RESUMO
BACKGROUND: Survivin is an inhibitor of apoptosis protein (IAP), encoded by the Baculoviral IAP Repeat Containing 5 (BIRC5) gene located on q arm (25.3) on chromosome 17. It is expressed in various human cancers and involved in tumor resistance to radiation and chemotherapy. The genetic analysis of the BIRC5 gene and its protein survivin levels in buccal tissue related to oral squamous cell carcinoma (OSCC) in South Indian tobacco chewers has not been studied. Hence, the study was designed to quantify survivin in buccal tissue and its association with pretreatment hematological parameters and to analyze the BIRC5 gene sequence. METHOD: In a single centric case control study, buccal tissue survivin levels were measured by ELISA. A total of 189 study subjects were categorized into Group 1 (n = 63) habitual tobacco chewers with OSCC, Group 2 (n = 63) habitual tobacco chewers without OSCC, and Group 3 (n = 63) healthy subjects as control. Retrospective hematological data were collected from Group 1 subjects and statistically analyzed. The BIRC5 gene was sequenced and data were analyzed using a bioinformatics tool. RESULTS: Survivin protein mean ± SD in Group 1 was (1670.9 ± 796.21 pg/mL), in Group 2 it was (1096.02 ± 346.17 pg/mL), and in Group 3 it was (397.5 ± 96.1 pg/mL) with significance (p < 0.001). Survivin levels showed significance with cut-off levels of absolute monocyte count (AMC), neutrophil/lymphocyte ratio (NLR), and lymphocyte/monocyte ratio (LMR) at (p = 0.001). The unique variants found only in OSCC patients were T â G in the promoter region, G â C in exon 3, C â A, A â G, G â T, T â G, A â C, G â A in exon 4, C â A, G â T, G â C in the exon 5 region. CONCLUSIONS: The tissue survivin level increased in OSCC patients compared to controls; pretreatment AMC, LMR, and NLR may serve as add-on markers along with survivin to measure the progression of OSCC. Unique mutations in the promoter and exons 3-5 were observed in sequence analysis and were associated with survivin concentrations.
Assuntos
Neoplasias Bucais , Carcinoma de Células Escamosas de Cabeça e Pescoço , Survivina , Uso de Tabaco , Tabaco sem Fumaça , Carcinoma de Células Escamosas de Cabeça e Pescoço/sangue , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Neoplasias Bucais/sangue , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Uso de Tabaco/genética , Uso de Tabaco/metabolismo , Tabaco sem Fumaça/efeitos adversos , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Survivina/genética , Survivina/metabolismo , Bochecha , Regiões Promotoras Genéticas , Mutação , Monócitos , Linfócitos , Contagem de LeucócitosRESUMO
Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury1-4. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries5. Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.
Assuntos
Consumo de Bebidas Alcoólicas , Predisposição Genética para Doença , Variação Genética , Internacionalidade , Herança Multifatorial , Uso de Tabaco , Humanos , Predisposição Genética para Doença/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Herança Multifatorial/genética , Fatores de Risco , Uso de Tabaco/genética , Consumo de Bebidas Alcoólicas/genética , Transcriptoma , Tamanho da Amostra , Loci Gênicos/genética , Europa (Continente)/etnologiaRESUMO
BACKGROUND: Smoking and alcohol consumption may compromise health by way of epigenetic modifications. Epigenetic signatures of alcohol and tobacco consumption could provide insights into the reversibility of phenotypic changes incurred with differing levels of lifestyle exposures. This study describes and validates two novel epigenetic signatures of tobacco (EpiTob) and alcohol (EpiAlc) consumption and investigates their association with disease outcomes. METHODS: The epigenetic signatures, EpiTob and EpiAlc, were developed using data from the Swiss Kidney Project on Genes in Hypertension (SKIPOGH) (N = 689). Epigenetic and phenotypic data available from the 1921 (N = 550) and 1936 (N = 1091) Lothian Birth Cohort (LBC) studies, and two publicly available datasets on GEO Accession (GSE50660, N = 464; and GSE110043, N = 94) were used to validate the signatures. A multivariable logistic regression model, adjusting for age and sex, was used to assess the association between self-reported tobacco or alcohol consumption and the respective epigenetic signature, as well as to estimate the association between CVD and epigenetic signatures. A Cox proportional hazard model was used to estimate the risk of mortality in association with the EpiTob and EpiAlc signatures. RESULTS: The EpiTob signature was positively associated with self-reported tobacco consumption for current or never smokers with explained variance ranging from 0.49 (LBC1921) to 0.72 (LBC1936) (pseudo-R2). In the SKIPOGH, LBC1921 and LBC1936 cohorts, the epigenetic signature for alcohol consumption explained limited variance in association with self-reported alcohol status [i.e., non-drinker, moderate drinker, and heavy drinker] (pseudo-R2 = 0.05, 0.03 and 0.03, respectively), although this improved considerably when measuring self-reported alcohol consumption with standardized units consumed per week (SKIPOGH R2 = 0.21; LBC1921 R2 = 0.31; LBC1936 R2 = 0.41). Both signatures were associated with history of CVD in SKIPOGH and LBC1936, but not in LBC1921. The EpiTob signature was associated with increased risk of all-cause and lung-cancer specific mortality in the 1936 and 1921 LBC cohorts. CONCLUSIONS: This study found the EpiTob and EpiAlc signatures to be well-correlated with self-reported exposure status and associated with long-term health outcomes. Epigenetic signatures of lifestyle exposures may reduce measurement issues and biases and could aid in risk stratification for informing early-stage targeted interventions.
