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1.
Artigo em Inglês | MEDLINE | ID: mdl-34205269

RESUMO

Previous studies have identified variants in genes encoding proteins associated with the degree of addiction, smoking onset, and cessation. We aimed to describe thirty-one single nucleotide polymorphisms (SNPs) in seven candidate genomic regions spanning six genes associated with tobacco-smoking in a cross-sectional study from two different interventions for quitting smoking: (1) thirty-eight smokers were recruited via multimedia to participate in e-Decídete! program (e-Dec) and (2) ninety-four attended an institutional smoking cessation program on-site. SNPs genotyping was done by real-time PCR using TaqMan probes. The analysis of alleles and genotypes was carried out using the EpiInfo v7. on-site subjects had more years smoking and tobacco index than e-Dec smokers (p < 0.05, both); in CYP2A6 we found differences in the rs28399433 (p < 0.01), the e-Dec group had a higher frequency of TT genotype (0.78 vs. 0.35), and TG genotype frequency was higher in the on-site group (0.63 vs. 0.18), same as GG genotype (0.03 vs. 0.02). Moreover, three SNPs in NRXN1, two in CHRNA3, and two in CHRNA5 had differences in genotype frequencies (p < 0.01). Cigarettes per day were different (p < 0.05) in the metabolizer classification by CYP2A6 alleles. In conclusion, subjects attending a mobile smoking cessation intervention smoked fewer cigarettes per day, by fewer years, and by fewer cumulative pack-years. There were differences in the genotype frequencies of SNPs in genes related to nicotine metabolism and nicotine dependence. Slow metabolizers smoked more cigarettes per day than intermediate and normal metabolizers.


Assuntos
Abandono do Hábito de Fumar , Tabagismo , Estudos Transversais , Citocromo P-450 CYP2A6/genética , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Fumar/genética , Tabagismo/genética
2.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071592

RESUMO

Lung cancer remains the leading cause of cancer related mortality worldwide. We aimed to test whether a simple blood biomarker (extracellular vesicle miRNAs) can discriminate between cases with and without lung cancer. METHODS: plasma extracellular vesicles (EVs) were isolated from four cohorts (n = 20 in each): healthy non-smokers, healthy smokers, lung cancer, and stable COPD participants. EV miRNA expression was evaluated using the miRCURY LNA miRNA Serum/Plasma assay for 179 specific targets. Significantly dysregulated miRNAs were assessed for discriminatory power using ROC curve analysis. RESULTS: 15 miRNAs were differentially expressed between lung cancer and healthy non-smoking participants, with the greatest single miRNA being miR-205-5p (AUC 0.850), improving to AUC 0.993 in combination with miR-199a-5p. Moreover, 26 miRNAs were significantly dysregulated between lung cancer and healthy smoking participants, with the greatest single miRNA being miR-497-5p (AUC 0.873), improving to AUC 0.953 in combination with miR-22-5p; 14 miRNAs were significantly dysregulated between lung cancer and stable COPD participants, with the greatest single miRNA being miR-27a-3p (AUC 0.803), with two other miRNAs (miR-106b-3p and miR-361-5p) further improving discriminatory power (AUC 0.870). CONCLUSION: this case control study suggests miRNAs in EVs from plasma holds key biological information specific for lung cancer and warrants further prospective assessment.


Assuntos
Biomarcadores Tumorais/genética , Vesículas Extracelulares/genética , Neoplasias Pulmonares/genética , MicroRNAs/genética , Doença Pulmonar Obstrutiva Crônica/genética , Fumar/genética , Idoso , Biomarcadores Tumorais/sangue , Detecção Precoce de Câncer/métodos , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Neoplasias Pulmonares/diagnóstico , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Curva ROC
3.
Genome Med ; 13(1): 66, 2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33883027

RESUMO

BACKGROUND: The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression. METHODS: We analyzed RNA-sequencing data from bronchial epithelial brushings obtained from uninfected individuals. We related ACE2 gene expression to host and environmental factors in the SPIROMICS cohort of smokers with and without chronic obstructive pulmonary disease (COPD) and replicated these associations in two asthma cohorts, SARP and MAST. To identify airway biology beyond ACE2 binding that may contribute to increased susceptibility, we used gene set enrichment analyses to determine if gene expression changes indicative of a suppressed airway immune response observed early in SARS-CoV-2 infection are also observed in association with host factors. To identify host genetic variants affecting COVID-19 susceptibility in SPIROMICS, we performed expression quantitative trait (eQTL) mapping and investigated the phenotypic associations of the eQTL variants. RESULTS: We found that ACE2 expression was higher in relation to active smoking, obesity, and hypertension that are known risk factors of COVID-19 severity, while an association with interferon-related inflammation was driven by the truncated, non-binding ACE2 isoform. We discovered that expression patterns of a suppressed airway immune response to early SARS-CoV-2 infection, compared to other viruses, are similar to patterns associated with obesity, hypertension, and cardiovascular disease, which may thus contribute to a COVID-19-susceptible airway environment. eQTL mapping identified regulatory variants for genes implicated in COVID-19, some of which had pheWAS evidence for their potential role in respiratory infections. CONCLUSIONS: These data provide evidence that clinically relevant variation in the expression of COVID-19-related genes is associated with host factors, environmental exposures, and likely host genetic variation.


