in Chinese lung adenocarcinoma, and the clinical utility of eRNA-based molecular subtypes remain largely unknown. Methods: A genome-wide profiling of eRNAs was performed in 80 Chinese lung adenocarcinoma patients with RNA-seq data. Functional eRNAs and associated genes were identified between paired adenocarcinoma and adjacent samples. Unsupervised clustering of functional eRNAs was conducted and the associations with molecular characteristics and clinical outcomes were accessed by integrating whole-genome sequencing data and clinical data. Additionally, 481 lung adenocarcinoma patients were used for the validation based on The Cancer Genome Atlas (TCGA) dataset. Results: A total of 3297 eRNAs with sufficient expression were identified, which were globally upregulated in adenocarcinoma samples compared to matched-adjacent pairs (P = 7.61×10-3). Further analyses indicated that these upregulated eRNAs were correlated with copy number amplification (CNA) status (Cor = 0.22, P = 0.045), and eRNA-correlated genes were primarily involved in cell cycle and immune system-related pathways. Based on the co-expression analysis of eRNAs with protein-coding genes, we defined 188 functional eRNAs and their correlated genes were overrepresented in cancer driver genes (ER = 1.98, P = 5.95×10-12) and clinically-actionable genes (ER = 2.19, P = 3.44×10-4). The eRNA-based consensus clustering further identified a novel molecular subtype with immune deficiency and a high-level of genomic alterations, which was associated with poor clinical outcomes of lung adenocarcinoma patients (OS: HR = 1.91, P = 0.015; PFI: HR = 1.64, P = 0.034). Conclusions: The genome-wide identification and characterization of eRNAs reveal novel regulators for the development of lung cancer, which provides a new biological dimension for the understanding of eRNAs during lung carcinogenesis and emphasize the clinical utility of eRNA-based molecular subtypes in the treatment of lung adenocarcinoma.

7.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 49(4): 474-479, 2020 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-32985161

RESUMO

OBJECTIVE: To investigate the psychological and behavior status of minor children of medical staff in Hubei province during the coronavirus disease 2019 (COVID-19) epidemic. METHODS: A cross-sectional questionnaire survey was conducted through WeChat from March 13 to 15, 2020, which included a general data questionnaire and Conners parental assessment questionnaire (PSQ). The questionnaires received from outside of Hubei province were excluded through IP address, and the questionnaires with answer time <150 s were also excluded. The influence of parental work status on the psychological behavior was analyzed in children of different age groups. RESULTS: A total of 391 valid questionnaires were collected, there were 207 males (52.9%) and 184 females (47.1%); 91 (23.3%) aged 3 to 6, 183 (46.8%) aged 6 to 10, and 117 (29.9%) aged 10 to 16. Both parents were medical staff in 87 participants(22.3%), one parent was medical staff in 139(35.5%) participants, and no parents were medical staff in 165 (42.2%) participants. In 3-<6 years group, there was no significant difference in the PSQ scores of the children in each factor level (all P>0.05) between children with parents as medical staff and those without. In 6-<10 years group, children with both parents as medical staff had higher hyperactivity-impulse factor score, learning problem factor score and total score than those without parents as medical staff (all P<0.05), while they had higher learning problem factor score than those with one parent as medical staff (P<0.05); the anxiety score of children with one or both parents as medical staff was higher than that of those without parents as medical staff (all P<0.05). In 10 to 16 years group, the behavior problems, learning problems, hyperactivity-impulse, more dynamic index and the total score in children with one parent as medical staff were lower than those with both parents as medical staff or without parents as medical staff (P<0.05 or P<0.01); while there were no significant differences in psychosomatic problems, anxiety factor scores between children with one parent as medical staff and other two groups (all P>0.05). CONCLUSIONS: s During COVID-19 epidemic period, the psychological and behavior status of minor children of Hubei medical staff with different ages shows differences with those without parents as medical staff, particularly in 6-<10 years and 10 to 16 year groups. It is necessary to pay attention to the psychological and behavioral status of children of medical staff in these age groups.


