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1.
Anticancer Res ; 40(7): 3707-3712, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620609

RESUMO

BACKGROUND/AIM: Oral cancer incidence is highest worldwide in Taiwan, and practical markers for personalized therapeutic strategies such as immunotherapies, is lacking. Interleukin-12 (IL12) is a cytokine that is reported to exhibit potent tumoricidal effects, however, its genotypic contribution to oral cancer is still largely unknown. We aimed to examine whether IL12A rs568408 and rs2243115 genotypes are associated with oral cancer risk in Taiwan. MATERIALS AND METHODS: Genotypic characteristics of IL12A were determined among 958 oral cancer cases and age- and gender-matched individuals via typical polymerase chain reaction-restriction fragment length polymorphism methodology. RESULTS: The variant genotypes of IL12A rs568408 and rs2243115 were not found to be significantly associated with elevated oral cancer risk (all p>0.05). Moreover, there was no interaction between IL12A genotypes and personal smoking, alcohol drinking and betel quid chewing behaviors (all p>0.05). CONCLUSION: IL12A rs568408 and rs2243115 genotypes may not serve as good predictors for oral cancer risk.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença/genética , Subunidade p35 da Interleucina-12/genética , Neoplasias Bucais/genética , Polimorfismo de Nucleotídeo Único/genética , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/genética , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Estudos de Associação Genética/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Fragmento de Restrição/genética , Fatores de Risco , Fumar/efeitos adversos , Fumar/genética , Taiwan
2.
PLoS One ; 15(7): e0235486, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32609762

RESUMO

Thioredoxin-interacting protein (TXNIP) inhibits the activity of thioredoxin (TXN), leading to increased oxidative stress. Expression of the TXNIP gene is regulated by DNA methylation. However, no study has reported the influence of lifestyle factors on TXNIP DNA methylation. Our goal was to determine the association between smoking habits and TXNIP DNA methylation levels in a Japanese population. We conducted a cross-sectional study of 417 subjects (180 males and 237 females) participating in a health examination. We used a pyrosequencing assay to determine TXNIP DNA methylation levels in leukocytes. The mean TXNIP DNA methylation level in current smokers (75.3%) was significantly lower than that in never and ex-smokers (never: 78.1%, p < 0.001; ex: 76.9%, p = 0.013). Multivariable logistic regression analyses showed that the OR for TXNIP DNA hypomethylation was significantly higher in current smokers than that in never smokers, and significantly higher in current smokers with years of smoking ≥ 35 and Brinkman Index ≥ 600 compared to that in non-smokers. In conclusion, we found that current smokers had TXNIP DNA hypomethylation compared to never and ex-smokers. Moreover, long-term smoking and high smoking exposure also were associated with TXNIP DNA hypomethylation.


Assuntos
Proteínas de Transporte/genética , Metilação de DNA , Hábitos , Leucócitos/metabolismo , Fumar/genética , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade
3.
PLoS Med ; 17(7): e1003178, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32701947