Assuntos
Brônquios , COVID-19/genética , Mucosa Respiratória , SARS-CoV-2 , Adulto , Idoso , Idoso de 80 Anos ou mais , Enzima de Conversão de Angiotensina 2/genética , Asma/genética , COVID-19/imunologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/imunologia , Expressão Gênica , Variação Genética , Humanos , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/imunologia , Doença Pulmonar Obstrutiva Crônica/genética , Locos de Características Quantitativas , Fatores de Risco , Fumar/genética
4.
Orphanet J Rare Dis ; 16(1): 127, 2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33706792

RESUMO

BACKGROUND: Leber's hereditary optic neuropathy (LHON) is a rare mitochondrial disorder, characterized by acute or subacute bilateral vision loss, frequently leading to significant chronic disability, mainly in young people. The causal LHON mutations of the mitochondrial DNA have incomplete penetrance, with the highest risk of disease manifestation for male mutation carriers in the second and third decades of life. Here we evaluated smoking, alcohol drinking habits, health-related quality of life (QOL) and psychiatric comorbidities in a cohort of LHON patients and asymptomatic mutation carriers from a tertiary referral centre. METHODS: Cross-sectional analysis of the ongoing Munich LHON prospective cohort study. Participants included all LHON patients and asymptomatic LHON mutation carriers older than 16 years at baseline, who were recruited between February 2014 and June 2015 and consented to participate. General, neurological and ophthalmological investigations were performed, including validated questionnaires on smoking, alcohol drinking habits, depressive symptoms and health-related QOL. RESULTS: Seventy-one participants were included, 34 LHON patients (82% male) and 37 asymptomatic mutation carriers (19% male). Median age at baseline was 36 years (range 18-75 years). For LHON patients, median age at visual loss onset was 27 years (9 to 72 years). Smoking is more frequent in LHON patients than asymptomatic LHON mutation carriers, and significantly more frequent in both groups than in the general population. Sixty percent of LHON patients, who smoked at disease onset, stopped or significantly reduced smoking after visual loss onset, yet 40% of LHON patients continued to smoke at study baseline. Excessive alcohol consumption is more frequent in male LHON patients than in LHON asymptomatic and more frequent than in the male general population. Further, female asymptomatic LHON mutation carriers are at risk for depression and worse mental QOL scores. CONCLUSIONS: Given the high prevalence of smoking and excessive drinking in LHON mutation carriers, implementing effective measures to reduce these risk factors may have a significant impact in reducing LHON disease conversion risk. The underrecognized prevalence of mental health issues in this population of LHON mutation carriers highlights the need for awareness and more timely diagnosis, which may lead to improved outcomes.


Assuntos
Atrofia Óptica Hereditária de Leber , Qualidade de Vida , Adolescente , Adulto , Idoso , Estudos Transversais , DNA Mitocondrial/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Atrofia Óptica Hereditária de Leber/epidemiologia , Atrofia Óptica Hereditária de Leber/genética , Estudos Prospectivos , Fumar/genética , Adulto Jovem
5.
PLoS Med ; 18(3): e1003555, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33735204

RESUMO

BACKGROUND: Tobacco smoking and e-cigarette use are strongly associated, but it is currently unclear whether this association is causal, or due to shared factors that influence both behaviours such as a shared genetic liability. The aim of this study was to investigate whether polygenic risk scores (PRS) for smoking initiation are associated with ever use of e-cigarettes. METHODS AND FINDINGS: Smoking initiation PRS were calculated for young adults (N = 7,859, mean age = 24 years, 51% male) of European ancestry in the Avon Longitudinal Study of Parents and Children, a prospective birth cohort study initiated in 1991. PRS were calculated using the GWAS & Sequencing Consortium of Alcohol and Nicotine use (GSCAN) summary statistics. Five thresholds ranging from 5 × 10-8 to 0.5 were used to calculate 5 PRS for each individual. Using logistic regression, we investigated the association between smoking initiation PRS and the main outcome, self-reported e-cigarette use (n = 2,894, measured between 2016 and 2017), as well as self-reported smoking initiation and 8 negative control outcomes (socioeconomic position at birth, externalising disorders in childhood, and risk-taking in young adulthood). A total of 878 young adults (30%) had ever used e-cigarettes at 24 years, and 150 (5%) were regular e-cigarette users at 24 years. We observed positive associations of similar magnitude between smoking initiation PRS (created using the p < 5 × 10-8 threshold) and both smoking initiation (odds ratio (OR) = 1.29, 95% CI 1.19 to 1.39, p < 0.001) and ever e-cigarette use (OR = 1.24, 95% CI 1.14 to 1.34, p < 0.001) by the age of 24 years, indicating that a genetic predisposition to smoking initiation is associated with an increased risk of using e-cigarettes. At lower p-value thresholds, we observed an association between smoking initiation PRS and ever e-cigarette use among never smokers. We also found evidence of associations between smoking initiation PRS and some negative control outcomes, particularly when less stringent p-value thresholds were used to create the PRS, but also at the strictest threshold (e.g., gambling, number of sexual partners, conduct disorder at 7 years, and parental socioeconomic position at birth). However, this study is limited by the relatively small sample size and potential for collider bias. CONCLUSIONS: Our results indicate that there may be a shared genetic aetiology between smoking and e-cigarette use, and also with socioeconomic position, externalising disorders in childhood, and risky behaviour more generally. This indicates that there may be a common genetic vulnerability to both smoking and e-cigarette use, which may reflect a broad risk-taking phenotype.