Assuntos
Doenças Cardiovasculares , Nicotiana , Humanos , Metilação de DNA , Uso de Tabaco/efeitos adversos , Uso de Tabaco/genética , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/genética , Estilo de Vida , EtanolRESUMO
BACKGROUND: Northeast (NE) India is a subject of debate for predicting its involvement in prehistoric anatomically modern human (AMH) dispersal. The unique lifestyle and genetic characteristics of native ethnic groups in this region are believed to be responsible for their susceptibility to tobacco-related oral cancer (TrOC). The present study assessed mitochondrial macro-haplogroup (mHG) diversity and TrOC susceptibility autosomal loci to evaluate the impact of prehistoric AMH dispersal on the present day's high TrOC prevalence in major NE Indian ethnics. METHODS: We considered 175 unrelated individuals from 35 ethnic groups and previously published 374 sequences for sequencing-based assessment of mtDNA-based marker by subsequent analyses like haplogroup diversity, phylogenetic, genetic structure by AMOVA, and MDS, descriptive statistics of demographic parameters, and migration analysis. Besides, we selected prolonged tobacco-chewing 124 case-control individuals from similar ethnic backgrounds for genotyping 115 autosomal loci in Sequenom iPLEX MassARRAY™ platform and mined 1000genome data (n = 398) for consequent global admixture and ancestry-specific allele frequencies-based analyses. RESULTS: Our mtDNA-based findings suggested that NE populations were distinct from other Indian populations, owing to the first wave of migration from ancient southern China (â¼54kya) and two successive spatial expansion events at â¼45kya and â¼43kya. Consequently, it probably acted as another source for prehistoric AMH dispersal in N/NE Asia. Besides, the second wave of back-migration from SE Asia (â¼40kya) probably replaced the mitochondrial footprints of survivors from the first migrants and introduced the TrOC susceptibility traits in this region. Afterward, the autosomal marker-based observations on the transition of the disease-associated admixture component 'K6' from SE Asia reconfirmed these results. Moreover, we also observed that the mitochondrial mHG 'R' is significantly associated with the risk of TrOC (OR > 9.5) in NE India. Furthermore, the possible onset of the phenotypic expression of those traits was predicted at â¼4kya, thus, contributing to present-day's TrOC prevalence. CONCLUSIONS: This study reflects its uniqueness by revealing an updated AMH dispersal route for the peopling in and out of NE India, which probably introduced the disease-causing traits in the ancestral NE Indian population. Those traits were then imprinted in their genome to get transferred through their respective generations, forming the present-day's TrOC-prevalent NE Indian population.
Assuntos
Neoplasias Bucais/epidemiologia , Uso de Tabaco/epidemiologia , Adulto , Povo Asiático/genética , Estudos de Casos e Controles , DNA Mitocondrial/genética , Etnicidade/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Variação Genética , Genética Populacional/métodos , Haplótipos , Migração Humana , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/sangue , Neoplasias Bucais/etiologia , Neoplasias Bucais/genética , Filogenia , Fumar Tabaco , Uso de Tabaco/sangue , Uso de Tabaco/genética , Adulto JovemRESUMO
BACKGROUND: Cooking oil fumes (COFs) with smoking habits is a substantial risk that aggravates genetic modifications. The current study was to estimate the biological markers of genetic toxicity counting Micronucleus changes (MN), Chromosome Aberrations (CA) and DNA modifications among COFs exposures and control subjects inherent from South India. MATERIALS AND METHODS: Present analysis comprised 212 COFs with tobacco users and equivalent number of control subjects. RESULTS: High frequency of CA (Chromatid type: and chromosome type) were identified in group II experimental subjects also high amount of MN and DNA damage frequency were significantly (p < 0.05) in both subjects (experimental smokers and non-smokers). Present analysis was observed absence of consciousness among the COFs exposures about the destructive level of health effects of tobacco habits in working environment. CONCLUSION: COFs exposed workers with tobacco induce the significant alteration in chromosomal level. Furthermore, a high level of rate of genetic diseases (spontaneous abortion) were identified in the experimental subjects. This finding will be helpful for preventive measures of COFs exposed workers and supportive for further molecular analysis.