RESUMO

BACKGROUND: Smoking is a well-established cause of lung cancer and there is strong evidence that smoking also increases the risk of several other cancers. Alcohol consumption has been inconsistently associated with cancer risk in observational studies. This mendelian randomisation (MR) study sought to investigate associations in support of a causal relationship between smoking and alcohol consumption and 19 site-specific cancers. METHODS AND FINDINGS: We used summary-level data for genetic variants associated with smoking initiation (ever smoked regularly) and alcohol consumption, and the corresponding associations with lung, breast, ovarian, and prostate cancer from genome-wide association studies consortia, including participants of European ancestry. We additionally estimated genetic associations with 19 site-specific cancers among 367,643 individuals of European descent in UK Biobank who were 37 to 73 years of age when recruited from 2006 to 2010. Associations were considered statistically significant at a Bonferroni corrected p-value below 0.0013. Genetic predisposition to smoking initiation was associated with statistically significant higher odds of lung cancer in the International Lung Cancer Consortium (odds ratio [OR] 1.80; 95% confidence interval [CI] 1.59-2.03; p = 2.26 × 10-21) and UK Biobank (OR 2.26; 95% CI 1.92-2.65; p = 1.17 × 10-22). Additionally, genetic predisposition to smoking was associated with statistically significant higher odds of cancer of the oesophagus (OR 1.83; 95% CI 1.34-2.49; p = 1.31 × 10-4), cervix (OR 1.55; 95% CI 1.27-1.88; p = 1.24 × 10-5), and bladder (OR 1.40; 95% CI 1.92-2.65; p = 9.40 × 10-5) and with statistically nonsignificant higher odds of head and neck (OR 1.40; 95% CI 1.13-1.74; p = 0.002) and stomach cancer (OR 1.46; 95% CI 1.05-2.03; p = 0.024). In contrast, there was an inverse association between genetic predisposition to smoking and prostate cancer in the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome consortium (OR 0.90; 95% CI 0.83-0.98; p = 0.011) and in UK Biobank (OR 0.90; 95% CI 0.80-1.02; p = 0.104), but the associations did not reach statistical significance. We found no statistically significant association between genetically predicted alcohol consumption and overall cancer (n = 75,037 cases; OR 0.95; 95% CI 0.84-1.07; p = 0.376). Genetically predicted alcohol consumption was statistically significantly associated with lung cancer in the International Lung Cancer Consortium (OR 1.94; 95% CI 1.41-2.68; p = 4.68 × 10-5) but not in UK Biobank (OR 1.12; 95% CI 0.65-1.93; p = 0.686). There was no statistically significant association between alcohol consumption and any other site-specific cancer. The main limitation of this study is that precision was low in some analyses, particularly for analyses of alcohol consumption and site-specific cancers. CONCLUSIONS: Our findings support the well-established relationship between smoking and lung cancer and suggest that smoking may also be a risk factor for cancer of the head and neck, oesophagus, stomach, cervix, and bladder. We found no evidence supporting a relationship between alcohol consumption and overall or site-specific cancer risk.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Análise da Randomização Mendeliana/métodos , Neoplasias/etiologia , Fumar/genética , Bancos de Espécimes Biológicos , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Reino Unido
4.
Nature ; 583(7818): 807-812, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32669708

RESUMO

The majority of targeted therapies for non-small-cell lung cancer (NSCLC) are directed against oncogenic drivers that are more prevalent in patients with light exposure to tobacco smoke1-3. As this group represents around 20% of all patients with lung cancer, the discovery of stratified medicine options for tobacco-associated NSCLC is a high priority. Umbrella trials seek to streamline the investigation of genotype-based treatments by screening tumours for multiple genomic alterations and triaging patients to one of several genotype-matched therapeutic agents. Here we report the current outcomes of 19 drug-biomarker cohorts from the ongoing National Lung Matrix Trial, the largest umbrella trial in NSCLC. We use next-generation sequencing to match patients to appropriate targeted therapies on the basis of their tumour genotype. The Bayesian trial design enables outcome data from open cohorts that are still recruiting to be reported alongside data from closed cohorts. Of the 5,467 patients that were screened, 2,007 were molecularly eligible for entry into the trial, and 302 entered the trial to receive genotype-matched therapy-including 14 that re-registered to the trial for a sequential trial drug. Despite pre-clinical data supporting the drug-biomarker combinations, current evidence shows that a limited number of combinations demonstrate clinically relevant benefits, which remain concentrated in patients with lung cancers that are associated with minimal exposure to tobacco smoke.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Marcadores Genéticos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Terapia de Alvo Molecular , Medicina de Precisão , Fumar/genética , Teorema de Bayes , Carcinoma Pulmonar de Células não Pequenas/etiologia , Protocolos Clínicos , Ensaios Clínicos como Assunto , Estudos de Coortes , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/etiologia , Oncogenes/genética , Seleção de Pacientes , Fumaça/efeitos adversos , Triagem
5.
Int J Mol Sci ; 21(10)2020 May 21.
Artigo em Inglês | MEDLINE | ID: covidwho-327277

RESUMO

The COVID-19 pandemic is marked by a wide range of clinical disease courses, ranging from asymptomatic to deadly. There have been many studies seeking to explore the correlations between COVID-19 clinical outcomes and various clinical variables, including age, sex, race, underlying medical problems, and social habits. In particular, the relationship between smoking and COVID-19 outcome is controversial, with multiple conflicting reports in the current literature. In this study, we aim to analyze how smoking may affect the SARS-CoV-2 infection rate. We analyzed sequencing data from lung and oral epithelial samples obtained from The Cancer Genome Atlas (TCGA). We found that the receptor and transmembrane protease necessary for SARS-CoV-2 entry into host cells, ACE2 and TMPRSS2, respectively, were upregulated in smoking samples from both lung and oral epithelial tissue. We then explored the mechanistic hypothesis that smoking may upregulate ACE2 expression through the upregulation of the androgen pathway. ACE2 and TMPRSS2 upregulation were both correlated to androgen pathway enrichment and the specific upregulation of central pathway regulatory genes. These data provide a potential model for the increased susceptibility of smoking patients to COVID-19 and encourage further exploration into the androgen and tobacco upregulation of ACE2 to understand the potential clinical ramifications.


