Search

Your search keyword '"Raverdy, Violeta"' showing total 10 results
Start Over Author "Raverdy, Violeta" Topic humans
10 results on '"Raverdy, Violeta"'

1. The histone demethylase Phf2 acts as a molecular checkpoint to prevent NAFLD progression during obesity.

Author

Bricambert, Julien, Alves-Guerra, Marie-Clotilde, Esteves, Pauline, Prip-Buus, Carina, Bertrand-Michel, Justine, Guillou, Hervé, Chang, Christopher J, Vander Wal, Mark N, Canonne-Hergaux, François, Mathurin, Philippe, Raverdy, Violeta, Pattou, François, Girard, Jean, Postic, Catherine, and Dentin, Renaud

Subjects
Liver, Cells, Cultured, Animals, Mice, Inbred C57BL, Mice, Knockout, Humans, Mice, Obesity, Glucose, Glutathione, Homeodomain Proteins, Nuclear Proteins, Histones, Transcription Factors, Enzyme Activation, Methylation, Oxidative Stress, Male, Pentose Phosphate Pathway, NF-E2-Related Factor 2, Promoter Regions, Genetic, Histone Demethylases, Non-alcoholic Fatty Liver Disease, Demethylation, Digestive Diseases, Prevention, Liver Disease, Chronic Liver Disease and Cirrhosis, Genetics, Nutrition, 2.1 Biological and endogenous factors, Metabolic and Endocrine, Cancer, Cells, Cultured, Inbred C57BL, Knockout, Promoter Regions, Genetic
Abstract

Aberrant histone methylation profile is reported to correlate with the development and progression of NAFLD during obesity. However, the identification of specific epigenetic modifiers involved in this process remains poorly understood. Here, we identify the histone demethylase Plant Homeodomain Finger 2 (Phf2) as a new transcriptional co-activator of the transcription factor Carbohydrate Responsive Element Binding Protein (ChREBP). By specifically erasing H3K9me2 methyl-marks on the promoter of ChREBP-regulated genes, Phf2 facilitates incorporation of metabolic precursors into mono-unsaturated fatty acids, leading to hepatosteatosis development in the absence of inflammation and insulin resistance. Moreover, the Phf2-mediated activation of the transcription factor NF-E2-related factor 2 (Nrf2) further reroutes glucose fluxes toward the pentose phosphate pathway and glutathione biosynthesis, protecting the liver from oxidative stress and fibrogenesis in response to diet-induced obesity. Overall, our findings establish a downstream epigenetic checkpoint, whereby Phf2, through facilitating H3K9me2 demethylation at specific gene promoters, protects liver from the pathogenesis progression of NAFLD.

Published
2018

2. Low copy number of the salivary amylase gene predisposes to obesity

Author

Falchi, Mario, El-Sayed Moustafa, Julia Sarah, Takousis, Petros, Pesce, Francesco, Bonnefond, Amélie, Andersson-Assarsson, Johanna C, Sudmant, Peter H, Dorajoo, Rajkumar, Al-Shafai, Mashael Nedham, Bottolo, Leonardo, Ozdemir, Erdal, So, Hon-Cheong, Davies, Robert W, Patrice, Alexandre, Dent, Robert, Mangino, Massimo, Hysi, Pirro G, Dechaume, Aurélie, Huyvaert, Marlène, Skinner, Jane, Pigeyre, Marie, Caiazzo, Robert, Raverdy, Violeta, Vaillant, Emmanuel, Field, Sarah, Balkau, Beverley, Marre, Michel, Visvikis-Siest, Sophie, Weill, Jacques, Poulain-Godefroy, Odile, Jacobson, Peter, Sjostrom, Lars, Hammond, Christopher J, Deloukas, Panos, Sham, Pak Chung, McPherson, Ruth, Lee, Jeannette, Tai, E Shyong, Sladek, Robert, Carlsson, Lena MS, Walley, Andrew, Eichler, Evan E, Pattou, Francois, Spector, Timothy D, and Froguel, Philippe