Assuntos
Aberrações Cromossômicas/induzido quimicamente , Culinária , Dano ao DNA/efeitos dos fármacos , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Óleos/toxicidade , Adulto , Poluentes Ocupacionais do Ar/toxicidade , Estudos de Casos e Controles , Análise Citogenética , Feminino , Humanos , Índia , Masculino , Testes para Micronúcleos , Pessoa de Meia-Idade , Exposição Ocupacional/análise , Uso de Tabaco/genéticaRESUMO
The role of tobacco in carcinogenesis has received increasing attention across a number of disciplines in recent years. Accumulating evidences reveal that tobacco consumption affects various epigenetic modifications, especially DNA methylation. However, the genetic modifications of methylation patterns involved in tobacco-attributable cancers remain poorly understood. In this manuscript, aberrant DNA methylation patterns were investigated in 9 tobacco-attributable cancers. Differential methylated probes (DMPs) were identified in each cancer type and a total of 2,392 hyper- and 736 hypomethylated pan-cancer DMPs (PDMPs) were screened out for further analysis. PDMP-associated genes were mostly enriched in metabolism-associated pathways, suggesting the potential roles of methylation alternation in reprogramming cancer cell metabolism. Hypomethylated PDMPs cg12422154, cg02772121 and cg06051311 constituted an enhancer region, significantly downregulating TRIM15, TRIM26 and RPP21, which serve as epigenetically therapeutic biomarkers. Forty-three hypermethylated and 13 hypomethylated transcription factor motifs were clustered into 6 groups, and exhibited various biological functions. Forty-nine PDMPs were reported to be associated with prognosis, providing effective tools to predict clinical outcomes. In summary, our studies revealed the characteristics, influences and potential mechanisms of DNA methylation patterns of tobacco-attributable cancer.
Assuntos
Metilação de DNA , Neoplasias/genética , Uso de Tabaco/genética , Carcinogênese/genética , Ilhas de CpG , Bases de Dados Factuais , Bases de Dados Genéticas , Epigênese Genética , Expressão Gênica , Perfilação da Expressão Gênica/métodos , Humanos , Neoplasias/etiologia , Prognóstico , Regiões Promotoras Genéticas , Uso de Tabaco/efeitos adversos , Transcriptoma , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/genéticaRESUMO
BACKGROUND: LATS1 (Large Tumor Suppressor, isoform 1) is a gene that forms a complex with the cyclin-dependent kinase, CDK1, and regulates cell cycle progression. Genetic modifications lead to a loss in the activity of LATS1 gene. OSCC is the most commonly emerging cancer caused by genetic as well as epigenetic changes. Epigenetics changes vary from one population to another because these are influenced by dietary factors and environmental factors. Tobacco chewing and smoking has been reported as major risk factors in OSCC. No report was found in the previous literature showing promoter hypermethylation of LATS1 gene. METHODS: A total of 50 OSCC patients and 20 normal individuals were recruited in this study. Blood samples (50) from OSCC patients and blood samples (20) from healthy individuals as controls were used in the present study. Isolation of genomic DNA was carried out from blood using the standard phenol-chloroform extraction. Further Isolated DNA was modified with sodium bisulfite using the agarose bead method and finally, the methylation studies of LATS1 gene were carried out using Methylation-Specific PCR (MSP-PCR). RESULTS: 19 out of 50 patients (38.0%) were found to be methylated for LATS1 gene.; a statistically significant result was obtained (p -value= < 0.05) with an odds ratio of 0.37 in cases compared to controls. The status of methylation of LATS1 genes was also found to be statistically significantly associated with smokers and tobacco chewers (p-value = < 0.05). The methylation of LATS1 gene showed a significant risk of developing OSCC in patients. CONCLUSION: These results suggest that the LATS1 gene may provide a better alternative as a diagnostic biomarker. This is the first report on the promoter hypermethylation of LATS1 gene in OSCC patients among the North Indian population.
.
Assuntos
Metilação de DNA , Neoplasias Bucais/genética , Regiões Promotoras Genéticas/genética , Proteínas Serina-Treonina Quinases/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Estudos de Casos e Controles , Humanos , Índia , Fumar Tabaco/genética , Uso de Tabaco/genética , Tabaco sem FumaçaRESUMO
Individuals most often use several rather than one substance among alcohol, cigarettes or cannabis. This widespread co-occurring use of multiple substances is thought to stem from a common liability that is partly genetic in origin. Genetic risk may indirectly contribute to a common liability to substance use through genetically influenced mental health vulnerabilities and individual traits. To test this possibility, we used polygenic scores indexing mental health and individual traits and examined their association with the common versus specific liabilities to substance use. We used data from the Avon Longitudinal Study of Parents and Children (N = 4218) and applied trait-state-occasion models to delineate the common and substance-specific factors based on four classes of substances (alcohol, cigarettes, cannabis and other illicit substances) assessed over time (ages 17, 20 and 22). We generated 18 polygenic scores indexing genetically influenced mental health vulnerabilities and individual traits. In multivariable regression, we then tested the independent contribution of selected polygenic scores to the common and substance-specific factors. Our results implicated several genetically influenced traits and vulnerabilities in the common liability to substance use, most notably risk taking (bstandardised = 0.14; 95% confidence interval [CI] [0.10, 0.17]), followed by extraversion (bstandardised = -0.10; 95% CI [-0.13, -0.06]), and schizophrenia risk (bstandardised = 0.06; 95% CI [0.02, 0.09]). Educational attainment (EA) and body mass index (BMI) had opposite effects on substance-specific liabilities such as cigarette use (bstandardised-EA = -0.15; 95% CI [-0.19, -0.12]; bstandardised-BMI = 0.05; 95% CI [0.02, 0.09]) and alcohol use (bstandardised-EA = 0.07; 95% CI [0.03, 0.11]; bstandardised-BMI = -0.06; 95% CI [-0.10, -0.02]). These findings point towards largely distinct sets of genetic influences on the common versus specific liabilities.