Assuntos
Androgênios/metabolismo , Infecções por Coronavirus/metabolismo , Peptidil Dipeptidase A/genética , Pneumonia Viral/metabolismo , Serina Endopeptidases/genética , Fumar/metabolismo , Regulação para Cima , Células Epiteliais Alveolares/metabolismo , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/genética , Humanos , Mucosa Bucal/metabolismo , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/epidemiologia , Pneumonia Viral/genética , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Serina Endopeptidases/metabolismo , Fumar/epidemiologia , Fumar/genética
6.
Int J Mol Sci ; 21(10)2020 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-32455539

RESUMO

The COVID-19 pandemic is marked by a wide range of clinical disease courses, ranging from asymptomatic to deadly. There have been many studies seeking to explore the correlations between COVID-19 clinical outcomes and various clinical variables, including age, sex, race, underlying medical problems, and social habits. In particular, the relationship between smoking and COVID-19 outcome is controversial, with multiple conflicting reports in the current literature. In this study, we aim to analyze how smoking may affect the SARS-CoV-2 infection rate. We analyzed sequencing data from lung and oral epithelial samples obtained from The Cancer Genome Atlas (TCGA). We found that the receptor and transmembrane protease necessary for SARS-CoV-2 entry into host cells, ACE2 and TMPRSS2, respectively, were upregulated in smoking samples from both lung and oral epithelial tissue. We then explored the mechanistic hypothesis that smoking may upregulate ACE2 expression through the upregulation of the androgen pathway. ACE2 and TMPRSS2 upregulation were both correlated to androgen pathway enrichment and the specific upregulation of central pathway regulatory genes. These data provide a potential model for the increased susceptibility of smoking patients to COVID-19 and encourage further exploration into the androgen and tobacco upregulation of ACE2 to understand the potential clinical ramifications.


Assuntos
Androgênios/metabolismo , Infecções por Coronavirus/metabolismo , Peptidil Dipeptidase A/genética , Pneumonia Viral/metabolismo , Serina Endopeptidases/genética , Fumar/metabolismo , Regulação para Cima , Células Epiteliais Alveolares/metabolismo , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/genética , Humanos , Mucosa Bucal/metabolismo , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/epidemiologia , Pneumonia Viral/genética , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Serina Endopeptidases/metabolismo , Fumar/epidemiologia , Fumar/genética
7.
Nat Commun ; 11(1): 2485, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32427931

RESUMO

Cigarette smoke first interacts with the lung through the cellularly diverse airway epithelium and goes on to drive development of most chronic lung diseases. Here, through single cell RNA-sequencing analysis of the tracheal epithelium from smokers and non-smokers, we generate a comprehensive atlas of epithelial cell types and states, connect these into lineages, and define cell-specific responses to smoking. Our analysis infers multi-state lineages that develop into surface mucus secretory and ciliated cells and then contrasts these to the unique specification of submucosal gland (SMG) cells. Accompanying knockout studies reveal that tuft-like cells are the likely progenitor of both pulmonary neuroendocrine cells and CFTR-rich ionocytes. Our smoking analysis finds that all cell types, including protected stem and SMG populations, are affected by smoking through both pan-epithelial smoking response networks and hundreds of cell-specific response genes, redefining the penetrance and cellular specificity of smoking effects on the human airway epithelium.


Assuntos
Células Epiteliais/metabolismo , Perfilação da Expressão Gênica/métodos , Pulmão/metabolismo , Mucosa Respiratória/metabolismo , Fumar/genética , Traqueia/metabolismo , Animais , Células Cultivadas , Técnicas de Inativação de Genes , Redes Reguladoras de Genes , Humanos , Pulmão/citologia , Camundongos , Células NIH 3T3 , não Fumantes/estatística & dados numéricos , Mucosa Respiratória/citologia , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Fumantes/estatística & dados numéricos , Traqueia/citologia
9.
PLoS Comput Biol ; 16(4): e1007768, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32302299