Assuntos
Infecções por Coronavirus , Coronavirus , Corpo Clínico , Saúde Mental , Pandemias , Pneumonia Viral , Adolescente , Betacoronavirus , Criança , Pré-Escolar , China/epidemiologia , Estudos Transversais , Feminino , Humanos , Masculino , Corpo Clínico/estatística & dados numéricos , Saúde Mental/estatística & dados numéricos , Inquéritos e Questionários
8.
Brain Imaging Behav ; 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737823

RESUMO

A new method, called granger causality density (GCD), could reflect the directed information flow of the epileptiform activity, which is much closely match with excitatory and inhibitory imbalance theory of epilepsy. Here, we investigated if GCD could effectively localize the Rolandic focus in 50 patients with benign childhood epilepsy with central-temporal spikes (BECTS) from 27 normal children. The BECTS were classified into ictal epileptiform discharges (IEDs; 12 females, 15 males;age, 8.15 ± 1.68 years) and non-IEDs (10 females, 13 males; age, 9.09 ± 1.98 years) subgroups depending on the presence of central-temporal spikes. Multiple correlation-modality analyses (Pearson, across-voxel and across-subject correlations) were used to calculate the couplings between the GCD maps and IEDs-related brain activation map. The individual lateralization coefficient of localize IEDs and multiple regression analysis were used to identify the reliability of the GCD method in localizing the Rolandic focus. In this study, multiple correlation-modality analyses showed that the IEDs-related brain activation map and the GCD maps had highly temporal (coefficient ׀r\= 0.56 ~ 0.65) and spatial (\r\=0.53~0.91) (r\=~ couplings. The proposed GCD method and multiple regression analyses showed consistent findings with the clinical EEG recordings in lateralization of Rolandic focus. Furthermore, the GCD method could reflect the epilepsy-related brain activity during non-IEDs substate. Therefore, the proposed GCD method has the potential to be served as an effective and reliable neuroimaging biomarker to localize the Rolandic focus of BECTS. These findings are critical for clinical early diagnosis, and may promote the progression of treatment and management of pediatric epilepsy.

9.
Brain Imaging Behav ; 2020 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-32367486

RESUMO

Sleep-related attentional bias and instinctual craving-sleep status may be associated with value-driven selective attention network and SEEKING system. We hypothesized that the two networks might be important components and underlie etiology of inability to initiate or/and maintain sleep in patients with chronic insomnia (PIs). Our aim is to investigate whether frequency-frequency couplings(temporal and spatial coupling, and differences of a set of imaging parameters) could elevate the sensibility to characterize the two insomnia-related networks in studying their relationships with sleep parameters and post-insomnia emotions. Forty-eight PIs and 48 status-matched good sleepers were requested to complete sleep and emotion-related questionnaires. Receiver operating characteristic curve was used to calculate the discriminatory power of a set of parameters. Granger causality and mediating causality analysis were used to address the causal relationships between the two networks and sleep/emotion-related parameters. Frequency-frequency couplings could characterize the two networks with high discriminatory power (AUC, 0.951; sensitivity, 87.5%; specificity, 95.8%), which suggested that the frequency-frequency couplings could be served as a useful biomarker to address the insomnia-related brain networks. Functional deficits of the SEEKING system played decreased mediator acting in post-insomnia negative emotions (decreased frequency-frequency coupling). Functional hyperarousal of the value-driven attention network played decreased mediator acting in sleep regulation (increased frequency-frequency coupling). Granger causality analysis showed decreased causal effect connectivity between and within the two networks. The between-network causal effect connectivity segregation played decreased mediator acting in sleep regulation (decreased connectivity). These findings suggest that the functional deficits and segregation of the two systems may underlie etiology of PIs.

11.
Int J Cancer ; 146(10): 2855-2864, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-31577861

RESUMO

Genome-wide association studies (GWAS) have identified 45 susceptibility loci associated with lung cancer. Only less than SNPs, small insertions and deletions (INDELs) are the second most abundant genetic polymorphisms in the human genome. INDELs are highly associated with multiple human diseases, including lung cancer. However, limited studies with large-scale samples have been available to systematically evaluate the effects of INDELs on lung cancer risk. Here, we performed a large-scale meta-analysis to evaluate INDELs and their risk for lung cancer in 23,202 cases and 19,048 controls. Functional annotations were performed to further explore the potential function of lung cancer risk INDELs. Conditional analysis was used to clarify the relationship between INDELs and SNPs. Four new risk loci were identified in genome-wide INDEL analysis (1p13.2: rs5777156, Insertion, OR = 0.92, p = 9.10 × 10-8 ; 4q28.2: rs58404727, Deletion, OR = 1.19, p = 5.25 × 10-7 ; 12p13.31: rs71450133, Deletion, OR = 1.09, p = 8.83 × 10-7 ; and 14q22.3: rs34057993, Deletion, OR = 0.90, p = 7.64 × 10-8 ). The eQTL analysis and functional annotation suggested that INDELs might affect lung cancer susceptibility by regulating the expression of target genes. After conducting conditional analysis on potential causal SNPs, the INDELs in the new loci were still nominally significant. Our findings indicate that INDELs could be potentially functional genetic variants for lung cancer risk. Further functional experiments are needed to better understand INDEL mechanisms in carcinogenesis.