Subjects
Biological Sciences, Genetics, Cancer, Body Mass Index, Carbohydrate Metabolism, Gene Dosage, Genetic Predisposition to Disease, Genomics, Humans, Microarray Analysis, Obesity, Odds Ratio, Salivary alpha-Amylases, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Common multi-allelic copy number variants (CNVs) appear enriched for phenotypic associations compared to their biallelic counterparts. Here we investigated the influence of gene dosage effects on adiposity through a CNV association study of gene expression levels in adipose tissue. We identified significant association of a multi-allelic CNV encompassing the salivary amylase gene (AMY1) with body mass index (BMI) and obesity, and we replicated this finding in 6,200 subjects. Increased AMY1 copy number was positively associated with both amylase gene expression (P = 2.31 × 10(-14)) and serum enzyme levels (P < 2.20 × 10(-16)), whereas reduced AMY1 copy number was associated with increased BMI (change in BMI per estimated copy = -0.15 (0.02) kg/m(2); P = 6.93 × 10(-10)) and obesity risk (odds ratio (OR) per estimated copy = 1.19, 95% confidence interval (CI) = 1.13-1.26; P = 1.46 × 10(-10)). The OR value of 1.19 per copy of AMY1 translates into about an eightfold difference in risk of obesity between subjects in the top (copy number > 9) and bottom (copy number < 4) 10% of the copy number distribution. Our study provides a first genetic link between carbohydrate metabolism and BMI and demonstrates the power of integrated genomic approaches beyond genome-wide association studies.

Published
2014

3. Discovery of drug-omics associations in type 2 diabetes with generative deep-learning models

Author

Allesøe, Rosa Lundbye, Lundgaard, Agnete Troen, Hernández Medina, Ricardo, Aguayo-Orozco, Alejandro, Johansen, Joachim, Nissen, Jakob Nybo, Brorsson, Caroline, Mazzoni, Gianluca, Niu, Lili, Biel, Jorge Hernansanz, Leal Rodríguez, Cristina, Brasas, Valentas, Webel, Henry, Benros, Michael Eriksen, Pedersen, Anders Gorm, Chmura, Piotr Jaroslaw, Jacobsen, Ulrik Plesner, Mari, Andrea, Koivula, Robert, Mahajan, Anubha, Vinuela, Ana, Tajes, Juan Fernandez, Sharma, Sapna, Haid, Mark, Hong, Mun-Gwan, Musholt, Petra B, De Masi, Federico, Vogt, Josef, Pedersen, Helle Krogh, Gudmundsdottir, Valborg, Jones, Angus, Kennedy, Gwen, Bell, Jimmy, Thomas, E Louise, Frost, Gary, Thomsen, Henrik, Hansen, Elizaveta, Hansen, Tue Haldor, Vestergaard, Henrik, Muilwijk, Mirthe, Blom, Marieke T, 't Hart, Leen M, Pattou, Francois, Raverdy, Violeta, Brage, Soren, Kokkola, Tarja, Heggie, Alison, McEvoy, Donna, Mourby, Miranda, Kaye, Jane, Hattersley, Andrew, McDonald, Timothy, Ridderstråle, Martin, Walker, Mark, Forgie, Ian, Giordano, Giuseppe N, Pavo, Imre, Ruetten, Hartmut, Pedersen, Oluf, Hansen, Torben, Dermitzakis, Emmanouil, Franks, Paul W, Schwenk, Jochen M, Adamski, Jerzy, McCarthy, Mark I, Pearson, Ewan, Banasik, Karina, Rasmussen, Simon, Brunak, Søren, IMI DIRECT Consortium, Lundgaard, Agnete Troen [0000-0001-7447-6560], Hernández Medina, Ricardo [0000-0001-6373-2362], Johansen, Joachim [0000-0001-7052-1870], Niu, Lili [0000-0003-4571-4368], Biel, Jorge Hernansanz [0000-0002-3125-2951], Leal Rodríguez, Cristina [0000-0002-3133-0630], Benros, Michael Eriksen [0000-0003-4939-9465], Pedersen, Anders Gorm [0000-0001-9650-8965], Jacobsen, Ulrik Plesner [0000-0001-9181-6854], Koivula, Robert [0000-0002-1646-4163], Vinuela, Ana [0000-0003-3771-8537], Haid, Mark [0000-0001-6118-1333], Hong, Mun-Gwan [0000-0001-8603-8293], Kennedy, Gwen [0000-0002-9856-3236], Thomas, E Louise [0000-0003-4235-4694], Frost, Gary [0000-0003-0529-6325], Hansen, Tue Haldor [0000-0001-5948-8993], Kaye, Jane [0000-0002-7311-4725], Hattersley, Andrew [0000-0001-5620-473X], Ridderstråle, Martin [0000-0002-3270-9167], Pedersen, Oluf [0000-0002-3321-3972], Hansen, Torben [0000-0001-8748-3831], Schwenk, Jochen M [0000-0001-8141-8449], Rasmussen, Simon [0000-0001-6323-9041], Brunak, Søren [0000-0003-0316-5866], and Apollo - University of Cambridge Repository

Subjects
Deep Learning, Diabetes Mellitus, Type 2, Humans, Algorithms
Abstract

The application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug-omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug-drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities.