RESUMO

Mediation analysis with high-dimensional DNA methylation markers is important in identifying epigenetic pathways between environmental exposures and health outcomes. There have been some methodology developments of mediation analysis with high-dimensional mediators. However, high-dimensional mediation analysis methods for time-to-event outcome data are still yet to be developed. To address these challenges, we propose a new high-dimensional mediation analysis procedure for survival models by incorporating sure independent screening and minimax concave penalty techniques for variable selection, with the Sobel and the joint method for significance test of indirect effect. The simulation studies show good performance in identifying correct biomarkers, false discovery rate control, and minimum estimation bias of the proposed procedure. We also apply this approach to study the causal pathway from smoking to overall survival among lung cancer patients potentially mediated by 365,307 DNA methylations in the TCGA lung cancer cohort. Mediation analysis using a Cox proportional hazards model estimates that patients who have serious smoking history increase the risk of lung cancer through methylation markers including cg21926276, cg27042065, and cg26387355 with significant hazard ratios of 1.2497(95%CI: 1.1121, 1.4045), 1.0920(95%CI: 1.0170, 1.1726), and 1.1489(95%CI: 1.0518, 1.2550), respectively. The three methylation sites locate in the three genes which have been showed to be associated with lung cancer event or overall survival. However, the three CpG sites (cg21926276, cg27042065 and cg26387355) have not been reported, which are newly identified as the potential novel epigenetic markers linking smoking and survival of lung cancer patients. Collectively, the proposed high-dimensional mediation analysis procedure has good performance in mediator selection and indirect effect estimation.


Assuntos
Biologia Computacional/métodos , Modelos Estatísticos , Análise de Sobrevida , Adulto , Idoso , Idoso de 80 Anos ou mais , Metilação de DNA/genética , Epigenômica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Pessoa de Meia-Idade , Fumar/genética , Fumar/mortalidade
10.
Tohoku J Exp Med ; 250(2): 109-119, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32115493

RESUMO

Colorectal cancer is the third cause of cancer and the second leading cause of death worldwide. The CD44 gene plays a key role in malignant processes, including growth, survival, epithelial to mesenchymal transition and metastasis. It is also known that some variants as rs187116 (c.67+4883G>A) and rs7116432 (c.2024+779A>G) can modulate the function of the CD44 gene and malignant transformation in several neoplasms. This study aims to explore, for the first time, the association of the CD44 rs187116 and rs7116432 variants in patients with colorectal cancer. Genomic DNA from 250 patients and 250 healthy blood donors were analyzed. The identification of variants was made by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. Association was calculated by the odds ratio (OR) test and multivariate analysis. Individuals carrying the G/A and A/A genotypes for the rs187116 polymorphism showed an increased risk for colorectal cancer (OR = 3.11, 95% CI: 1.87-5.16, P = 0.001 and OR = 3.59, 95% CI: 2.06-6.25, P = 0.001, respectively). After adjusting for age and gender, these same genotypes and the G/G genotype of the rs7116432 polymorphism were associated with TNM stage and tumor location in the colon. Moreover, the A-G (rs187116 and rs7116432) haplotype was associated with increased risk; while, the haplotype G-A (rs187116 and rs7116432) was related with decreased risk. In conclusion, our results suggest that the here analyzed CD44 variants are involved with risk, TNM stage and tumor location in colorectal cancer.


Assuntos
Neoplasias Colorretais/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Receptores de Hialuronatos/genética , Fatores Etários , Alcoolismo/genética , Estudos de Casos e Controles , Neoplasias Colorretais/patologia , Feminino , Frequência do Gene/genética , Haplótipos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Análise Multivariada , Estadiamento de Neoplasias , Polimorfismo de Fragmento de Restrição , Fumar/genética
11.
Croat Med J ; 61(1): 8-17, 2020 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-32118373

RESUMO

AIM: To evaluate the association between spontaneous preterm birth (SPTB) and DNA methyltransferase (DNMT)1, 3A, 3B, and 3L gene polymorphisms, and their contribution to the clinical characteristics of women with SPTB and their newborns. METHODS: This case-control study, conducted in 2018, enrolled 162 women with SPTB and 162 women with term delivery. DNMT1 rs2228611, DNMT3A rs1550117, DNMT3B rs1569686, DNMT3B rs2424913, and DNMT3L rs2070565 single nucleotide polymorphisms were genotyped using polymerase chain reaction and restriction fragment length polymorphism methods. The clinical characteristics included in the analysis were family history of preterm birth, maternal smoking, maternal age, gestational week at delivery, and fetal birth weight. RESULTS: DNMT gene polymorphisms were not significantly associated with SPTB. DNMT3B rs1569686 and rs2424913 minor alleles (T) were significantly more frequent in women with familial PTB than in women with non-familial PTB, increasing the odds for familial PTB 3.30 and 3.54 times under dominant genetic models. They were also significantly more frequent in women with SPTB who smoked before pregnancy, reaching the most significant association under additive genetic models (odds ratio 6.86, 95% confidence interval 2.25-20.86, P<0.001; odds ratio 3.77, 95% confidence interval 1.36-10.52, P=0.011, respectively). CONCLUSIONS: DNMT3B rs1569686 and rs2424913 gene polymorphisms might be associated with positive family history of PTB and smoking status.


Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Nascimento Prematuro/genética , Fumar/genética , Adolescente , Adulto , Estudos de Casos e Controles , Saúde da Família , Feminino , Frequência do Gene , Técnicas de Genotipagem , Idade Gestacional , Humanos , Recém-Nascido , Razão de Chances , Reação em Cadeia da Polimerase , Gravidez , Adulto Jovem
12.
PLoS One ; 15(2): e0222552, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32097409

RESUMO

BACKGROUND: Cigarette smoking is associated with an increased risk of developing respiratory diseases and various types of cancer. Early identification of such unfavorable outcomes in patients who smoke is critical for optimizing personalized medical care. METHODS: Here, we perform a comprehensive analysis using Systems Biology tools of publicly available data from a total of 6 transcriptomic studies, which examined different specimens of lung tissue and/or cells of smokers and nonsmokers to identify potential markers associated with lung cancer. RESULTS: Expression level of 22 genes was capable of classifying smokers from non-smokers. A machine learning algorithm revealed that AKR1B10 was the most informative gene among the 22 differentially expressed genes (DEGs) accounting for the classification of the clinical groups. AKR1B10 expression was higher in smokers compared to non-smokers in datasets examining small and large airway epithelia, but not in the data from a study of sorted alveolar macrophages. Moreover, AKR1B10 expression was relatively higher in lung cancer specimens compared to matched healthy tissue obtained from nonsmoking individuals. Although the overall accuracy of AKR1B10 expression level in distinction between cancer and healthy lung tissue was 76%, with a specificity of 98%, our results indicated that such marker exhibited low sensitivity, hampering its use for cancer screening such specific setting. CONCLUSION: The systematic analysis of transcriptomic studies performed here revealed a potential critical link between AKR1B10 expression, smoking and occurrence of lung cancer.


Assuntos
Aldo-Ceto Redutases/metabolismo , Neoplasias Pulmonares/etiologia , Fumar/efeitos adversos , Biologia de Sistemas/métodos , Transcriptoma , Aldo-Ceto Redutases/genética , Biomarcadores Tumorais , Perfilação da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Fumar/genética
13.
BMC Bioinformatics ; 21(1): 36, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32000657

RESUMO

BACKGROUND: In methylation analyses like epigenome-wide association studies, a high amount of biomarkers is tested for an association between the measured continuous outcome and different covariates. In the case of a continuous covariate like smoking pack years (SPY), a measure of lifetime exposure to tobacco toxins, a spike at zero can occur. Hence, all non-smokers are generating a peak at zero, while the smoking patients are distributed over the other SPY values. Additionally, the spike might also occur on the right side of the covariate distribution, if a category "heavy smoker" is designed. Here, we will focus on methylation data with a spike at the left or the right of the distribution of a continuous covariate. After the methylation data is generated, analysis is usually performed by preprocessing, quality control, and determination of differentially methylated sites, often performed in pipeline fashion. Hence, the data is processed in a string of methods, which are available in one software package. The pipelines can distinguish between categorical covariates, i.e. for group comparisons or continuous covariates, i.e. for linear regression. The differential methylation analysis is often done internally by a linear regression without checking its inherent assumptions. A spike in the continuous covariate is ignored and can cause biased results. RESULTS: We have reanalysed five data sets, four freely available from ArrayExpress, including methylation data and smoking habits reported by smoking pack years. Therefore, we generated an algorithm to check for the occurrences of suspicious interactions between the values associated with the spike position and the non-spike positions of the covariate. Our algorithm helps to decide if a suspicious interaction can be found and further investigations should be carried out. This is mostly important, because the information on the differentially methylated sites will be used for post-hoc analyses like pathway analyses. CONCLUSIONS: We help to check for the validation of the linear regression assumptions in a methylation analysis pipeline. These assumptions should also be considered for machine learning approaches. In addition, we are able to detect outliers in the continuous covariate. Therefore, more statistical robust results should be produced in methylation analysis using our algorithm as a preprocessing step.