Assuntos
Consumo de Bebidas Alcoólicas/epidemiologia , Herança Multifatorial , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Adolescente , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/psicologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Estudos Longitudinais , Masculino , Análise Multivariada , Análise de Regressão , Fatores de Risco , Esquizofrenia/epidemiologia , Esquizofrenia/genética , Transtornos Relacionados ao Uso de Substâncias/genética , Transtornos Relacionados ao Uso de Substâncias/psicologia , Uso de Tabaco/epidemiologia , Uso de Tabaco/genética , Uso de Tabaco/psicologia , Reino Unido/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Alcohol consumption and smoking, 2 major risk factors for cardiovascular disease (CVD), often occur together. The objective of this study is to use a wide range of CVD risk factors and outcomes to evaluate potential total and direct causal roles of alcohol and tobacco use on CVD risk factors and events. METHODS AND FINDINGS: Using large publicly available genome-wide association studies (GWASs) (results from more than 1.2 million combined study participants) of predominantly European ancestry, we conducted 2-sample single-variable Mendelian randomization (SVMR) and multivariable Mendelian randomization (MVMR) to simultaneously assess the independent impact of alcohol consumption and smoking on a wide range of CVD risk factors and outcomes. Multiple sensitivity analyses, including complementary Mendelian randomization (MR) methods, and secondary alcohol consumption and smoking datasets were used. SVMR showed genetic predisposition for alcohol consumption to be associated with CVD risk factors, including high-density lipoprotein cholesterol (HDL-C) (beta 0.40, 95% confidence interval (CI), 0.04-0.47, P value = 1.72 × 10-28), triglycerides (TRG) (beta -0.23, 95% CI, -0.30, -0.15, P value = 4.69 × 10-10), automated systolic blood pressure (BP) measurement (beta 0.11, 95% CI, 0.03-0.18, P value = 4.72 × 10-3), and automated diastolic BP measurement (beta 0.09, 95% CI, 0.03-0.16, P value = 5.24 × 10-3). Conversely, genetically predicted smoking was associated with increased TRG (beta 0.097, 95% CI, 0.014-0.027, P value = 6.59 × 10-12). Alcohol consumption was also associated with increased myocardial infarction (MI) and coronary heart disease (CHD) risks (MI odds ratio (OR) = 1.24, 95% CI, 1.03-1.50, P value = 0.02; CHD OR = 1.21, 95% CI, 1.01-1.45, P value = 0.04); however, its impact was attenuated in MVMR adjusting for smoking. Conversely, alcohol maintained an association with coronary atherosclerosis (OR 1.02, 95% CI, 1.01-1.03, P value = 5.56 × 10-4). In comparison, after adjusting for alcohol consumption, smoking retained its association with several CVD outcomes including MI (OR = 1.84, 95% CI, 1.43, 2.37, P value = 2.0 × 10-6), CHD (OR = 1.64, 95% CI, 1.28-2.09, P value = 8.07 × 10-5), heart failure (HF) (OR = 1.61, 95% CI, 1.32-1.95, P value = 1.9 × 10-6), and large artery atherosclerosis (OR = 2.4, 95% CI, 1.41-4.07, P value = 0.003). Notably, using the FinnGen cohort data, we were able to replicate the association between smoking and several CVD outcomes including MI (OR = 1.77, 95% CI, 1.10-2.84, P value = 0.02), HF (OR = 1.67, 95% CI, 1.14-2.46, P value = 0.008), and peripheral artery disease (PAD) (OR = 2.35, 95% CI, 1.38-4.01, P value = 0.002). The main limitations of this study include possible bias from unmeasured confounders, inability of summary-level MR to investigate a potentially nonlinear relationship between alcohol consumption and CVD risk, and the generalizability of the UK Biobank (UKB) to other populations. CONCLUSIONS: Evaluating the widest range of CVD risk factors and outcomes of any alcohol consumption or smoking MR study to date, we failed to find a cardioprotective impact of genetically predicted alcohol consumption on CVD outcomes. However, alcohol was associated with and increased HDL-C, decreased TRG, and increased BP, which may indicate pathways through impact CVD risk, warranting further study. We found smoking to be a risk factor for many CVDs even after adjusting for alcohol. While future studies incorporating alcohol consumption patterns are necessary, our data suggest causal inference between alcohol, smoking, and CVD risk, further supporting that lifestyle modifications might be able to reduce overall CVD risk.
Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Doenças Cardiovasculares/epidemiologia , Polimorfismo de Nucleotídeo Único , Uso de Tabaco/efeitos adversos , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/genética , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Fatores de Risco de Doenças Cardíacas , Humanos , Análise da Randomização Mendeliana , Análise Multivariada , Medição de Risco , Uso de Tabaco/epidemiologia , Uso de Tabaco/genéticaRESUMO
Tobacco exposure is one of the major risks for the initiation and progress of lung cancer. The exact corresponding mechanisms, however, are mainly unknown. Recently, a growing body of evidence has been collected supporting the involvement of DNA methylation in the regulation of gene expression in cancer cells. The identification of tobacco-related signature methylation probes and the analysis of their regulatory networks at different molecular levels may be of a great help for understanding tobacco-related tumorigenesis. Three independent lung adenocarcinoma (LUAD) datasets were used to train and validate the tobacco exposure pattern classification model. A deep selecting method was proposed and used to identify methylation signature probes from hundreds of thousands of the whole epigenome probes. Then, BIMC (biweight midcorrelation coefficient) algorithm, SRC (Spearman's rank correlation) analysis, and shortest path tracing method were explored to identify associated genes at gene regulation level and protein-protein interaction level, respectively. Afterwards, the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis and GO (Gene Ontology) enrichment analysis were used to analyze their molecular functions and associated pathways. 105 probes were identified as tobacco-related DNA methylation signatures. They belong to 95 genes which are involved in hsa04512, hsa04151, and other important pathways. At gene regulation level, 33 genes are uncovered to be highly related to signature probes by both BIMC and SRC methods. Among them, FARSB and other eight genes were uncovered as Hub genes in the gene regulatory network. Meanwhile, the PPI network about these 33 genes showed that MAGOH, FYN, and other five genes were the most connected core genes among them. These analysis results may provide clues for a clear biological interpretation in the molecular mechanism of tumorigenesis. Moreover, the identified signature probes may serve as potential drug targets for the precision medicine of LUAD.
Assuntos
Adenocarcinoma de Pulmão , Metilação de DNA , DNA de Neoplasias , Bases de Dados Genéticas , Epigenoma , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Neoplasias Pulmonares , Uso de Tabaco , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Perfilação da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Uso de Tabaco/efeitos adversos , Uso de Tabaco/genética , Uso de Tabaco/metabolismoRESUMO
Peri-implantitis is similar to periodontitis in both symptoms and treatment; however, their level of similarity remains controversial. Here, we compared multiple cases of periodontitis and peri-implantitis through transcriptome and methylome profiling, and analyzed the effects of smoking as a typical risk factor. Human gingival tissues were obtained from 20 patients with periodontitis or peri-implantitis via periodontal surgical procedures. Total RNA and genomic DNA were isolated, and transcriptome and methylome datasets were generated. Comprehensive analysis of differential gene expression, DNA methylation, and protein-protein interactions indicated that periodontitis and peri-implantitis share biological similarities; however, hierarchical clustering between the two disease groups revealed distinct molecular characteristics. These differences might be related to structural differences in natural tooth-bone and implant-bone. Additionally, smoking differentially affected periodontitis and peri-implantitis in terms of host-defense mechanism impairment. Within the limitations of this study, the results provide evidence that peri-implantitis is distinct from periodontitis and that smoking potentially affects disease progression. Our study provides a foundation for the rational design of a large-scale study in the future for a more comprehensive analysis that includes microbiome and clinical data.
Assuntos
Peri-Implantite/genética , Periodontite/genética , Epigenoma/genética , Feminino , Perfilação da Expressão Gênica/métodos , Gengiva/microbiologia , Humanos , Masculino , Microbiota/genética , Pessoa de Meia-Idade , Peri-Implantite/metabolismo , Fatores de Risco , Fumar , Uso de Tabaco/efeitos adversos , Uso de Tabaco/genética , Transcriptoma/genéticaRESUMO
Detrimental effect of bad oral habits, such as smoking and chewing tobacco, on chronic periodontitis (CP) manifest chronic inflammation of gingival tissues which majorly results in gum bleeding, and teeth loss. A genetic association study of Interleukin 1 beta (IL1ß) has been conducted in CP patients having smoking and chewing tobacco habits in regular life style. A molecular docking study has been consequently done to analyze the effect of tobacco on CP progression in depth. All statistical evaluation has been done by using SPSS v16.0. The findings of the study show the significant association of IL1ß gene polymorphisms with CP increased susceptibility in combination of oral habits as mentioned earlier. The docking profile has showed the highest binding affinity of IL1ß protein with the Nicotine derived Nitrosamine Ketone (NNK), one of the derivatives of nicotine which is in-taken through the habits associated with smoking and chewing tobacco. Nicotine, N-nitrosoanabasine, and N-nitrosonornicotine, the other derivatives, have also demonstrated significant impact over the IL1ß protein-caused altered expression. Thus, this study concluded that the harmful effect of tobacco may increase the inflammation in periodontia by inducing the inflammatory active site of the IL1ß protein in the CP patients.