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina/estatística & dados numéricos , Fumar/genética , Fumar Tabaco/epidemiologia , Vaping/epidemiologia , Estudos de Coortes , Inglaterra/epidemiologia , Humanos , Fatores de Risco , Adulto Jovem
6.
J Psychiatr Res ; 137: 215-224, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33691233

RESUMO

While 17% of US adults use tobacco regularly, smoking rates among persons with schizophrenia are upwards of 60%. Research supports a shared etiological basis for smoking and schizophrenia, including findings from genome-wide association studies (GWAS). However, few studies have directly tested whether the same or distinct genetic variants also influence smoking behavior among schizophrenia cases. Using data from the Psychiatric Genomics Consortium (PGC) study of schizophrenia (35476 cases, 46839 controls), we estimated genetic correlations between these traits and tested whether polygenic risk scores (PRS) constructed from the results of smoking behaviors GWAS were associated with schizophrenia risk or smoking behaviors among schizophrenia cases. Results indicated significant genetic correlations of schizophrenia with smoking initiation (rg = 0.159; P = 5.05 × 10-10), cigarettes-smoked-per-day (rg = 0.094; P = 0.006), and age-of-onset of smoking (rg = 0.10; P = 0.009). Comparing smoking behaviors among schizophrenia cases to the general population, we observe positive genetic correlations for smoking initiation (rg = 0.624, P = 0.002) and cigarettes-smoked-per-day (rg = 0.689, P = 0.120). Similarly, TAG-based PRS for smoking initiation and cigarettes-smoked-per-day were significantly associated with smoking initiation (P = 3.49 × 10-5) and cigarettes-smoked-per-day (P = 0.007) among schizophrenia cases. We performed the first GWAS of smoking behavior among schizophrenia cases and identified a novel association with cigarettes-smoked-per-day upstream of the TMEM106B gene on chromosome 7p21.3 (rs148253479, P = 3.18 × 10-8, n = 3520). Results provide evidence of a partially shared genetic basis for schizophrenia and smoking behaviors. Additionally, genetic risk factors for smoking behaviors were largely shared across schizophrenia and non-schizophrenia populations. Future research should address mechanisms underlying these associations to aid both schizophrenia and smoking treatment and prevention efforts.


Assuntos
Estudo de Associação Genômica Ampla , Esquizofrenia , Adulto , Predisposição Genética para Doença/genética , Genômica , Humanos , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/epidemiologia , Esquizofrenia/genética , Fumar/genética
7.
Mol Biol Rep ; 48(2): 1103-1114, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33559820

RESUMO

Few studies evaluate interrelationships between periodontitis (P) and Type 2 Diabetes Mellitus (T2DM). The aim of this study is to investigate the genetic susceptibility to periodontitis alone, or concomitant with T2DM (as comorbidities), analyzing single nucleotide polymorphisms (SNPs) in the Interleukin 17 alpha (IL17A) gene, considering the biochemical profile and smoking habits on the subjects' periodontal status. We investigated 879 individuals divided into: T2DM subjects also affected by severe or moderate periodontitis (T2DM-P, n = 199); non-diabetics with severe or moderate periodontitis (PERIODONTITIS, n = 342); and healthy subjects (HEALTHY, n = 338). Subjects underwent complete periodontal examination, history of smoking habits, glycemic and lipid biochemical evaluation. DNA from buccal cells was utilized to genotype the SNPs rs2275913, rs3819024 and rs10484879. The impact of the subjects' biochemical profile was analyzed in their periodontal status. Each SNP was analyzed independently, and as haplotypes, by multiple logistic regressions, adjusted for covariates, and also stratifying the groups by age, sex and smoking habits. Independently of the periodontitis degree, poorly-controlled T2DM subjects showed worse glycemic and lipid profile. Multiple logistic regressions demonstrated that smokers and former-smokers carrying the GG genotype of rs3819024 seemed to have higher risk for T2DM-Periodontitis (OR = 6.33; 95% CI = 1.26-31.77, p = 0.02), and mainly for T2DM alone (OR = 5.11; 95% CI = 1.37-19.06, p = 0.01), than never smokers. We found the potential effect of smoking habits in the association of IL17A-rs3819024-GG with diseased phenotypes. Because the observed wide confidence intervals, further studies enrolling larger populations, and SNPs' functional evaluations are needed to better understand our findings.