Published
2023

4. High Prevalence of Obesity in Severe Acute Respiratory Syndrome Coronavirus‐2 (SARS‐CoV‐2) Requiring Invasive Mechanical Ventilation

Author

Simonnet, Arthur, Chetboun, Mikael, Poissy, Julien, Raverdy, Violeta, Noulette, Jerome, Duhamel, Alain, Labreuche, Julien, Mathieu, Daniel, Pattou, Francois, Jourdain, Merce, Caizzo, Robert, Caplan, Morgan, Cousin, Nicolas, Duburcq, Thibault, Durand, Arthur, El kalioubie, Ahmed, Favory, Raphael, Garcia, Bruno, Girardie, Patrick, Goutay, Julien, Houard, Marion, Jaillette, Emmanuelle, Kostuj, Nicolas, Ledoux, Geoffrey, Moreau, Anne Sophie, Niles, Christopher, Nseir, Saad, Onimus, Thierry, Parmentier, Erika, Préau, Sebastien, Robriquet, Laurent, Rouze, Anahita, Six, Sophie, Verkindt, Hélène, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Recherche translationnelle sur le diabète - U 1190 (RTD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), his work was supported by grants from the European Commission (FEDER 12003944), Agence National de la Recherche (European Genomic Institute for Diabetes, E.G.I.D., ANR-10-LABX-46), and Foundation Coeur et Arteres (FCA R15112EE)., LICORN and Lille COVID-19 and Obesity study group : Enagnon Kazali Alidjinou (1), Laurence Bocket (1), Pauline Boddaert (2), Robert Caizzo (3, 4), Morgan Caplan (2), Nicolas Cousin (2), Thibault Duburcq (2), Arthur Durand (2), Ahmed El kalioubie (2), Raphael Favory (2), Bruno Garcia (2), Patrick Girardie (2), Julien Goutay (2), Marion Houard (2), Emmanuelle Jaillette (2), Nicolas Kostuj (2), Geoffrey Ledoux (2), Daniel Mathieu (2), Anne Sophie Moreau (2), Olivier Nigeon (2), Christopher Niles (2), Saad Nseir (2), Thierry Onimus (2), Erika Parmentier (2), Sebastien Préau (2), Laurent Robriquet (2), Anahita Rouze (2), Sophie Six (2), Claire Tinez (1), Aurelia Toussaint (2), Hélène Verkindt (3, 4), 1. CHU Lille, Department of Virology, Center of Biology and Pathology, 59000, Lille, France, 2. CHU Lille, Department of Intensive Care, 59000, Lille, France, 3. Inserm, Univ Lille, CHU Lille, Lille Pasteur Institute, European Genomic Institute for Diabetes, U1190, 59000, Lille France, 4. CHU Lille, Integrated Center for Obesity, 59000, Lille, France, ANR-10-LABX-0046,EGID,EGID Diabetes Pole(2010), and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille

Subjects
Male, obesity, [SDV]Life Sciences [q-bio], Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Medicine (miscellaneous), Severe Acute Respiratory Syndrome, 0302 clinical medicine, Endocrinology, Risk Factors, Prevalence, 030212 general & internal medicine, Young adult, intensive care, 2. Zero hunger, Nutrition and Dietetics, Middle Aged, 3. Good health, Hospitalization, Female, France, Erratum, Coronavirus Infections, Adult, medicine.medical_specialty, SRAS‐Cov‐2, Pneumonia, Viral, body mass index, 030209 endocrinology & metabolism, mechanical ventilation, Young Adult, Betacoronavirus, 03 medical and health sciences, COVID‐19, Internal medicine, Intensive care, medicine, Humans, Risk factor, Pandemics, Aged, Retrospective Studies, Mechanical ventilation, SARS-CoV-2, business.industry, COVID-19, Retrospective cohort study, medicine.disease, Respiration, Artificial, Obesity, Pneumonia, Brief Cutting Edge Reports, business, Body mass index
Abstract

