29 research outputs found

    An arrhythmogenic metabolite in atrial fibrillation

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    Abstract Background Long-chain acyl-carnitines (ACs) are potential arrhythmogenic metabolites. Their role in atrial fibrillation (AF) remains incompletely understood. Using a systems medicine approach, we assessed the contribution of C18:1AC to AF by analysing its in vitro effects on cardiac electrophysiology and metabolism, and translated our findings into the human setting. Methods and results Human iPSC-derived engineered heart tissue was exposed to C18:1AC. A biphasic effect on contractile force was observed: short exposure enhanced contractile force, but elicited spontaneous contractions and impaired Ca2+ handling. Continuous exposure provoked an impairment of contractile force. In human atrial mitochondria from AF individuals, C18:1AC inhibited respiration. In a population-based cohort as well as a cohort of patients, high C18:1AC serum concentrations were associated with the incidence and prevalence of AF. Conclusion Our data provide evidence for an arrhythmogenic potential of the metabolite C18:1AC. The metabolite interferes with mitochondrial metabolism, thereby contributing to contractile dysfunction and shows predictive potential as novel circulating biomarker for risk of AF

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

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    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

    Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes

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    BACKGROUND:DNA methylation is affected by the activities of the key enzymes and intermediate metabolites of the one-carbon pathway, one of which involves homocysteine. We investigated the effect of the well-known genetic variant associated with mildly elevated homocysteine: MTHFR 677C>T independently and in combination with other homocysteine-associated variants, on genome-wide leukocyte DNA-methylation. METHODS:Methylation levels were assessed using Illumina 450k arrays on 9,894 individuals of European ancestry from 12 cohort studies. Linear-mixed-models were used to study the association of additive MTHFR 677C>T and genetic-risk score (GRS) based on 18 homocysteine-associated SNPs, with genome-wide methylation. RESULTS:Meta-analysis revealed that the MTHFR 677C>T variant was associated with 35 CpG sites in cis, and the GRS showed association with 113 CpG sites near the homocysteine-associated variants. Genome-wide analysis revealed that the MTHFR 677C>T variant was associated with 1 trans-CpG (nearest gene ZNF184), while the GRS model showed association with 5 significant trans-CpGs annotated to nearest genes PTF1A, MRPL55, CTDSP2, CRYM and FKBP5. CONCLUSIONS:Our results do not show widespread changes in DNA-methylation across the genome, and therefore do not support the hypothesis that mildly elevated homocysteine is associated with widespread methylation changes in leukocytes

    Retour d'expérience concernant le data challenge épigénétique et médiation à large échelle d'Aussois

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    National audienceLa médiation est un outil statistique permettant d'identifier des liens de causalité entre des variables environnementales et un phénotype par l'inclusion d'une troisième variable : le médiateur. L'étude de la médiation est un réel enjeu statistique car les jeux de données étudiés présentent un grand nombre de médiateurs, souvent corrélés, et complexes de part leur nature biologique. Un data challenge a été organisé pour présenter l'analyse de médiation à des chercheurs de plusieurs disciplines, favoriser les échanges entre les participants et en évaluer les méthodes couramment utilisées. Cet article détaille les objectifs pratiques et pédagogiques de l'événement : la préparation des jeux de données, la conception d'un site web pour l'évaluation des épreuves, des sessions pratiques et pédagogiques, et une restitution du déroulement des épreuves. En conclusion, le data challenge d'Aussois a été une expérience transdisciplinaire enrichissante sur le plan scientifique et méthodologique

    bioSyntax: syntax highlighting for computational biology

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    Background: Computational biology requires the reading and comprehension of biological data files. Plain-text formats such as SAM, VCF, GTF, PDB and FASTA, often contain critical information which is obfuscated by the data structure complexity. Results: bioSyntax ( https://biosyntax.org/ ) is a freely available suite of biological syntax highlighting packages for vim, gedit, Sublime, VSCode, and less. bioSyntax improves the legibility of low-level biological data in the bioinformatics workspace. Conclusion: bioSyntax supports computational scientists in parsing and comprehending their data efficiently and thus can accelerate research output.Medicine, Faculty ofScience, Faculty ofOther UBCNon UBCMedical Genetics, Department ofReviewedFacult

    Genome-wide investigation of DNA methylation marks associated with FV Leiden mutation.

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    In order to investigate whether DNA methylation marks could contribute to the incomplete penetrance of the FV Leiden mutation, a major genetic risk factor for venous thrombosis (VT), we measured genome-wide DNA methylation levels in peripheral blood samples of 98 VT patients carrying the mutation and 251 VT patients without the mutation using the dedicated Illumina HumanMethylation450 array. The genome-wide analysis of 388,120 CpG probes identified three sites mapping to the SLC19A2 locus whose DNA methylation levels differed significantly (p<3 10-8) between carriers and non-carriers. The three sites replicated (p<2 10-7) in an independent sample of 214 individuals from five large families ascertained on VT and FV Leiden mutation among which 53 were carriers and 161 were non-carriers of the mutation. In both studies, these three CpG sites were also associated (2.33 10-11<p<3.02 10-4) with biomarkers of the Protein C pathway known to be influenced by the FV Leiden mutation. A comprehensive linkage disequilibrium (LD) analysis of the whole locus revealed that the original associations were due to LD between the FV Leiden mutation and a block of single nucleotide polymorphisms (SNP) located in SLC19A2. After adjusting for this block of SNPs, the FV Leiden mutation was no longer associated with any CpG site (p>0.05). In conclusion, our work clearly illustrates some promises and pitfalls of DNA methylation investigations on peripheral blood DNA in large epidemiological cohorts. DNA methylation levels at SLC19A2 are influenced by SNPs in LD with FV Leiden, but these DNA methylation marks do not explain the incomplete penetrance of the FV Leiden mutation