Assuntos
Diabetes Mellitus Tipo 2/genética , Interleucina-17/genética , Periodontite/genética , Fumar/genética , Adulto , Idoso , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/patologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Haplótipos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mucosa Bucal/metabolismo , Periodontite/epidemiologia , Periodontite/patologia , Polimorfismo de Nucleotídeo Único/genética , Fumar/epidemiologia
8.
Psychopharmacology (Berl) ; 238(4): 1171-1181, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33506304

RESUMO

RATIONALE: There is strong evidence that nicotine can enhance cognitive functions and growing evidence that this effect may be larger in young healthy APOE ε4 carriers. However, the moderating effects of the APOE ε4 allele on cognitive impairments caused by nicotine deprivation in chronic smokers have not yet been studied with brain indices. OBJECTIVE: We sought to determine whether young female carriers of the APOE ε4 allele, relative to noncarriers, would exhibit larger abstinence-induced decreases in P3b amplitude during a two-stimulus auditory oddball task. METHODS: We compared parietal P3bs in female chronic smokers with either APOE ε3/ε3 (n = 54) or ε3/ε4 (n = 20) genotype under nicotine-sated conditions and after 12-17-h nicotine deprivation. RESULTS: Nicotine deprivation significantly reduced P3b amplitudes in APOE ε4 carriers, but not in APOE-ε3/ε3 individuals, such that the difference seen prior to nicotine deprivation was eliminated. CONCLUSIONS: The results suggest that subjects with the APOE ε4 allele are more sensitive to nicotine, which could influence smoking patterns, the risk for nicotine dependence, and the cognitive effects of nicotine use in these individuals.


Assuntos
Apolipoproteína E3/genética , Eletroencefalografia/efeitos dos fármacos , Abandono do Hábito de Fumar/psicologia , Fumar/psicologia , Estimulação Acústica , Adulto , Feminino , Genótipo , Heterozigoto , Humanos , Masculino , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Lobo Parietal/fisiopatologia , Desempenho Psicomotor/efeitos dos fármacos , Fumar/genética , Adulto Jovem
9.
Thorax ; 76(3): 272-280, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33419953

RESUMO

IMPORTANCE: While cholinergic receptor nicotinic alpha 5 (CHRNA5) variants have been linked to lung cancer, chronic obstructive pulmonary disease (COPD) and smoking addiction in case-controls studies, their corelationship is not well understood and requires retesting in a cohort study. OBJECTIVE: To re-examine the association between the CHRNA5 variant (rs16969968 AA genotype) and the development of lung cancer, relative to its association with COPD and smoking. METHODS: In 9270 Non-Hispanic white subjects from the National Lung Screening Trial, a substudy of high-risk smokers were followed for an average of 6.4 years. We compared CHRNA5 genotype according to baseline smoking exposure, lung function and COPD status. We also compared the lung cancer incidence rate, and used multiple logistic regression and mediation analysis to examine the role of the AA genotype of the CHRNA5 variant in smoking exposure, COPD and lung cancer. RESULTS: As previously reported, we found the AA high-risk genotype was associated with lower lung function (p=0.005), greater smoking intensity (p<0.001), the presence of COPD (OR 1.28 (95% CI 1.10 to 1.49) p=0.0015) and the development of lung cancer (HR 1.41, (95% CI 1.03 to 1.93) p=0.03). In a mediation analyses, the AA genotype was independently associated with smoking intensity (OR 1.42 (95% CI 1.25 to 1.60, p<0.0001), COPD (OR 1.25, (95% CI 1.66 to 2.53), p=0.0015) and developing lung cancer (OR 1.37, (95% CI 1.03 to 1.82) p=0.03). CONCLUSION: In this large-prospective study, we found the CHRNA5 rs 16 969 968 AA genotype to be independently associated with smoking exposure, COPD and lung cancer (triple whammy effect).