Objective The Covid‐19 pandemic is rapidly spreading worldwide, notably in Europe and North America, where obesity is highly prevalent. The relation between obesity and severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) has not been fully documented. Methods In this retrospective cohort study we analyzed the relationship between clinical characteristics, including body mass index (BMI), and the requirement for invasive mechanical ventilation (IMV) in 124 consecutive patients admitted in intensive care for SARS‐CoV‐2, in a single French center. Results Obesity (BMI >30 kg/m2) and severe obesity (BMI >35 kg/m2) were present in 47.6% and 28.2% of cases, respectively. Overall, 85 patients (68.6%) required IMV. The proportion of patients who required IMV increased with BMI categories (p35 kg/m2 (85.7%). In multivariate logistic regression, the need for IMV was significantly associated with male sex (p35 kg/m2 vs patients with BMI

Published
2020

5. A tool to predict progression of non-alcoholic fatty liver disease in severely obese patients

Author

Deuffic-Burban, Sylvie, Bauvin, Pierre, Delacôte, Claire, Lassailly, Guillaume, Ntandja Wandji, Line Carolle, Gnemmi, Viviane, Dautrecque, Flavien, Louvet, Alexandre, Caiazzo, Robert, Raverdy, Violeta, Leteurtre, Emmanuelle, Pattou, François, Deuffic‐Burban, Sylvie, Mathurin, Philippe, Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service des Maladies de l'Appareil Digestif et de la Nutrition [CHRU Lille], Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Recherche translationnelle sur le diabète - U 1190 (RTD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, This work is supported by the French government, managed by the National Research Agency (ANR) under the Future Investment Program (PIA2) with the reference ANR-16-RHUS-0006_PreciNASH., ANR-16-RHUS-0006,PreciNASH,PreciNASH(2016), CHU Lille, Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Bauvin, Pierre, PreciNASH - - PreciNASH2016 - ANR-16-RHUS-0006 - RHUS - VALID, Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), European Genomic Institute for Diabetes - FR 3508 (EGID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), and Deuffic-Burban, Sylvie

Subjects
Adult, Liver Cirrhosis, Male, medicine.medical_specialty, Cirrhosis, Biopsy, Population, Bariatric Surgery, Disease, Overweight, 03 medical and health sciences, Liver disease, 0302 clinical medicine, disease progression, Non-alcoholic Fatty Liver Disease, Diabetes mellitus, Internal medicine, medicine, Humans, risk factors, Obesity, education, ComputingMilieux_MISCELLANEOUS, education.field_of_study, Hepatology, business.industry, Fatty liver, fibrosis, NASH, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, [INFO.INFO-MO]Computer Science [cs]/Modeling and Simulation, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Markov model, 3. Good health, Liver, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, 030220 oncology & carcinogenesis, 030211 gastroenterology & hepatology, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, [INFO.INFO-MO] Computer Science [cs]/Modeling and Simulation, medicine.symptom, Steatohepatitis, business
Abstract

International audience; Background & aims: Severely obese patients are a growing population at risk of non-alcoholic fatty liver disease (NAFLD). Considering the increasing burden, a predictive tool of NAFLD progression would be of interest. Our objective was to provide a tool allowing general practitioners to identify and refer the patients most at risk, and specialists to estimate disease progression and adapt the therapeutic strategy.Methods: This predictive tool is based on a Markov model simulating steatosis, fibrosis and non-alcoholic steatohepatitis (NASH) evolution. This model was developped from data of 1801 severely obese, bariatric surgery candidates, with histological assessment, integrating duration of exposure to risk factors. It is then able to predict current disease severity in the absence of assessment, and future cirrhosis risk based on current stage.Results: The model quantifies the impact of sex, body-mass index at 20, diabetes, age of overweight onset, on progression. For example, for 40-year-old severely obese patients seen by the general practitioners: (a) non-diabetic woman overweight at 20, and (b) diabetic man overweight at 10, without disease assessment, the model predicts their current risk to have NASH or F3-F4: for (a) 5.7% and 0.6%, for (b) 16.1% and 10.0% respectively. If those patients have been diagnosed F2 by the specialist, the model predicts the 5-year cirrhosis risk: 1.8% in the absence of NASH and 6.0% in its presence for (a), 10.3% and 26.7% respectively, for (b).Conclusions: This model provides a decision-making tool to predict the risk of liver disease that could help manage severely obese patients.

