Étude d'association entre l'asthme et les gènes associés à ce phénotype et à la pollution de l'air, dans un échantillon d'asthme provenant d'un environnement régional caractérisé par différentes industries

"Mémoire présenté à la Faculté des études supérieures et postdoctorales de l'Université Laval comme exigence partielle du programme de maîtrise en médecine expérimentale offert à l'Université du Québec à Chicoutimi en vertu d'un protocole d'entente avec l'Université Laval pour l'obtention du grade de Maître ès sciences (M.Sc.)"L'asthme est un trait complexe et son développement serait associé à différents facteurs tant environnementaux que génétiques. L'interaction entre ces facteurs a précédemment été associée au développement et à la persistance du phénotype. Une analyse des polymorphismes situés au niveau des gènes précédemment associés à l’asthme et à un environnement particulier a été effectuée dans la collection familiale asthmatique du Saguenay-Lac-Saint-Jean (étude SLSJ). L’environnement de cette région est caractérisé, entre autres, par la présence d ’industries de l’aluminium et de pâtes et papiers. Une stratification selon la proximité entre ces industries et le lieu de résidence des individus a été effectuée afin de déterminer l’impact de ces environnements sur la susceptibilité de certains déterminants génétiques sur le développement de l’asthme. Les résultats ont démontré une seule association pour un polymorphisme du gène Catalase (CAT) avec l’asthme dans l’étude SLSJ. La stratification en fonction de la distance physique de résidence par rapport aux industries n 'a pas permis d ’associer de nouveaux déterminants génétiques à l'asthm e ou d ’accroître la significativité de l’association entre CAT et l’asthme. Ces résultats suggèrent que CAT est associée à l’asthme dans l’étude SLSJ indépendamment de la proximité aux industries et donc de l’exposition à un environnement "à risque"

A functional genomics pipeline to identify high-value asthma and allergy CpGs in the human methylome

BACKGROUND: DNA methylation of cytosines at cytosine-phosphate-guanine (CpG) dinucleotides (CpGs) is a widespread epigenetic mark, but genome-wide variation has been relatively unexplored due to the limited representation of variable CpGs on commercial high-throughput arrays. OBJECTIVES: To explore this hidden portion of the epigenome, this study combined whole-genome bisulfite sequencing with in silico evidence of gene regulatory regions to design a custom array of high-value CpGs. This study focused on airway epithelial cells from children with and without allergic asthma because these cells mediate the effects of inhaled microbes, pollution, and allergens on asthma and allergic disease risk. METHODS: This study identified differentially methylated regions from whole-genome bisulfite sequencing in nasal epithelial cell DNA from a total of 39 children with and without allergic asthma of both European and African ancestries. This study selected CpGs from differentially methylated regions, previous allergy or asthma epigenome-wide association studies (EWAS), or genome-wide association study loci, and overlapped them with functional annotations for inclusion on a custom Asthma&Allergy array. This study used both the custom and EPIC arrays to perform EWAS of allergic sensitization (AS) in nasal epithelial cell DNA from children in the URECA (Urban Environment and Childhood Asthma) birth cohort and using the custom array in the INSPIRE [Infant Susceptibility to Pulmonary Infections and Asthma Following RSV Exposure] birth cohort. Each CpG on the arrays was assigned to its nearest gene and its promotor capture Hi-C interacting gene and performed expression quantitative trait methylation (eQTM) studies for both sets of genes. RESULTS: Custom array CpGs were enriched for intermediate methylation levels compared to EPIC CpGs. Intermediate methylation CpGs were further enriched among those associated with AS and for eQTMs on both arrays. CONCLUSIONS: This study revealed signature features of high-value CpGs and evidence for epigenetic regulation of genes at AS EWAS loci that are robust to race/ethnicity, ascertainment, age, and geography

Association study of genes associated to asthma in a specific environment, in an asthma familial collection located in a rural area influenced by different industries

Eight candidate genes selected in this study were previously associated with gene-environment interactions in asthma in an urban area. These genes were analyzed in a familial collection from a founder and remote population (Saguenay–Lac-Saint-Jean; SLSJ) located in an area with low air levels of ozone but with localized areas of relatively high air pollutant levels, such as sulphur dioxide, when compared to many urban areas. Polymorphisms (SNPs) were extracted from the genome-wide association study (GWAS) performed on the SLSJ familial collection. A transmission disequilibrium test (TDT) was performed using the entire family sample (1,428 individuals in 254 nuclear families). Stratification according to the proximity of aluminium, pulp and paper industries was also analyzed. Two genes were associated with asthma in the entire sample before correction (CAT and NQO1) and one was associated after correction for multiple analyses (CAT). Two genes were associated when subjects were stratified according to the proximity of aluminium industries (CAT and NQO1) and one according to the proximity of pulp and paper industries (GSTP1). However, none of them resisted correction for multiple analyses. Given that the spatial pattern of environmental exposures can be complex and inadequately represented by a few stationary monitors and that exposures can also come from sources other than the standard outdoor air pollution (e.g., indoor air, occupation, residential wood smoke), a new approach and new tools are required to measure specific and individual pollutant exposures in order to estimate the real impact of gene-environment interactions on respiratory health