Assuntos
Predisposição Genética para Doença , Neoplasias Pulmonares/genética , Proteínas do Tecido Nervoso/genética , Doença Pulmonar Obstrutiva Crônica/genética , Receptores Nicotínicos/genética , Fumar/genética , Feminino , Genótipo , Humanos , Incidência , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , RNA/genética , Receptores Nicotínicos/metabolismo , Fatores de Risco , Fumar/metabolismo , Estados Unidos/epidemiologia
10.
Toxicol Appl Pharmacol ; 412: 115389, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33385404

RESUMO

Cytochrome P450 (CYP) gene expression exhibits large interindividual variation attributable to diverse regulatory factors including microRNAs (miRNAs) and hepatic transcription factors (TFs). We used real-time qPCR with 106 human liver samples to measure the expression and interindividual variation of seven miRNAs and four TFs that have been reported to regulate the expression of CYPs; we also identified factors that influence their expression. The results show that expression of the seven miRNAs and the four TFs exhibits a non-normal distribution and the expression variability is high (89- to 618-fold for miRNA and 12- to 85-fold for TFs). Age contributed to the interindividual variation for miR-148a, miR-27b and miR-34a, whereas cigarette smoking and alcohol consumption significantly reduced HNF4α mRNA levels. Association analysis showed significant correlations among the seven miRNAs as well as the four TFs. Furthermore, we systematically evaluated the impact of the seven miRNAs and four TFs on protein content, mRNA levels, translation efficiency and activity of 10 CYPs. The results show that numerous associations (positive and negative) are present between the seven miRNAs or the four TFs and the 10 CYP phenotypes (as indicated by mRNA, protein and activity); specifically, miR-27b, miR-34a and all four TFs played key roles in the interindividual variation of CYPs. Our results extend previous findings and suggest that miR-27b and miR-34a may be potential direct or indirect master regulators of CYP expression and thereby contribute to the interindividual variations in CYP-mediated drug metabolism.


Assuntos
Variação Biológica da População , Sistema Enzimático do Citocromo P-450/genética , Fígado/enzimologia , MicroRNAs/genética , Fatores de Transcrição/genética , Fatores Etários , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Feminino , Regulação Enzimológica da Expressão Gênica , Heterogeneidade Genética , Fator 4 Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/metabolismo , Humanos , Isoenzimas , Masculino , MicroRNAs/metabolismo , Fenótipo , Fumar/genética , Fumar/metabolismo , Fatores de Transcrição/metabolismo
11.
Hum Genet ; 140(6): 849-861, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33385171

RESUMO

Mitochondrial (MT) dysfunction is a hallmark of aging and has been associated with most aging-related diseases as well as immunological processes. However, little is known about aging, lifestyle and genetic factors influencing mitochondrial DNA (mtDNA) abundance. In this study, mtDNA abundance was estimated from the weighted intensities of probes mapping to the MT genome in 295,150 participants from the UK Biobank. We found that the abundance of mtDNA was significantly elevated in women compared to men, was negatively correlated with advanced age, higher smoking exposure, greater body-mass index, higher frailty index as well as elevated red and white blood cell count and lower mortality. In addition, several biochemistry markers in blood-related to cholesterol metabolism, ion homeostasis and kidney function were found to be significantly associated with mtDNA abundance. By performing a genome-wide association study, we identified 50 independent regions genome-wide significantly associated with mtDNA abundance which harbour multiple genes involved in the immune system, cancer as well as mitochondrial function. Using mixed effects models, we estimated the SNP-heritability of mtDNA abundance to be around 8%. To investigate the consequence of altered mtDNA abundance, we performed a phenome-wide association study and found that mtDNA abundance is involved in risk for leukaemia, hematologic diseases as well as hypertension. Thus, estimating mtDNA abundance from genotyping arrays has the potential to provide novel insights into age- and disease-relevant processes, particularly those related to immunity and established mitochondrial functions.


Assuntos
Envelhecimento/genética , DNA Mitocondrial/genética , Genoma Mitocondrial , Doenças Hematológicas/genética , Hipertensão/genética , Leucemia/genética , Idoso , Envelhecimento/imunologia , Bancos de Espécimes Biológicos , Índice de Massa Corporal , DNA Mitocondrial/imunologia , Contagem de Eritrócitos , Feminino , Estudo de Associação Genômica Ampla , Doenças Hematológicas/epidemiologia , Doenças Hematológicas/imunologia , Doenças Hematológicas/patologia , Humanos , Hipertensão/epidemiologia , Hipertensão/imunologia , Hipertensão/patologia , Imunidade Inata , Padrões de Herança/imunologia , Leucemia/epidemiologia , Leucemia/imunologia , Leucemia/patologia , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/genética , Mitocôndrias/imunologia , Polimorfismo de Nucleotídeo Único , Fumar/genética , Fumar/fisiopatologia , Reino Unido/epidemiologia
12.
PLoS One ; 16(1): e0245133, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33481818