Published
2020

6. Hepatic transcriptomic signatures of statin treatment are associated with impaired glucose homeostasis in severely obese patients

Author

Margerie, Daniel, Lefebvre, Philippe, Raverdy, Violeta, Schwahn, Uwe, Ruetten, Hartmut, Larsen, Philip, Duhamel, Alain, Labreuche, Julien, Thuillier, Dorothée, Derudas, Bruno, Gheeraert, Céline, Dehondt, Hélène, Dhalluin, Quentin, Alexandre, Jérémy, Caiazzo, Robert, Nesslany, Pamela, Verkindt, Helene, Pattou, François, Staels, Bart, Research & Development [Sanofi Avantis], Sanofi-Aventis Deutschland GmbH, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Recherche translationnelle sur le diabète - U 1190 (RTD), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Service de biostatistiques [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Chirurgie générale et endocrinienne [CHU Lille], his work was supported by grants from the European Genomic Institute for Diabetes (ANR-10-LABX-46), and «Fonds hospitalier d’aide à l’émergence et à la structuration des activités et des équipes de recherche» (CHU Lille, France). Bart Staels is a holder of an ERC Advanced Grant (694717). Bart Staels and Francois Pattou received funding for this project from Sanofi Aventis Deutschland GmbH. B.S. is supported by the European Research Council (ERC Grant Immunobile, contract 694717)., European Project: 694717,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ImmunoBile(2016), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Biostatistiques [CHRU Lille], Derudas, Marie-Hélène, and Bile acid, immune-metabolism, lipid and glucose homeostasis - ImmunoBile - - H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) 2016-09-01 - 2021-08-31 - 694717 - VALID

Subjects
Adult, Male, lcsh:Internal medicine, lcsh:QH426-470, Gene networks, Statin, lcsh:Genetics, Cholesterol, Glucose, Liver, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Homeostasis, Humans, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Iatrogenic diabetes, Obesity, Gene expression, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Propensity Score, Sterol Regulatory Element Binding Protein 1, Transcriptome, lcsh:RC31-1245, Research Article, Human
Abstract

Background Clinical data identified an association between the use of HMG-CoA reductase inhibitors (statins) and incident diabetes in patients with underlying diabetes risk factors such as obesity, hypertension and dyslipidemia. The molecular mechanisms however are unknown. Methods An observational cross-sectional study included 910 severely obese patients, mean (SD) body mass index (BMI) 46.7 (8.7), treated with or without statins (ABOS cohort: a biological atlas of severe obesity). Data and sample collection took place in France between 2006 and 2016. Transcriptomic signatures of statin treatment in human liver obtained from genome-wide transcriptomic profiling of five different statin drugs using microarrays were correlated to clinico-biological phenotypes and also assigned to biological pathways and mechanisms. Patients from the non-statin-users group were matched to patients in the statin users group by propensity score analysis to minimize confounding effects from age, gender, parental familial history of diabetes, BMI, waist circumference, systolic and diastolic blood pressure and use of anti-hypertensive drugs as pre-specified covariates. Results We determined the hepatic, statin-related gene signature from genome-wide transcriptomic profiling in severely obese patients with varying degrees of glucose tolerance and cardio-metabolic comorbidities. One hundred and fifty seven patients on statin treatment in the matched cohort showed higher diabetes prevalence (OR = 2.67; 95%CI, 1.60–4.45; P = 0.0002) and impairment of glucose homeostasis. This phenotype was associated with molecular signatures of increased hepatic de novo lipogenesis (DNL) via activation of sterol regulatory element-binding protein 1 (SREBP1) and concomitant upregulation of the expression of key genes in both fatty acid and triglyceride metabolism. Conclusions A DNL gene activation profile in response to statins is associated with insulin resistance and the diabetic status of the patients. Identified molecular signatures thus suggest that statin treatment increases the risk for diabetes in humans at least in part via induction of DNL. Trial registration NCT01129297. Registered May 242,010 (retrospectively registered). Electronic supplementary material The online version of this article (10.1186/s12920-019-0536-1) contains supplementary material, which is available to authorized users.