Combining omics data to identify genes associated with allergic rhinitis

Allergic rhinitis is a common chronic disorder characterized by immunoglobulin E-mediated inflammation. To identify new genes associated with this trait, we performed genome- and epigenome-wide association studies and linked marginally significant CpGs located in genes or its promoter and SNPs located 1 Mb from the CpGs, by identifying cis methylation quantitative trait loci (mQTL). This approach relies on functional cellular aspects rather than stringent statistical correction. We were able to identify one gene with significant cis-mQTL for allergic rhinitis, caudal-type homeobox 1 (CDX1). We also identified 11 genes with marginally significant cis-mQTLs (p < 0.05) including one with both allergic rhinitis with or without asthma (RNF39). Moreover, most SNPs identified were not located closest to the gene they were linked to through cis-mQTLs counting the one linked to CDX1 located in a gene previously associated with asthma and atopic dermatitis. By combining omics data, we were able to identify new genes associated with allergic rhinitis and better assess the genes linked to associated SNPs

Unpredictable pain timings lead to greater pain when people are highly intolerant of uncertainty

Abstract : Background and purpose: Many psychological factors are known to influence pain perception. Amongthem, intolerance of uncertainty (IU) may play a key modulating role in situations where uncertaintyprevails, especially uncertainty regarding the timing of painful events. The objective of this study was toexplore the impact of individual differences in IU on pain perception during predictable and unpredictablestimulation timings. We hypothesized that people with high IU, as opposed to those with low IU, wouldperceive more pain when the timing of painful stimulations cannot be predicted, as compared to whenthey can.Methods: Twenty (20) healthy adults, aged between 18 and 35 years old, were recruited. Painful sensa-tions were provoked using transcutaneous electrical stimulations of the right sural nerve. By measuringIU (Intolerance of Uncertainty Scale) and subjective pain (verbal numerical rating scale), it was possibleto test the relationship between IU and pain perception, by simulating predictable and unpredictablepainful experiences. This was done through cued shock interval (CSI) blocks, with either variable timingor fixed timings (long or short time frame). Self-administered questionnaires were also used to measurepain hypervigilance, pain catastrophizing, state anxiety, and trait anxiety.Results: Pearson correlations confirmed the presence of an association (r = 0.63) between IU and thechange in pain intensity provoked by unpredictable stimulation timings. Importantly, this associationwas significant only for stimulations provided at long CSIs, indicating that higher IU scores predictedhigher pain intensity scores when stimulation timings became unpredictable, and when the cued delaywas long. No association was found between pain scores and other psychological variables.Conclusions: Our results show that IU moderately correlates to the change in pain intensity provokedby unpredictable stimulation timings. High IU scores were associated with a worsening of the subjectivepain experience, especially during long delays in an unpredictable situation. These observations suggestthat IU could be considered as a psychological variable that is able to influence pain perception in certainsituations.Implications: Assessing and addressing IU could be an added value in pain-related therapy, especially in chronic pain

Nasal DNA methylation at three CpG sites predicts childhood allergic disease

Childhood allergic diseases, including asthma, rhinitis and eczema, are prevalent conditions that share strong genetic and environmental components. Diagnosis relies on clinical history and measurements of allergen-specific IgE. We hypothesize that a multi-omics model could accurately diagnose childhood allergic disease. We show that nasal DNA methylation has the strongest predictive power to diagnose childhood allergy, surpassing blood DNA methylation, genetic risk scores, and environmental factors. DNA methylation at only three nasal CpG sites classifies allergic disease in Dutch children aged 16 years well, with an area under the curve (AUC) of 0.86. This is replicated in Puerto Rican children aged 9-20 years (AUC 0.82). DNA methylation at these CpGs additionally detects allergic multimorbidity and symptomatic IgE sensitization. Using nasal single-cell RNA-sequencing data, these three CpGs associate with influx of T cells and macrophages that contribute to allergic inflammation. Our study suggests the potential of methylation-based allergy diagnosis