Assuntos
Periodontite Crônica , Estudos de Associação Genética , Interleucina-1beta , Uso de Tabaco , Adulto , Idoso , Periodontite Crônica/genética , Periodontite Crônica/metabolismo , Feminino , Humanos , Interleucina-1beta/química , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , Pessoa de Meia-Idade , Simulação de Acoplamento Molecular , Nicotina/química , Nicotina/metabolismo , Nitrosaminas/química , Nitrosaminas/metabolismo , Ligação Proteica , Uso de Tabaco/genética , Uso de Tabaco/metabolismo , Adulto JovemRESUMO
INTRODUCTION: Reducing adverse events from pharmacologic treatment is an important goal of precision medicine and identifying genetic predictors of adverse events is a step toward this goal. In 2012, King et al. reported associations between genetic variants and adverse events in a placebo-controlled smoking cessation trial of varenicline and bupropion. Strong associations were found between gastrointestinal adverse events and 11 variants in the CHRNA5-CHRNA3-CHRNB4 region of chromosome 15, a region repeatedly associated with smoking-related phenotypes. Our goal was to replicate, in an independent sample, the impact of variants in the CHRNA5-CHRNA3-CHRNB4 region on gastrointestinal adverse events and to extend the analyses to adherence and smoking cessation. METHODS: The University of Wisconsin Transdisciplinary Tobacco Use Research Center (TTURC) conducted a multiarmed, placebo-controlled smoking cessation trial of bupropion and nicotine replacement therapy that included 985 genotyped European-ancestry participants. We evaluated relationships between our key variables using logistic regression. RESULTS: Gastrointestinal adverse events were experienced by 31.6% TTURC participants. Each of the CHRNA5-CHRNA3-CHRNB4 associations from the King et al. study was found in TTURC, with the same direction of effect. Neither these variants nor the gastrointestinal adverse events themselves were associated with adherence to medication or successful smoking cessation. CONCLUSIONS: Variants in the CHRNA5-CHRNA3-CHRNB4 region of chromosome 15 are associated with gastrointestinal adverse events in smoking cessation. Additional independent variants in this region strengthen the association. The consistency between the results of these two independent studies supports the conclusion that these findings reflect biological response to the use of smoking cessation medication. IMPLICATIONS: The fact that our findings from the TTURC smoking cessation trial support the independent findings of King et al. suggest that associations of variants in the CHRNA5-CHRNA3-CHRNB4 region of chromosome 15 with gastrointestinal adverse events while taking medications for smoking cessation reflect biology. However, although adherence to medication was a strong predictor of successful smoking cessation in TTURC, neither adverse events nor the genetic variants associated with them predicted either adherence or successful cessation in this study. Thus, although we should strive to minimize adverse events during treatment, we should not expect that to increase successful smoking cessation substantially.
Assuntos
Cromossomos Humanos Par 15/genética , Gastroenteropatias/genética , Proteínas do Tecido Nervoso/genética , Receptores Nicotínicos/genética , Agentes de Cessação do Hábito de Fumar/efeitos adversos , Uso de Tabaco/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Bupropiona/efeitos adversos , Feminino , Gastroenteropatias/induzido quimicamente , Variação Genética/genética , Humanos , Masculino , Pessoa de Meia-Idade , Família Multigênica/genética , Valor Preditivo dos Testes , Abandono do Hábito de Fumar/métodos , Uso de Tabaco/terapia , Vareniclina/efeitos adversos , Adulto JovemRESUMO
BACKGROUND: Substance use, substance use disorders (SUDs), and psychiatric disorders commonly co-occur. Genetic risk common to these complex traits is an important explanation; however, little is known about how polygenic risk for tobacco or alcohol use overlaps the genetic risk for the comorbid SUDs and psychiatric disorders. METHODS: We constructed polygenic risk scores (PRSs) using GWAS meta-analysis summary statistics from a large discovery sample, GWAS & Sequencing Consortium of Alcohol and Nicotine use (GSCAN), for smoking initiation (SI; Nâ¯=â¯631,564), age of initiating regular smoking (AI; Nâ¯=â¯258,251), cigarettes per day (CPD; Nâ¯=â¯258,999), smoking cessation (SC; Nâ¯=â¯312,273), and drinks per week (DPW; Nâ¯=â¯527,402). We then estimated the fixed effect of these PRSs on the liability to 15 phenotypes related to tobacco and alcohol use, substance use disorders, and psychiatric disorders in an independent target sample of Australian adults. RESULTS: After adjusting for multiple testing, 10 of 75 combinations of discovery and target phenotypes remained significant. PRS-SI (R2 range: 1.98%-5.09 %) was positively associated with SI, DPW, and with DSM-IV and FTND nicotine dependence, and conduct disorder. PRS-AI (R2: 3.91 %) negatively associated with DPW. PRS-CPD (R2: 1.56 %-1.77 %) positively associated with DSM-IV nicotine dependence and conduct disorder. PRS-DPW (R2: 3.39 %-6.26 %) positively associated with only DPW. The variation of DPW was significantly influenced by sex*PRS-SI, sex*PRS-AI and sex*PRS-DPW. Such interaction effect was not detected in the other 14 phenotypes. CONCLUSIONS: Polygenic risks associated with tobacco use are also associated with liability to alcohol consumption, nicotine dependence, and conduct disorder.