RESUMO

The tumor suppressor gene TP53 and its downstream genes P21 and MDM2 play crucial roles in combating DNA damage at the G1/S cell cycle checkpoint. Polymorphisms in these genes can lead to the development of various diseases. This study was conducted to examine a potential association between tobacco substance usage (TSU) and single-nucleotide polymorphism (SNP) at the exon regions of the P53, P21, and MDM2 genes by comparing populations of smokers and non-smokers from Saudi Arabia. P53 rs1042522 (C/G), P21 rs1801270 (A/C), and MDM2 rs769412 (A/G) were investigated by genotyping 568 blood specimens: 283 from male/female smokers and 285 from male/female non-smokers. The results obtained from the smokers and their control non-smokers were compared according to age, sex, duration of smoking, and type of TSU. Heterozygous CG, homozygous GG, and CG+GG genotypes, as well as the G allele of rs1042522 were significantly associated with TSU in Saudi smokers compared with non-smokers. The C allele frequency of rs1801270 was also associated with TSU in smokers (OR = 1.33, p = 0.049) in comparison with non-smokers, in younger smokers (≤29 years) (OR = 1.556, p = 0.03280) in comparison with non-smokers of the same age, in smokers who had smoked cigarettes for seven years or less (OR = 1.596, p = 0.00882), and in smokers who had consumed shisha (OR = 1.608, p = 0.04104) in comparison with the controls. However, the genotypic and allelic frequencies for rs769412 did not show significant associations with TSU in Saudis. The selected SNP of P53 was strongly associated with TSU and may be linked to TSU-induced diseases in the Saudi Arabian population.


Assuntos
Heterozigoto , Homozigoto , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Fumar/genética , Proteína Supressora de Tumor p53/genética , Adulto , Alelos , Feminino , Frequência do Gene , Humanos , Masculino , Arábia Saudita
13.
Drug Alcohol Depend ; 220: 108517, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33454625

RESUMO

BACKGROUND: Epidemiological data suggest that smoking may be a risk factor for schizophrenia (SCZ), but more evidence is needed. Two regions coding nicotinic acetylcholine receptor (nAchR) subunits, atCHRNA2 and the CHRNA5/A3/B4 cluster, were associated with SCZ in genome-wide association studies (GWAS). Additionally, a signal at CHRNA4 is near significance. CHRNA2 was also associated with cannabis use disorder (CUD). These regions were also associated with smoking behaviors. If tobacco is a risk factor, the GWAS signals at smoking behaviors and SCZ have to be due to the same causal variants, i.e. they have to colocalize, although colocalization does not necessarily imply causality. Here, we present colocalization analysis at these loci between SCZ and smoking behaviors. METHODS: The Bayesian approach implemented in coloc was used to check for posterior probability of colocalization versus independent signals at the three loci with some evidence of association with SCZ and smoking behaviors, using GWAS summary statistics. Colocalization was also assessed for positive control traits and CUD. Three different sensibility analyses were used to confirm the results. A visualization tool, LocusCompare, was used to facilitate interpretation of the coloc results. RESULTS: Evidence for colocalization of GWAS signals between SCZ and smoking behaviors was found for CHRNA2. Evidence for independent causal variants was found for the other two loci. CUD GWAS signal at CHRNA2 colocalizes with SCZ and smoking behaviors. CONCLUSIONS: Overall, the results indicate that the association between some nAchR subunit genes and SCZ cannot be solely explained by their effect on smoking behaviors.


Assuntos
Estudo de Associação Genômica Ampla , Receptores Nicotínicos/genética , Esquizofrenia/genética , Fumar/genética , Teorema de Bayes , Humanos , Proteínas do Tecido Nervoso , Subunidades Proteicas
14.
Med Sci Sports Exerc ; 53(3): 487-495, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32868581

RESUMO

PURPOSE: Greater leisure-time physical activity (LTPA) associates with healthier lives, but knowledge regarding occupational physical activity (OPA) is more inconsistent. DNA methylation (DNAm) patterns capture age-related changes in different tissues. We aimed to assess how LTPA and OPA are associated with three DNAm-based epigenetic age estimates, namely, DNAm age, PhenoAge, and GrimAge. METHODS: The participants were young adult (21-25 yr, n = 285) and older (55-74 yr, n = 235) twin pairs, including 16 pairs with documented long-term LTPA discordance. Genome-wide DNAm from blood samples was used to compute DNAm age, PhenoAge, and GrimAge Age acceleration (Acc), which describes the difference between chronological and epigenetic ages. Physical activity was assessed with sport, leisure-time, and work indices based on the Baecke Questionnaire. Genetic and environmental variance components of epigenetic age Acc were estimated by quantitative genetic modeling. RESULTS: Epigenetic age Acc was highly heritable in young adult and older twin pairs (~60%). Sport index was associated with slower and OPA with faster DNAm GrimAge Acc after adjusting the model for sex. Genetic factors and nonshared environmental factors in common with sport index explained 1.5%-2.7% and 1.9%-3.5%, respectively, of the variation in GrimAge Acc. The corresponding proportions considering OPA were 0.4%-1.8% and 0.7%-1.8%, respectively. However, these proportions were minor (<0.5%) after adjusting the model for smoking status. CONCLUSIONS: LTPA associates with slower and OPA with faster epigenetic aging. However, adjusting the models for smoking status, which may reflect the accumulation of unhealthy lifestyle habits, attenuated the associations.