Assuntos
Metilação de DNA , Fumar/genética , Adulto , Algoritmos , Análise de Variância , Humanos , Modelos Lineares , Aprendizado de Máquina , Pessoa de Meia-Idade , Fumar/metabolismo
14.
Am J Respir Crit Care Med ; 201(9): 1099-1109, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31995399

RESUMO

Rationale: Smoking results in at least a decade lower life expectancy. Mortality among current smokers is two to three times as high as never smokers. DNA methylation is an epigenetic modification of the human genome that has been associated with both cigarette smoking and mortality.Objectives: We sought to identify DNA methylation marks in blood that are predictive of mortality in a subset of the COPDGene (Genetic Epidemiology of COPD) study, representing 101 deaths among 667 current and former smokers.Methods: We assayed genome-wide DNA methylation in non-Hispanic white smokers with and without chronic obstructive pulmonary disease (COPD) using blood samples from the COPDGene enrollment visit. We tested whether DNA methylation was associated with mortality in models adjusted for COPD status, age, sex, current smoking status, and pack-years of cigarette smoking. Replication was performed in a subset of 231 individuals from the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) study.Measurements and Main Results: We identified seven CpG sites associated with mortality (false discovery rate < 20%) that replicated in the ECLIPSE cohort (P < 0.05). None of these marks were associated with longitudinal lung function decline in survivors, smoking history, or current smoking status. However, differential methylation of two replicated PIK3CD (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta) sites were associated with lung function at enrollment (P < 0.05). We also observed associations between DNA methylation and gene expression for the PIK3CD sites.Conclusions: This study is the first to identify variable DNA methylation associated with all-cause mortality in smokers with and without COPD. Evaluating predictive epigenomic marks of smokers in peripheral blood may allow for targeted risk stratification and aid in delivery of future tailored therapeutic interventions.


Assuntos
Biomarcadores Tumorais/sangue , Metilação de DNA , Valor Preditivo dos Testes , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/mortalidade , Fumar/genética , Fumar/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Epigênese Genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
15.
Gene ; 724: 143684, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30898706

RESUMO

AIM: The long noncoding RNAs (lncRNAs) have gradually been reported to be an important class of RNAs with pivotal roles in the development and progression of myocardial infarction (MI). In this study, we hypothesized that genetic variant of cyclin-dependent kinase inhibitor 2B antisense RNA (ANRIL) and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) may affect the prognosis of MI patients. METHODS: The study included 401 Han Chinese MI patients and 409 controls. Four lncRNA tag single nucleotide polymorphisms (SNPs)-ANRIL rs9632884 and rs1537373, MALAT1 rs619586 and rs3200401-were selected. SNP genotyping was performed by an improved multiplex ligation detection reaction assay. RESULTS: rs9632884 and rs3200401 SNPs were significantly associated with lipid levels in both controls and MI patients (P < 0.003-0.046). Several SNPs interacted with sex and age to modify total cholesterol, low-density lipoprotein cholesterol, and creatinine levels to modify the risk of MI. No association between the lncRNAs SNPs and susceptibility to MI was found (P > 0.05 for all). CONCLUSIONS: Taken together, this study provides additional evidence that genetic variation of the ANRIL rs9632884 and MALAT1 rs3200401 can mediate lipid levels in MI patients.


Assuntos
Colesterol/sangue , Infarto do Miocárdio/genética , RNA Longo não Codificante/genética , Triglicerídeos/sangue , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Colesterol/genética , Doença da Artéria Coronariana/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Hipertensão/genética , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Polimorfismo de Nucleotídeo Único , Fumar/genética , Triglicerídeos/genética
16.
Respir Res ; 20(1): 268, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31791327

RESUMO

BACKGROUND: Active smoking is the main risk factor for COPD. Here, epigenetic mechanisms may play a role, since cigarette smoking is associated with differential DNA methylation in whole blood. So far, it is unclear whether epigenetics also play a role in subjects with COPD who never smoked. Therefore, we aimed to identify differential DNA methylation associated with lung function in never smokers. METHODS: We determined epigenome-wide DNA methylation levels of 396,243 CpG-sites (Illumina 450 K) in blood of never smokers in four independent cohorts, LifeLines COPD&C (N = 903), LifeLines DEEP (N = 166), Rotterdam Study (RS)-III (N = 150) and RS-BIOS (N = 206). We meta-analyzed the cohort-specific methylation results to identify differentially methylated CpG-sites with FEV1/FVC. Expression Quantitative Trait Methylation (eQTM) analysis was performed in the Biobank-based Integrative Omics Studies (BIOS). RESULTS: A total of 36 CpG-sites were associated with FEV1/FVC in never smokers at p-value< 0.0001, but the meta-analysis did not reveal any epigenome-wide significant CpG-sites. Of interest, 35 of these 36 CpG-sites have not been associated with lung function before in studies including subjects irrespective of smoking history. Among the top hits were cg10012512, cg02885771, annotated to the gene LTV1 Ribosome Biogenesis factor (LTV1), and cg25105536, annotated to Kelch Like Family Member 32 (KLHL32). Moreover, a total of 11 eQTMS were identified. CONCLUSIONS: With the identification of 35 CpG-sites that are unique for never smokers, our study shows that DNA methylation is also associated with FEV1/FVC in subjects that never smoked and therefore not merely related to smoking.