Assuntos
Predisposição Genética para Doença/genética , Mutação INDEL/genética , Neoplasias Pulmonares/genética , Estudo de Associação Genômica Ampla , Humanos
13.
Lancet Respir Med ; 7(10): 881-891, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31326317

RESUMO

BACKGROUND: Genetic variation has an important role in the development of non-small-cell lung cancer (NSCLC). However, genetic factors for lung cancer have not been fully identified, especially in Chinese populations, which limits the use of existing polygenic risk scores (PRS) to identify subpopulations at high risk of lung cancer for prevention. We therefore aimed to identify novel loci associated with NSCLC risk, and generate a PRS and evaluate its utility and effectiveness in the prediction of lung cancer risk in Chinese populations. METHODS: To systematically identify genetic variants for NSCLC risk, we newly genotyped 19 546 samples from Chinese NSCLC cases and controls from the Nanjing Medical University Global Screening Array Project and did a meta-analysis of genome-wide association studies (GWASs) of 27 120 individuals with NSCLC and 27 355 without NSCLC (13 327 cases and 13 328 controls of Chinese descent as well as 13 793 cases and 14 027 controls of European descent). We then built a PRS for Chinese populations from all reported single-nucleotide polymorphisms that have been reported to be associated with lung cancer risk at genome-wide significance level. We evaluated the utility and effectiveness of the generated PRS in predicting subpopulations at high-risk of lung cancer in an independent prospective cohort of 95 408 individuals from the China Kadoorie Biobank (CKB) with more than 10 years' follow-up. FINDINGS: We identified 19 susceptibility loci to be significantly associated with NSCLC risk at p≤5·0 × 10-8, including six novel loci. When applied to the CKB cohort, the PRS of the risk loci successfully predicted lung cancer incident cases in a dose-response manner in participants at a high genetic risk (top 10%) than those at a low genetic risk (bottom 10%; adjusted hazard ratio 1·96, 95% CI 1·53-2·51; ptrend=2·02 × 10-9). Specially, we observed consistently separated curves of lung cancer events in individuals at low, intermediate, and high genetic risk, respectively, and PRS was an independent effective risk stratification indicator beyond age and smoking pack-years. INTERPRETATION: We have shown for the first time that GWAS-derived PRS can be effectively used in discriminating subpopulations at high risk of lung cancer, who might benefit from a practically feasible PRS-based lung cancer screening programme for precision prevention in Chinese populations. FUNDING: National Natural Science Foundation of China, the Priority Academic Program for the Development of Jiangsu Higher Education Institutions, National Key R&D Program of China, Science Foundation for Distinguished Young Scholars of Jiangsu, and China's Thousand Talents Program.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Predisposição Genética para Doença/genética , Neoplasias Pulmonares/genética , Medição de Risco/métodos , Adulto , Idoso , China , Feminino , Loci Gênicos/genética , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco
15.
Diabetes Care ; 42(8): 1414-1421, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31152121

RESUMO

OBJECTIVE: Type 1 diabetes (T1D) is a highly heritable disease with much lower incidence but more adult-onset cases in the Chinese population. Although genome-wide association studies (GWAS) have identified >60 T1D loci in Caucasians, less is known in Asians. RESEARCH DESIGN AND METHODS: We performed the first two-stage GWAS of T1D using 2,596 autoantibody-positive T1D case subjects and 5,082 control subjects in a Chinese Han population and evaluated the associations between the identified T1D risk loci and age and fasting C-peptide levels at T1D diagnosis. RESULTS: We observed a high genetic correlation between children/adolescents and adult T1D case subjects (r g = 0.87), as well as subgroups of autoantibody status (r g ≥ 0.90). We identified four T1D risk loci reaching genome-wide significance in the Chinese Han population, including two novel loci, rs4320356 near BTN3A1 (odds ratio [OR] 1.26, P = 2.70 × 10-8) and rs3802604 in GATA3 (OR 1.24, P = 2.06 × 10-8), and two previously reported loci, rs1770 in MHC (OR 4.28, P = 2.25 × 10-232) and rs705699 in SUOX (OR 1.46, P = 7.48 × 10-20). Further fine mapping in the MHC region revealed five independent variants, including another novel locus, HLA-C position 275 (omnibus P = 9.78 × 10-12), specific to the Chinese population. Based on the identified eight variants, we achieved an area under the curve value of 0.86 (95% CI 0.85-0.88). By building a genetic risk score (GRS) with these variants, we observed that the higher GRS were associated with an earlier age of T1D diagnosis (P = 9.08 × 10-11) and lower fasting C-peptide levels (P = 7.19 × 10-3) in individuals newly diagnosed with T1D. CONCLUSIONS: Our results extend current knowledge on genetic contributions to T1D risk. Further investigations in different populations are needed for genetic heterogeneity and subsequent precision medicine.