Assuntos
Envelhecimento/fisiologia , Metilação de DNA/fisiologia , Epigênese Genética/fisiologia , Exercício Físico/fisiologia , Atividades de Lazer , Saúde do Trabalhador , Adulto , Fatores Etários , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Fatores Sexuais , Fumar/efeitos adversos , Fumar/genética , Fumar/fisiopatologia , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Adulto Jovem
15.
Am J Epidemiol ; 190(5): 875-885, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33106845

RESUMO

Risk of chronic obstructive pulmonary disease (COPD) is determined by both cigarette smoking and genetic susceptibility, but little is known about gene-by-smoking interactions. We performed a genome-wide association analysis of 179,689 controls and 21,077 COPD cases from UK Biobank subjects of European ancestry recruited from 2006 to 2010, considering genetic main effects and gene-by-smoking interaction effects simultaneously (2-degrees-of-freedom (df) test) as well as interaction effects alone (1-df interaction test). We sought to replicate significant results in COPDGene (United States, 2008-2010) and SpiroMeta Consortium (multiple countries, 1947-2015) data. We considered 2 smoking variables: 1) ever/never and 2) current/noncurrent. In the 1-df test, we identified 1 genome-wide significant locus on 15q25.1 (cholinergic receptor nicotinic ß4 subunit, or CHRNB4) for ever- and current smoking and identified PI*Z allele (rs28929474) of serpin family A member 1 (SERPINA1) for ever-smoking and 3q26.2 (MDS1 and EVI1 complex locus, or MECOM) for current smoking in an analysis of previously reported COPD loci. In the 2-df test, most of the significant signals were also significant for genetic marginal effects, aside from 16q22.1 (sphingomyelin phosphodiesterase 3, or SMPD3) and 19q13.2 (Egl-9 family hypoxia inducible factor 2, or EGLN2). The significant effects at 15q25.1 and 19q13.2 loci, both previously described in prior genome-wide association studies of COPD or smoking, were replicated in COPDGene and SpiroMeta. We identified interaction effects at previously reported COPD loci; however, we failed to identify novel susceptibility loci.


Assuntos
Interação Gene-Ambiente , Estudo de Associação Genômica Ampla , Doença Pulmonar Obstrutiva Crônica/genética , Fumar/genética , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Testes de Função Respiratória , Reino Unido
16.
Neuropsychopharmacology ; 46(3): 554-560, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32731254

RESUMO

Numerous DNA methylation (DNAm) biomarkers of cigarette smoking have been identified in peripheral blood studies, but because of tissue specificity, blood-based studies may not detect brain-specific smoking-related DNAm differences that may provide greater insight as neurobiological indicators of smoking and its exposure effects. We report the first epigenome-wide association study (EWAS) of smoking in human postmortem brain, focusing on nucleus accumbens (NAc) as a key brain region in developing and reinforcing addiction. Illumina HumanMethylation EPIC array data from 221 decedents (120 European American [23% current smokers], 101 African American [26% current smokers]) were analyzed. DNAm by smoking (current vs. nonsmoking) was tested within each ancestry group using robust linear regression models adjusted for age, sex, cell-type proportion, DNAm-derived negative control principal components (PCs), and genotype-derived PCs. The resulting ancestry-specific results were combined via meta-analysis. We extended our NAc findings, using published smoking EWAS results in blood, to identify DNAm smoking effects that are unique (tissue-specific) vs. shared between tissues (tissue-shared). We identified seven CpGs (false discovery rate < 0.05), of which three CpGs are located near genes previously indicated with blood-based smoking DNAm biomarkers: ZIC1, ZCCHC24, and PRKDC. The other four CpGs are novel for smoking-related DNAm changes: ABLIM3, APCDD1L, MTMR6, and CTCF. None of the seven smoking-related CpGs in NAc are driven by genetic variants that share association signals with predisposing genetic risk variants for smoking, suggesting that the DNAm changes reflect consequences of smoking. Our results provide the first evidence for smoking-related DNAm changes in human NAc, highlighting CpGs that were undetected as peripheral biomarkers and may reflect brain-specific responses to smoking exposure.


Assuntos
Metilação de DNA , Epigênese Genética , Estudo de Associação Genômica Ampla , Humanos , não Fumantes , Núcleo Accumbens , Fumantes , Fumar/genética
18.
Life Sci ; 265: 118797, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33285162

RESUMO

AIMS: Lung cancer was the most fatal malignancy, dominated the cancer related mortality list for years, and we tried to distinguish the lung adenocarcinoma patients at higher risk from those bearing lower therapy resistance and recurrence risk. MATERIALS: Patients information from clinical Sequencing Cohorts and from the Regional Medical Center of the Middle-West China were included. The whole-exome sequencing was analyzed for risk evaluation. KEY FINDINGS: We found that Smoking stimulated the oncogenic genes mutations, and the most frequently mutated genes of EGFR, KRAS, and TP53 (E/K/P) were identified. Different N stage affected the survival prognosis of patients bearing E/K/P mutations, but the T stage and AJCC stage did not. Radiation failed to prolong survival of phase II/III patients who didn't receive surgery. In those received surgery, radiation also failed to prolong survival of phase II/III patients. Radiation did not improve the prognosis in patients bearing E/K/P mutation burdens, whose differences were identified in gender or smoking-history classified groups. SIGNIFICANCE: Smoking status and history contributed to oncogenic mutation burdens associated therapy resistance, and the aggressive treatment, especially to radiation, may lead to worse therapy response to current and past smoking behavior.