Assuntos
Metilação de DNA/genética , Epigênese Genética/genética , Estudo de Associação Genômica Ampla/métodos , Doença Pulmonar Obstrutiva Crônica/genética , Adulto , Estudos de Coortes , Ilhas de CpG/genética , Feminino , Volume Expiratório Forçado/genética , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Valores de Referência , Fumantes , Fumar/genética
17.
Genes (Basel) ; 10(12)2019 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-31766738

RESUMO

Gene Networks (GN), have emerged as an useful tool in recent years for the analysis of different diseases in the field of biomedicine. In particular, GNs have been widely applied for the study and analysis of different types of cancer. In this context, Lung carcinoma is among the most common cancer types and its short life expectancy is partly due to late diagnosis. For this reason, lung cancer biomarkers that can be easily measured are highly demanded in biomedical research. In this work, we present an application of gene co-expression networks in the modelling of lung cancer gene regulatory networks, which ultimately served to the discovery of new biomarkers. For this, a robust GN inference was performed from microarray data concomitantly using three different co-expression measures. Results identified a major cluster of genes involved in SRP-dependent co-translational protein target to membrane, as well as a set of 28 genes that were exclusively found in networks generated from cancer samples. Amongst potential biomarkers, genes N C K A P 1 L and D M D are highlighted due to their implications in a considerable portion of lung and bronchus primary carcinomas. These findings demonstrate the potential of GN reconstruction in the rational prediction of biomarkers.


Assuntos
Biomarcadores Tumorais/genética , Redes Reguladoras de Genes , Neoplasias Pulmonares/genética , Algoritmos , Biologia Computacional , Distrofina/genética , Expressão Gênica , Humanos , Pulmão/metabolismo , Proteínas de Membrana/genética , Mutação , Fumar/genética
18.
Hum Genomics ; 13(1): 59, 2019 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-31779701

RESUMO

BACKGROUND: Tobacco smoking induces immunomodulatory and pro-inflammatory effects associated with transcriptome changes in monocytes and other immune cell types. While smoking is prevalent in HIV-infected (HIV+) individuals, few studies have investigated its effects on gene expression in this population. Here, we report whole-transcriptome analyses of 125 peripheral blood monocyte samples from ART-treated HIV+ and uninfected (HIV-) men enrolled in the Multicenter AIDS Cohort Study (MACS) (n = 25 HIV+ smokers, n = 60 HIV+ non-smokers, n = 40 HIV- non-smoking controls). Gene expression profiling was performed using Illumina HumanHT-12 Expression BeadChip microarrays. Differential expression analysis was performed with weighted linear regression models using the R limma package, followed by functional enrichment and Ingenuity Pathway analyses. RESULTS: A total of 286 genes were differentially expressed in monocytes from HIV+ smokers compared with HIV- non-smokers; upregulated genes (n = 180) were enriched for immune and interferon response, chemical/stress response, mitochondria, and extracellular vesicle gene ontology (GO) terms. Expression of genes related to immune/interferon responses (AIM2, FCGR1A-B, IFI16, SP100), stress/chemical responses (APAF1, HSPD1, KLF4), and mitochondrial function (CISD1, MTHFD2, SQOR) was upregulated in HIV+ non-smokers and further increased in HIV+ smokers. Gene expression changes associated with smoking in previous studies of human monocytes were also observed (SASH1, STAB1, PID1, MMP25). Depressive symptoms (CES-D scores ≥ 16) were more prevalent in HIV+ tobacco smokers compared with HIV+ and HIV- non-smokers (50% vs. 26% and 13%, respectively; p = 0.007), and upregulation of immune/interferon response genes, including IFI35, IFNAR1, OAS1-2, STAT1, and SP100, was associated with depressive symptoms in logistic regression models adjusted for HIV status and smoking (p < 0.05). Network models linked the Stat1-mediated interferon pathway to transcriptional regulator Klf4 and smoking-associated toll-like receptor scaffolding protein Sash1, suggesting inter-relationships between smoking-associated genes, control of monocyte differentiation, and interferon-mediated inflammatory responses. CONCLUSIONS: This study characterizes immune, interferon, stress response, and mitochondrial-associated gene expression changes in monocytes from HIV+ tobacco smokers, and identifies augmented interferon and stress responses associated with depressive symptoms. These findings help to explain complex interrelationships between pro-inflammatory effects of HIV and smoking, and their combined impact on comorbidities prevalent in HIV+ individuals.