Full Text
View/download PDF

7. Predicting and elucidating the etiology of fatty liver disease: A machine learning modeling and validation study in the IMI DIRECT cohorts

Author

Atabaki-Pasdar, Naeimeh, Ohlsson, Mattias, Viñuela, Ana, Frau, Francesca, Pomares-Millan, Hugo, Haid, Mark, Jones, Angus G, Thomas, E Louise, Koivula, Robert W, Kurbasic, Azra, Mutie, Pascal M, Fitipaldi, Hugo, Fernandez, Juan, Dawed, Adem Y, Giordano, Giuseppe N, Forgie, Ian M, McDonald, Timothy J, Rutters, Femke, Cederberg, Henna, Chabanova, Elizaveta, Dale, Matilda, Masi, Federico De, Thomas, Cecilia Engel, Allin, Kristine H, Hansen, Tue H, Heggie, Alison, Hong, Mun-Gwan, Elders, Petra JM, Kennedy, Gwen, Kokkola, Tarja, Pedersen, Helle Krogh, Mahajan, Anubha, McEvoy, Donna, Pattou, Francois, Raverdy, Violeta, Häussler, Ragna S, Sharma, Sapna, Thomsen, Henrik S, Vangipurapu, Jagadish, Vestergaard, Henrik, 'T Hart, Leen M, Adamski, Jerzy, Musholt, Petra B, Brage, Soren, Brunak, Søren, Dermitzakis, Emmanouil, Frost, Gary, Hansen, Torben, Laakso, Markku, Pedersen, Oluf, Ridderstråle, Martin, Ruetten, Hartmut, Hattersley, Andrew T, Walker, Mark, Beulens, Joline WJ, Mari, Andrea, Schwenk, Jochen M, Gupta, Ramneek, McCarthy, Mark I, Pearson, Ewan R, Bell, Jimmy D, Pavo, Imre, and Franks, Paul W

Subjects
Diabetes Complications, Fatty Liver, Machine Learning, Male, Models, Statistical, Humans, Reproducibility of Results, Female, Prospective Studies, Middle Aged, Risk Assessment, 3. Good health
Abstract

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent and causes serious health complications in individuals with and without type 2 diabetes (T2D). Early diagnosis of NAFLD is important, as this can help prevent irreversible damage to the liver and, ultimately, hepatocellular carcinomas. We sought to expand etiological understanding and develop a diagnostic tool for NAFLD using machine learning. METHODS AND FINDINGS: We utilized the baseline data from IMI DIRECT, a multicenter prospective cohort study of 3,029 European-ancestry adults recently diagnosed with T2D (n = 795) or at high risk of developing the disease (n = 2,234). Multi-omics (genetic, transcriptomic, proteomic, and metabolomic) and clinical (liver enzymes and other serological biomarkers, anthropometry, measures of beta-cell function, insulin sensitivity, and lifestyle) data comprised the key input variables. The models were trained on MRI-image-derived liver fat content (