Assuntos
Alcoolismo/epidemiologia , Alcoolismo/genética , Transtornos Mentais/epidemiologia , Transtornos Mentais/genética , Herança Multifatorial/genética , Tabagismo/epidemiologia , Tabagismo/genética , Adolescente , Adulto , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/genética , Austrália/epidemiologia , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Uso de Tabaco/epidemiologia , Uso de Tabaco/genética , Adulto JovemRESUMO
Individuals with schizophrenia have higher lifetime rates of substance use disorders than the general population, and research suggests high comorbidity rates may be partially explained by shared genetic influences related to common underlying etiology. Moreover, deficits in executive functions are thought to be central to the diagnosis of schizophrenia and are likewise associated with alcohol and tobacco use. The current study examined the associations between schizophrenia polygenic risk scores and tobacco and alcohol use and the mediation of these associations by executive function sub-domains. Results from the Psychiatric Genomics Consortium's meta-analysis of genome-wide association studies of schizophrenia were used to calculate polygenic risk scores in a sample of moderate drinkers. Schizophrenia risk scores were significantly associated with shifting-specific executive function deficits and tobacco use phenotypes. However, risk scores were not significantly associated with alcohol use and executive functions were not significantly associated with either tobacco or alcohol use. These findings extend previous research by suggesting that genetic risk for schizophrenia may be associated with specific sub-domains of executive function as well as smoking. The lack of a relation with alcohol use suggests genetic factors related to schizophrenia and executive functioning may not influence drinking in a non-disordered, social-drinking sample.
Assuntos
Consumo de Bebidas Alcoólicas/genética , Função Executiva , Esquizofrenia/genética , Transtornos Relacionados ao Uso de Substâncias/genética , Uso de Tabaco/genética , Adulto , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/psicologia , Comorbidade , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Fenótipo , Fatores de Risco , Esquizofrenia/epidemiologia , Psicologia do Esquizofrênico , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/psicologia , Uso de Tabaco/epidemiologia , Uso de Tabaco/psicologiaRESUMO
Studies testing the effect of single genetic variants on substance use have had modest success. This paper reviewed 39 studies using polygenic measures to test interaction with any type of environmental exposure (G×E) in alcohol, tobacco, and cannabis use. Studies using haplotype combinations, sum scores of candidate-gene risk alleles, and polygenic scores (PS) were included. Overall study quality was moderate, with lower ratings for the polygenic methods in the haplotype and candidate-gene score studies. Heterogeneity in investigated environmental exposures, genetic factors, and outcomes was substantial. Most studies (N = 30) reported at least one significant G×E interaction, but overall evidence was weak. The majority (N = 26) found results in line with differential susceptibility and diathesis-stress frameworks. Future studies should pay more attention to methodological and statistical rigor, and focus on replication efforts. Additional work is needed before firm conclusions can be drawn about the importance of G×E in the etiology of substance use.
Assuntos
Consumo de Bebidas Alcoólicas/genética , Interação Gene-Ambiente , Uso da Maconha/genética , Uso de Tabaco/genética , Alelos , Cannabis , Etanol , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Haplótipos/genética , Humanos , Herança Multifatorial/genética , Fatores de Risco , NicotianaRESUMO
BACKGROUND: Co-morbid substance use is very common. Despite a historical focus using genetic epidemiology to investigate comorbid substance use and misuse, few studies have examined substance-substance associations using polygenic risk score (PRS) methods. METHODS: Using summary statistics from the largest substance use GWAS to date (258,797- 632,802 subjects), GWAS and Sequencing Consortium of Alcohol and Nicotine use (GSCAN), we constructed PRSs for smoking initiation (PRS-SI), age of initiation of regular smoking (PRS-AI), cigarettes per day (PRS-CPD), smoking cessation (PRS-SC), and drinks per week (PRS-DPW). We then estimated the fixed effect of individual PRSs on 22 lifetime substance use and substance use disorder phenotypes collected in an independent sample of 2463 young Australian adults using genetic restricted maximal likelihood (GREML) in Genome-wide Complex Trait Analysis (GCTA), separately in females, males and both sexes together. RESULTS: After accounting for multiple testing, PRS-SI significantly explained variation in the risk of cocaine (0.67%), amphetamine (1.54%), hallucinogens (0.72%), ecstasy (1.66%) and cannabis initiation (0.97%), as well as DSM-5 alcohol use disorder (0.72%). PRS-DPW explained 0.75%, 0.59% and 0.90% of the variation of cocaine, amphetamine and ecstasy initiation respectively. None of the 22 phenotypes including emergent classes of substance use were significantly predicted by PRS-AI, PRS-CPD, and PRS-SC. CONCLUSIONS: To our knowledge, this is the first study to report significant genetic overlap between the polygenic risks for smoking initiation and alcohol consumption and the risk of initiating major classes of illicit substances. PRSs constructed from large discovery GWASs allows the detection of novel genetic associations.