Assuntos
Terapia Antirretroviral de Alta Atividade , Depressão/psicologia , Perfilação da Expressão Gênica , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , Interferons/genética , Fumar/psicologia , Estresse Psicológico/genética , Adulto , Idoso , Depressão/sangue , Regulação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Infecções por HIV/sangue , Infecções por HIV/psicologia , Soropositividade para HIV/tratamento farmacológico , Soropositividade para HIV/genética , Soropositividade para HIV/psicologia , Humanos , Interferons/metabolismo , Masculino , Pessoa de Meia-Idade , Transdução de Sinais/genética , Fumar/genética
19.
Am J Respir Cell Mol Biol ; 61(6): 678-688, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31486667

RESUMO

Chronic airway inflammation from recurring exposures to noxious environmental stimuli results in a progressive and irreversible airflow limitation and the lung parenchymal damage that characterizes chronic obstructive pulmonary disease (COPD). The large variability observed in the onset and progression of COPD is primarily driven by complex gene-environment interactions. The transcriptomic and epigenetic memory potential of lung epithelial and innate immune cells drive responses, such as mucus hyperreactivity and airway remodeling, that are tightly regulated by various molecular mechanisms, for which several candidate susceptibility genes have been described. However, the recently described noncoding RNA species, in particular the long noncoding RNAs, may also have an important role in modulating pulmonary responses to chronic inhalation of toxic substances and the development of COPD. This review outlines the features of long noncoding RNAs that have been implicated in regulating the airway inflammatory responses to cigarette smoke exposure and their possible association with COPD pathogenesis. As COPD continues to debilitate the increasingly aging population and contribute to higher morbidity and mortality rates worldwide, the search for better biomarkers and alternative therapeutic options is pivotal.


Assuntos
Doença Pulmonar Obstrutiva Crônica/genética , RNA Longo não Codificante/fisiologia , Transcriptoma , Envelhecimento/genética , Envelhecimento/metabolismo , Poluentes Atmosféricos/efeitos adversos , Animais , Biomarcadores , Senescência Celular , Células Epiteliais/metabolismo , Regulação da Expressão Gênica , Interação Gene-Ambiente , Humanos , Imunidade Inata/genética , Inflamação/genética , Inflamação/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/crescimento & desenvolvimento , Pulmão/metabolismo , Camundongos , Mitocôndrias/patologia , Modelos Animais , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/patologia , RNA Longo não Codificante/genética , Fumaça/efeitos adversos , Lesão por Inalação de Fumaça/complicações , Fumar/efeitos adversos , Fumar/genética , Tabaco
20.
Genet Epidemiol ; 43(8): 996-1017, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31544985

RESUMO

In genetic association studies, joint modeling of related traits/phenotypes can utilize the correlation between them and thereby provide more power and uncover additional information about genetic etiology. Moreover, detecting rare genetic variants are of current scientific interest as a key to missing heritability. Logistic Bayesian LASSO (LBL) has been proposed recently to detect rare haplotype variants using case-control data, that is, a single binary phenotype. As there is currently no haplotype association method that can handle multiple binary phenotypes, we extend LBL to fill this gap. We develop a bivariate model by using a latent variable to induce correlation between the two outcomes. We carry out extensive simulations to investigate the bivariate LBL and compare with the univariate LBL. The bivariate LBL performs better or similar to the univariate LBL in most settings. It has the highest gain in power when a haplotype is associated with both traits and it affects at least one trait in a direction opposite to the direction of the correlation between the traits. We analyze two data sets-Genetic Analysis Workshop 19 sequence data on systolic and diastolic blood pressures and a genome-wide association data set on lung cancer and smoking and detect several associated rare haplotypes.


Assuntos
Estudo de Associação Genômica Ampla , Haplótipos , Modelos Genéticos , Teorema de Bayes , Estudos de Casos e Controles , Humanos , Neoplasias Pulmonares/genética , Fenótipo , Fumar/genética
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