Assuntos
Adenocarcinoma de Pulmão/genética , Carcinogênese/genética , Neoplasias Pulmonares/genética , Mutação/genética , Oncogenes/genética , Fumar/genética , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/terapia , Idoso , Biomarcadores Tumorais/genética , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Feminino , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Mutação/efeitos dos fármacos , Oncogenes/efeitos dos fármacos , Fumar/patologia , Fumar/terapia , Taxa de Sobrevida/tendências , Resultado do Tratamento
19.
Gene ; 766: 145092, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32916247

RESUMO

Cigarette smoking is a major lifestyle factor leading to different human diseases. The DNA repair gene, thymine DNA glycosylase, is important to cell survival because it stops cells from becoming cancerous protecting/preventing DNA. Exposure to CS may induce genetic changes such as single nucleotide polymorphisms in DNA repair genes. Therefore, the purpose of this study was to investigate the genotype and allele distributions of four TDG SNPs with only smoking behavior in normal patients. Four TDG SNPs-rs4135066 (C/T), rs3751209 (A/G), rs1866074 (C/T), and rs1882018 (C/T) were analyzed by genotyping 235 and 239 blood samples collected from cigarette smokers and non-smokers, among the Saudi population. The results showed that TDG rs4135066 has a significant susceptibility effect observed in long-term smokers (>5 years; OR = 4.53; P = 0.0347) but not in short-term smokers (≤5 years) in contrast with non-smokers. Also, in smokers aged less than 29 years, the "CT," "TT," and "CT + TT" alleles of rs1882018 increased the risk of developing all diseases related to smoking by approximately 6, 4, and 5 times, respectively, in contrast with the ancestral "CC" homozygous allele. A comparison of the allele distributions of TDG SNPs in a Saudi population with those in other populations represented in the HapMap project showed that the genetic makeup of the Saudi Arabian population appears to differ from that of other ethnicities. Exceptions include the Yoruba people in Ibadan, Nigeria; those of Mexican ancestry in Los Angeles, California; the Luhya population in Webuye, Kenya; Gujarati Indians in Houston, Texas; and the Tuscan population in Italy, which showed similar allelic frequencies for rs3751209 compared to our Saudi population. In this ethnic, we have found a high variation in the distribution of the alleles and genotype frequencies on TDG gene. This variation on TDG SNP's with smoking could lead to increase the susceptibility to many diseases related to smoking habits in this population.


Assuntos
Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Fumar/genética , Timina DNA Glicosilase/genética , Adulto , Alelos , Grupos Étnicos/genética , Feminino , Frequência do Gene/genética , Genótipo , Humanos , Masculino
20.
Gene ; 766: 145151, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32950635

RESUMO

Smoking tobacco is the major hazard for lung cancer in Indian subcontinent especially men, compare to woman where, other important risk factors such as air pollutions are responsible. So, the aim of the study is to compare chronic smokers (CS) and non-smokers living in areas with air quality categorized as poor (AQI 201-300) or moderate (AQI 101-200). We measured the expression of non-small cell lung cancer (NSCLC) biomarkers;. IDH1, CEA, Cyfra21-1, and TPA through quantitative Real-Time PCR (qRT-PCR) and compared the levels of upregulation of the transcripts in stage IIIa NSCLC over control benign tissues among the smoking and AQI settings. Though the all biomarkers were significantly up-regulated in tumor tissues compared to control benign tissues, the fold change increase of IDH1 and CEA was highest in CS-poor/moderate AQI, followed by non-smokers-poor AQI and non-smokers moderate AQI. This indicates the aggressiveness and poor prognosis in CS living in either poor or moderate AQI areas. The level of Cyfra21-1 was lower in in the CS groups in comparison to non-smokers in the poor AQI area. This suggest higher Lung Squamous cell carcinoma histology in non-smokers living areas with poor AQI. Hence, we conclude that poor air quality can be as injurious for lung cancers as chronic smoking.


Assuntos
Antígenos de Neoplasias/genética , Antígeno Carcinoembrionário/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Isocitrato Desidrogenase/genética , Queratina-19/genética , Neoplasias Pulmonares/genética , Fumar/genética , Poluição do Ar , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/genética , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , não Fumantes , Prognóstico , Fumantes , Transcriptoma/genética
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