Assuntos
Consumo de Bebidas Alcoólicas/epidemiologia , Herança Multifatorial , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Uso de Tabaco/epidemiologia , Adulto , Consumo de Bebidas Alcoólicas/genética , Alcoolismo/epidemiologia , Alcoolismo/genética , Austrália/epidemiologia , Comorbidade , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Fenótipo , Fatores de Risco , Fumar/epidemiologia , Fumar/genética , Transtornos Relacionados ao Uso de Substâncias/genética , Uso de Tabaco/genética , Adulto JovemRESUMO
BACKGROUND: Smoking and use of Swedish smokeless tobacco (snus) are associated with increased risk of type 2 diabetes (T2D). Our aim was to estimate the unique and shared genetic components of these traits and to what extent the association is explained by shared genetic factors. METHODS: We used twins of the Swedish Twin Registry who responded to a questionnaire between 1998 and 2006 (n = 40 247) and were followed until 2015 in the National Prescription and Patient Registries. We estimated hazard ratios (HRs) and odds ratios (ORs) for the association between smoking/snus use and T2D (n = 2130) and used structural equation models to estimate genetic and environmental variance components and genetic correlations. RESULTS: Current smokers [HR 1.69, 95% confidence interval (CI), 1.49-1.92] and snus users (HR 1.19, 95% CI 1.01-1.41) had an increased risk of T2D. In within-pair analyses of monozygotic twins, corresponding ORs were 1.36, 95% CI 0.75-2.46 (smoking) and 1.54, 95% CI 0.80-2.99 (snus). Heritability was 43% (95% CI 36-51) for ever smoking, 58% (95% CI 44- 70) for ever snus use and 66% (95% CI 59-72) for T2D. The genetic correlation with T2D was 18% (95% CI 1-35) for smoking and -6% (95% CI -24 to 4) for snus use, indicating that only a small fraction of the genetic influence is shared. CONCLUSIONS: We could confirm that consumers of snus and cigarettes are at increased risk of T2D. Both snus use and smoking have strong genetic components, which appears to be attributable primarily to genes that are distinct from those promoting T2D.
Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Fumar/epidemiologia , Uso de Tabaco/epidemiologia , Adulto , Idoso , Diabetes Mellitus Tipo 2/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Modelos de Riscos Proporcionais , Fumar/genética , Suécia/epidemiologia , Uso de Tabaco/genética , Tabaco sem Fumaça , Gêmeos Dizigóticos , Gêmeos MonozigóticosRESUMO
BACKGROUND: Postsecondary students in Western countries exhibit a high prevalence of cannabis and tobacco use disorders. The etiology of these problems is contributed by several psychosocial factors, including childhood adversity and trauma; however, the mechanisms whereby these environmental determinants predispose to the use of these substances remain elusive, due to our poor knowledge of genetic and biological moderators. Converging evidence points to the monoamine oxidase A (MAOA) gene as a moderator of the effects of lifetime stress on the initiation of substance use. AIMS: Building on these premises, in this study, we analyzed whether MAOA upstream variable number tandem repeat (uVNTR) alleles interact with child maltreatment history to predict for lifetime cannabis and tobacco consumption. MATERIALS AND METHODS: Five hundred college students (age: 18-25 years) from a large Midwestern University were surveyed for their child maltreatment history (encompassing emotional, physical, and sexual abuse, as well as emotional and physical neglect) and lifetime consumption of cannabis and tobacco. Saliva samples were obtained to determine the MAOA uVNTR genotype of each participant. RESULTS: In female students, lifetime tobacco and cannabis use was predicted by the interaction of physical and emotional abuse with high-activity MAOA allelic variants; conversely, in males, the interaction of low-activity MAOA alleles and physical abuse was associated with lifetime use of tobacco, but not cannabis. DISCUSSION: These findings collectively suggest that the vulnerability to smoke tobacco and cannabis is predicted by sex-dimorphic interactions of MAOA gene with childhood abuse. CONCLUSION: These biosocial underpinnings of tobacco and cannabis use may prove important in the development of novel personalized preventive strategies for substance use disorders in adolescents.
Assuntos
Sobreviventes Adultos de Maus-Tratos Infantis , Uso da Maconha/epidemiologia , Uso da Maconha/genética , Monoaminoxidase/genética , Uso de Tabaco/epidemiologia , Uso de Tabaco/genética , Adolescente , Adulto , Interação Gene-Ambiente , Humanos , Repetições Minissatélites , Caracteres Sexuais , Fatores Sexuais , Estresse Psicológico/epidemiologia , Estresse Psicológico/genética , Estudantes , Universidades , Adulto JovemRESUMO
OBJECTIVE: Psychosocial stress is a key risk factor for substance abuse among adolescents. Recently, epigenetic processes such as DNA methylation have emerged as potential mechanisms that could mediate this relationship. The authors conducted a genome-wide methylation analysis to investigate whether differentially methylated regions are associated with psychosocial stress in an adolescent population. METHODS: A methylome-wide analysis of differentially methylated regions was used to examine a sample of 1,287 14-year-old adolescents (50.7% of them female) from the European IMAGEN study. The Illumina 450k array was used to assess DNA methylation, pyrosequencing was used for technical replication, and linear regression analyses were used to identify associations with psychosocial stress and substance use (alcohol and tobacco). Findings were replicated by pyrosequencing a test sample of 413 participants from the IMAGEN study. RESULTS: Hypermethylation in the sterile alpha motif/pointed domain containing the ETS transcription factor (SPDEF) gene locus was associated with a greater number of stressful life events in an allele-dependent way. Among individuals with the minor G-allele, SPDEF methylation moderated the association between psychosocial stress and substance abuse. SPDEF methylation interacted with lifetime stress in gray matter volume in the right cuneus, which in turn was associated with the frequency of alcohol and tobacco use. SPDEF was involved in the regulation of trans-genes linked to substance use. CONCLUSIONS: Taken together, the study findings describe a novel epigenetic mechanism that helps explain how psychosocial stress exposure influences adolescent substance abuse.