    Blood triglyceride levels are associated with DNA methylation at the serine metabolism gene PHGDH

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    Abstract Efficient interventions to reduce blood triglycerides are few; newer and more tolerable intervention targets are needed. Understanding the molecular mechanisms underlying blood triglyceride levels variation is key to identifying new therapies. To explore the role of epigenetic mechanisms on triglyceride levels, a blood methylome scan was conducted in 199 individuals from 5 French-Canadian families ascertained on venous thromboembolism, and findings were replicated in 324 French unrelated patients with venous thromboembolism. Genetic context and functional relevance were investigated. Two DNA methylation sites associated with triglyceride levels were identified. The first one, located in the ABCG1 gene, was recently reported, whereas the second one, located in the promoter of the PHGDH gene, is novel. The PHGDH methylation site, cg14476101, was found to be associated with variation in triglyceride levels in a threshold manner: cg14476101 was inversely associated with triglyceride levels only when triglyceride levels were above 1.12 mmol/L (discovery P-value = 8.4 × 10−6; replication P-value = 0.0091). Public databases findings supported a functional role of cg14476101 on PHGDH expression. PHGDH catalyses the first step in the serine biosynthesis pathway. These findings highlight the role of epigenetic regulation of the PHGDH gene in triglyceride metabolism, providing novel insights on putative intervention targets

    Epigenome-wide association study identifies DNA methylation markers for asthma remission in whole blood and nasal epithelium.

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    Background: Asthma is a chronic respiratory disease which is not curable, yet some patients experience spontaneous remission. We hypothesized that epigenetic mechanisms may be involved in asthma remission. Methods: Clinical remission (ClinR) was defined as the absence of asthma symptoms and medication for at least 12 months, and complete remission (ComR) was defined as ClinR with normal lung function and absence of airway hyperresponsiveness. We analyzed differential DNA methylation of ClinR and ComR comparing to persistent asthma (PersA) in whole blood samples (n = 72) and nasal brushing samples (n = 97) in a longitudinal cohort of well characterized asthma patients. Significant findings of whole blood DNA methylation were tested for replication in two independent cohorts, Lifelines and Epidemiological study on the Genetics and Environment of Asthma (EGEA). Results: We identified differentially methylated CpG sites associated with ClinR (7 CpG sites) and ComR (129 CpG sites) in whole blood. One CpG (cg13378519, Chr1) associated with ClinR was replicated and annotated to PEX11 (Peroxisomal Biogenesis Factor 11 Beta). The whole blood DNA methylation levels of this CpG were also different between ClinR and healthy subjects. One ComR-associated CpG (cg24788483, Chr10) that annotated to TCF7L2 (Transcription Factor 7 Like 2) was replicated and associated with expression of TCF7L2 gene. One out of seven ClinR-associated CpG sites and 8 out of 129 ComR-associated CpG sites identified from whole blood samples showed nominal significance (P < 0.05) and the same direction of effect in nasal brushes. Conclusion: We identified DNA methylation markers possibly associated with clinical and complete asthma remission in nasal brushes and whole blood, and two CpG sites identified from whole blood can be replicated in independent cohorts and may play a role in peroxisome proliferation and Wnt signaling pathway

    Genetic variation 25.1 Mb upstream of tissue factor pathway inhibitor is associated with TFPI plasma levels and venous thromboembolism

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    International audienceBackgroundTissue factor pathway inhibitor (TFPI) regulates fibrin clot formation, and low TFPI plasma levels increase the risk of arterial and venous thromboembolism (VTE). TFPI plasma levels are also heritable, and a previous linkage scan implicated the chromosome 2q region, but no specific genes.ObjectivesWe sought to replicate the linkage region in an independent sample and to identify the causal locus. MethodsWe first ran a linkage analysis of microsatellite markers and TFPI plasma levels in 251 individuals from the F5L Family Study and replicated the linkage peak on chromosome 2q (LOD=3.06). We next defined a follow-up region that included 112603 SNPs under the linkage peak, and meta-analyzed associations between these SNPs and TFPI plasma levels across the F5L Family Study and MARTHA, a study of 1033 unrelated VTE patients. SNPs with FDR q<0.10 were tested for association with TFPI plasma levels in 892 patients with coronary artery disease in the AtheroGene study.Results and ConclusionsOne SNP, rs62187992, was associated with TFPI plasma levels in all three samples (β=+0.14 P=4.23x10-6 combined; β=+0.16, P=0.02 in F5L Family Study; β=+0.13, P=6.3x10-4 in MARTHA; β=+0.17, P=0.03 in AtheroGene) and contributed to the linkage peak in the F5L Family Study. rs62187992 was also associated with clinical VTE (odds ratio=0.90, P=0.03) in the INVENT consortium of over 7000 cases and their controls and was marginally associated with TFPI expression (β=+0.19, P=0.08) in human aortic endothelial cells, a primary site of TFPI synthesis. The biological mechanisms underlying these associations remain to be elucidated
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