Assuntos
Fatores Etários , Antígenos CD/genética , Butirofilinas/genética , Diabetes Mellitus Tipo 1/genética , Fator de Transcrição GATA3/genética , Loci Gênicos/genética , Adolescente , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Autoanticorpos/sangue , Peptídeo C/sangue , Criança , China , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/imunologia , Jejum/sangue , Feminino , Estudo de Associação Genômica Ampla , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Masculino , Razão de Chances , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/genética , Fatores de Risco
16.
Mol Carcinog ; 58(7): 1303-1313, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31026380

RESUMO

Identification of long noncoding RNA (lncRNA) expression quantitative trait loci (lncR-eQTL) that associated with lung cancer can provide insights into regulatory mechanisms of lncRNA, and help reveal the role of lncRNA in lung cancer. A two-stage case-control design was implemented in this study. We first selected the lncRNAs that differently expressed based on the Cancer Genome Atlas (TCGA) project (75 normal and 708 tumor tissues) and identified eQTLs for selected lncRNAs based on data of 278 normal lung tissues from the the genotype-tissue expression database. Then we selected lncR-eQTLs that associated with lung cancer based on two lung cancer GWAS datasets (7127 cases and 6818 controls). Promising lncR-eQTLs were further replicated in an additional population (1056 cases and 1053 controls). Functional annotations of the identified lncR-eQTLs and related lncRNAs were finally performed by using multiple public databases. Our eQTL analysis finally detected three lncRNA-eQTLs, rs793544 in 3q13.12 (odds ratio [OR] = 1.15; confidence interval [CI]:1.09-1.22; P = 2.30 × 10-6 ), rs7234707 in 18p11.31 (OR = 1.1; CI:1.05-1.15; P = 9.01 × 10-5 ) and rs1600249 in 8p23.1 (OR = 1.1; CI:1.05-1.16; P = 1.27 × 10-4 ), that were consistently associated with the risk of lung cancer. These findings indicate that lncR-eQTLs may serve as novel susceptibility markers for lung cancer.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença/genética , Neoplasias Pulmonares/genética , RNA Longo não Codificante/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Humanos , Pulmão/patologia , Neoplasias Pulmonares/patologia , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética
17.
Carcinogenesis ; 40(2): 263-268, 2019 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-30689816

RESUMO

Even though genome-wide association studies (GWASs) have identified dozens of single nucleotide polymorphisms (SNPs) affecting the susceptibility to lung cancer, only a tiny fraction of heritability can be explained. Regulating the expression of surrounding genes is one of the important mechanisms for SNPs to exert their effect. So it is necessary to systematically evaluate the associations between expression quantitative trait loci (eQTL) and lung cancer risk. In this study, a two-stage case-control design was used to evaluate the associations of eQTL SNPs (eSNPs) defined by GTEx in normal lung tissues with the risk of lung cancer based on two GWAS datasets, including 7127 cases and 6818 controls. Promising variants were replicated in an independent population with 1026 lung cancer cases and 1006 controls. Functional annotations of the identified eSNPs and related genes were performed based on multiple public databases. Finally, we identified two potential eSNPs associated with the risk of lung cancer in 3q28 [rs505974, OR = 0.90 (0.86 - 0.94), P = 6.51 × 10-6] and 21q22.3 [rs79589812, OR = 1.38 (1.21 - 1.58), P = 2.46 × 10-6]. Subgroup analysis showed rs505974 might interact with smoking behaviour. Gene-set enrichment and pathway analysis revealed that rs505974 may affect the susceptibility to lung cancer via regulating the expression of CLDN16, which may be involved in the chemical carcinogenesis pathway, whereas rs79589812 may regulate the expression of SPATC1L, which may be involved in the base excision repair pathway. These results provide an overview of the associations between eSNPs and lung cancer in Asian populations.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença/genética , Neoplasias Pulmonares/genética , Locos de Características Quantitativas/genética , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Risco , Fumar/genética
18.
Front Oncol ; 9: 1492, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32010612