Manajemen Program Siaran Lokal Aceh TV Dalam Upaya Penyebarluasan Syariat Islam Dan Pelestarian Budaya Lokal

Managing broadcasting management is not easy. Managing the broadcasting business is a difficult and challenging. This research aims to analyze the activity of management and organizational performance ACEH TV television media in an effort to disseminate the Islamic Sharia and Preservation of Local Culture in Aceh. This research is descriptive qualitative. Informants of this research is managing director, program director, executive producer, cameraman / reporter, as well as additional informants Regional Chairman of the Indonesian Broadcasting Commission (KPID) Aceh, Aceh Province Department of Islamic Law, and local media observers. The location of this research is in Banda Aceh, Aceh province. Sampling was done purposively. Data collected through observation, interviews, and documentation. Data were analyzed by analysis of an interactive model of Miles and Huberman. The results showed that the ACEH TV as the medium of television that is broadcasting management ACEH have done according to a local television broadcasting standard. Agenda setting function of mass media performed in the ACEH TV dissemination of Islamic Shariah in Aceh and local culture to influence the people of Aceh to implement Islamic Sharia and also maintain the culture and local wisdom Aceh. It can be seen from all the programs that are aired ACEH TV is a program of local cultural nuances of Islamic law. There are still some shortcomings in running broadcasting broadcasting technology such as lack of equipment that is increasingly sophisticated. The results of image editing is very simple, and some programs presenter still looks stiff when in front of the camera

Nasal DNA methylation at three CpG sites predicts childhood allergic disease

Childhood allergic diseases, including asthma, rhinitis and eczema, are prevalent conditions that share strong genetic and environmental components. Diagnosis relies on clinical history and measurements of allergen-specific IgE. We hypothesize that a multi-omics model could accurately diagnose childhood allergic disease. We show that nasal DNA methylation has the strongest predictive power to diagnose childhood allergy, surpassing blood DNA methylation, genetic risk scores, and environmental factors. DNA methylation at only three nasal CpG sites classifies allergic disease in Dutch children aged 16 years well, with an area under the curve (AUC) of 0.86. This is replicated in Puerto Rican children aged 9-20 years (AUC 0.82). DNA methylation at these CpGs additionally detects allergic multimorbidity and symptomatic IgE sensitization. Using nasal single-cell RNA-sequencing data, these three CpGs associate with influx of T cells and macrophages that contribute to allergic inflammation. Our study suggests the potential of methylation-based allergy diagnosis

DNA methylation in childhood asthma : an epigenome-wide meta-analysis

Background DNA methylation profiles associated with childhood asthma might provide novel insights into disease pathogenesis. We did an epigenome-wide association study to assess methylation profiles associated with childhood asthma. Methods We did a large-scale epigenome-wide association study (EWAS) within the Mechanisms of the Development of ALLergy (MeDALL) project. We examined epigenome-wide methylation using Illumina Infinium Human Methylation450 BeadChips (450K) in whole blood in 207 children with asthma and 610 controls at age 4-5 years, and 185 children with asthma and 546 controls at age 8 years using a cross-sectional case-control design. After identification of differentially methylated CpG sites in the discovery analysis, we did a validation study in children (4-16 years; 247 cases and 2949 controls) from six additional European cohorts and meta-analysed the results. We next investigated whether replicated CpG sites in cord blood predict later asthma in 1316 children. We subsequently investigated cell-type-specific methylation of the identified CpG sites in eosinophils and respiratory epithelial cells and their related gene-expression signatures. We studied cell-type specificity of the asthma association of the replicated CpG sites in 455 respiratory epithelial cell samples, collected by nasal brushing of 16-year-old children as well as in DNA isolated from blood eosinophils (16 with asthma, eight controls [age 2-56 years]) and compared this with whole-blood DNA samples of 74 individuals with asthma and 93 controls (age 1-79 years). Whole-blood transcriptional profiles associated with replicated CpG sites were annotated using RNA-seq data of subsets of peripheral blood mononuclear cells sorted by fluorescence-activated cell sorting. Findings 27 methylated CpG sites were identified in the discovery analysis. 14 of these CpG sites were replicated and passed genome-wide significance (p Interpretation Reduced whole-blood DNA methylation at 14 CpG sites acquired after birth was strongly associated with childhood asthma. These CpG sites and their associated transcriptional profiles indicate activation of eosinophils and cytotoxic T cells in childhood asthma. Our findings merit further investigations of the role of epigenetics in a clinical context.Peer reviewe