RESUMO

Genome-wide association studies (GWASs) have identified hundreds of single nucleotide polymorphisms (SNPs) associated with cancer risk, several of which have shown pleiotropic effects across cancers. Therefore, we performed a systematic cross-cancer pleiotropic analysis to detect the effects of GWAS-identified variants from non-lung cancers on lung cancer risk in 12,843 cases and 12,639 controls from four lung cancer GWASs. The overall association between variants in each cancer and risk of lung cancer was explored using sequential kernel association test (SKAT) analysis. For single variant analysis, we combined the result of specific study using fixed-effect meta-analysis. We performed functional exploration of significant associations based on features from public databases. To further detect the biological mechanism underlying identified observations, pathway enrichment analysis were conducted with R package "clusterProfiler." SNP-set analysis revealed the overall associations between variants of 8 cancer types and lung cancer risk. Single variant analysis identified 6 novel SNPs related to lung cancer risk after multiple correction (P fdr < 0.10), including rs1707302 (1p34.1, OR = 0.93, 95% CI: 0.90-0.97, P = 7.60 × 10-4), rs2516448 (6p21.33, OR = 1.07, 95% CI: 1.03-1.11, P = 1.00 × 10-3), rs3869062 (6p22.1, OR = 0.91, 95% CI: 0.86-0.96, P = 7.10 × 10-4), rs174549 (11q12.2, OR = 0.90, 95% CI: 0.87-0.94, P = 1.00 × 10-7), rs7193541 (16q23.1, OR = 0.93, 95% CI: 0.90-0.96, P = 1.20 × 10-4), and rs8064454 (17q12, OR = 1.07, 95% CI: 1.03-1.11, P = 4.30 × 10-4). The eQTL analysis and functional annotation suggested that these variants might modify lung cancer susceptibility through regulating the expression of related genes. Pathway enrichment analysis showed that genes modulated by these variants play important roles in cancer carcinogenesis. Our findings demonstrate the pleiotropic associations between non-lung cancer susceptibility loci and lung cancer risk, providing important insights into the shared mechanisms of carcinogenesis across cancers.

19.
J Thorac Dis ; 11(12): 5407-5416, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32030259

RESUMO

Background: Nomograms have been widely used for estimating cancer prognosis. The aim of this study was to construct a clinical nomogram that would well predict overall survival of early stage non-small cell lung cancer (NSCLC) patients after surgery resection. Methods: A total of 443 patients diagnosed with pathologic stage I and II NSCLC who had undergone curative resection without neoadjuvant chemotherapy or radiotherapy were recruited and analyzed. The log-rank test and multivariate Cox regression analysis were used to select the most significant predictors in the final nomogram for predicting overall survival. Furthermore, the model was validated by bootstrap methods and measured by concordance index (C-index) and calibration plots. Results: Four independent predictors for overall survival were identified and included into the delineation of the nomogram (tumor differentiation, station of sampled lymph nodes, pathologic T and pathologic N). The model showed comparatively stable discrimination (bootstrap-corrected C-index =0.622, 95% CI: 0.572-0.672) and good calibration. Conclusions: We successfully developed a nomogram incorporating available clinicopathological variables to predict overall survival of early stage NSCLC patients after surgery resection, which might help clinician select better appropriate treatment decisions.

20.
J Clin Pharm Ther ; 44(1): 91-101, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30225937

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Previous studies have shown that various aspirin combinations might be beneficial for the treatment of acute cerebral infarction (ACI). The aim of this study was to evaluate the efficacy of six aspirin combinations in the treatment of ACI using network meta-analysis (NMA). The performance of these combinations is then ranked according to results of this analysis. METHODS: Multiple databases were consulted to find randomized controlled trials (RCT) of six different aspirin combinations for the treatment of ACI. NMA was conducted on the data using stata (13.0) software. The odds ratio (OR) was calculated. The studies included in this paper were divided into a control group (aspirin alone) and an observation group (one of six aspirin combinations). RESULTS: A total of 103 eligible RCTs were identified. A total of 13 317 cases were included in the study, and the results showed that the six types of aspirin combinations (aspirin with atorvastatin, ozagrel sodium, low molecular weight heparin [LMWH], clopidogrel, cilostazol and ginkgo damo) were all significantly superior (P < 0.05) to aspirin alone. The combination of aspirin with LMWH had the highest probability of being the most clinically efficacious intervention, with a surface under the cumulative ranking (SUCRA) curve of 79.1. The combination of aspirin with ozagrel sodium was the worst, with a SUCRA value of 29.7. WHAT IS NEW AND CONCLUSION: A combination of aspirin with LMWH is the best option among the six aspirin combinations considered for the treatment of ACI. The combination of aspirin with ozagrel sodium was ranked the last.


Assuntos
Aspirina/administração & dosagem , Infarto Cerebral/tratamento farmacológico , Inibidores da Agregação de Plaquetas/administração & dosagem , Doença Aguda , Infarto Cerebral/patologia , China , Quimioterapia Combinada , Humanos , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
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