8. Acyl-CoA-Binding Protein Is a Lipogenic Factor that Triggers Food Intake and Obesity

Author

Nektarios Tavernarakis, Mireia Niso-Santano, Lorenzo Galluzzi, Violeta Raverdy, Friedemann Loos, Guido Kroemer, François Pattou, Céline Cruciani-Guglielmacci, Patricia Boya, Justine Lallement, Frank Madeo, Jessica Denom, Ignacio Ramírez-Pardo, Karine Clément, Christophe Magnan, Isabelle Martins, Sylvère Durand, Raphaël G. P. Denis, Noélie Bossut, Maria Chiara Maiuri, Véronique Pelloux, Robert Caiazzo, Valentina Sica, Erwan Boedec, Alili Rohia, Stéphanie Migrenne-Li, José Manuel Bravo-San Pedro, Jonathan Pol, Nicolas Ramoz, Fernando Aranda, Philip Gorwood, Gerasimos Anagnostopoulos, Fanny Aprahamian, Carlos López-Otín, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut Gustave Roussy (IGR), Université Paris-Saclay, Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigaciones Biológicas (CSIC), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Clinique des maladies mentales et de l'encéphale (CMME - Service de psychiatrie), Hôpital Sainte-Anne-Université Paris Descartes - Paris 5 (UPD5), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition et obésités: approches systémiques (nutriomics) (UMR-S 1269 INSERM - Sorbonne Université), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Apoptose, cancer et immunité (U848), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Weill Medical College of Cornell University [New York], Sandra and Edward Meyer Cancer Center [New-York], Yale University School of Medicine, BioTechMed-Graz, Graz University of Technology [Graz] (TU Graz)-Medical University Graz-Karl-Franzens-Universität [Graz, Autriche], Institute of Molecular Biosciences, Karl-Franzens-Universität [Graz, Autriche], University of Crete [Heraklion] (UOC), Institute of Molecular Biology and Biotechnology (IMBB-FORTH), Foundation for Research and Technology - Hellas (FORTH), Universidad de Oviedo [Oviedo], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), University of Science & Technology of China [Suzhou], Karolinska Institutet [Stockholm], The authors thank CRC Core Facilities (CGB, CHIC, and CEF). G.K. is supported by the Ligue Contre le Cancer (équipe labelisée), Agence National de la Recherche (ANR) – projets blancs, Cancéropôle Île-de-France, Chancelerie Des universités de Paris (Legs Poix), the European Research Council (ERC), Inserm Transfert, Fondation Carrefour, Institut National du Cancer (INCa), Inserm (HTE), Institut Universitaire de France, Leducq Foundation, the Labex immuno-Oncology, the RHU Torino Lumière, the Seattle Foundation, and the SIRICs SOCRATE and CARPEM. C.M. and C.C.-G. are supported by Agence National de la Recherche (ANR-16-CE14-0026, fat4brain proposal), C.L.-O. is supported by 'Juan de Madariaga fellowship', S.B. is supported by the Swedish Research Council Vetenskapsrådet (2015-05468) and the Austrian Science Fund FWF (P27183-B24), and F.M. is supported by the Austrian Science Fund FWF (grants P23490-B20, P29262, P24381, P29203, and P27893), DKplus Metabolic and Cardiovascular Diseases (W1226), Austrian Science Ministry, Karl Franzens University ('Unkonventionelle Forschung' and 'flysleep'), NAWI Graz, and BioTechMed-Graz flagship project 'EPIAge.' K.C. is supported by ANR MICRO-Obes and AP/HP (PHRC Microbaria). L.G. is supported by an intramural startup from the Department of Radiation Oncology of Weill Cornell Medical College (New York, US) and by Sotio a.c. (Prague, Czech Republic)., The authors thank PreclinICAN (Institute of Cardiometabolism and Nutrition, IHU-ICAN, Paris, France) and 'Plateforme Imageries du Vivant' INSERM UMR 970 (PARCC-HEGP) for analyses of mouse whole-body composition and Functional & Physiological Exploration Platform (FPE) of the Unit 'Biologie Fonctionnelle et Adaptative' (University Paris Diderot, Sorbonne Paris Cité, BFA, UMR 8251 CNRS, Paris, France) for metabolic analyses., Ligue Nationale contre le Cancer (France), Agence Nationale de la Recherche (France), Chancellerie des Universités de Paris, European Research Council, Institut National du Cancer (France), Fondation Leducq, Swedish Research Council, Austrian Science Fund, Federal Ministry of Science, Research and Economy (Austria), Bravo-San-Pedro, José Manuel [0000-0002-5781-1133], Sica, Valentina [0000-0003-2770-5847], Martins, Isabelle [0000-0003-0885-613X], Pol, Jonathan G. [0000-0002-8355-7562], Loos, Friedemann [0000-0002-5976-5978], Maiuri, Maria Chiara [0000-0001-9760-7674], Niso-Santano, Mireia [0000-0002-6506-422X], Aranda, Fernando [0000-0002-9364-474X], Gorwood, Philip [0000-0003-1845-3676], Ramoz, Nicolas [0000-0002-8070-9938], Cleḿent, Karine [0000-0002-2489-3355], Pelloux, Véronique [0000-0003-3630-4746], Raverdy, Violeta [0000-0001-5754-2028], Denis, Raphaël G.P. [0000-0002-7677-7460], Boya, Patricia [0000-0003-3045-951X], Galluzzi, Lorenzo [0000-0003-2257-8500 ], Madeo, Frank [0000-0002-5070-1329], Cruciani-Guglielmacci, Céline [0000-0002-2562-5360], Tavernarakis, Nektarios [0000-0002-5253-1466 ], López-Otín, Carlos [0000-0001-6964-1904], Magnan, Christophe [0000-0002-7044-2571], Kroemer, Guido [0000-0002-9334-4405], CCSD, Accord Elsevier, Université Paris Descartes - Paris 5 (UPD5)-Hôpital Sainte-Anne, Nutrition et obésités: approches systémiques (UMR-S 1269) (Nutriomics), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Yale School of Medicine [New Haven, Connecticut] (YSM), Graz University of Technology [Graz] (TU Graz)-Karl-Franzens-Universität Graz-Medical University Graz, Karl-Franzens-Universität Graz, École Pratique des Hautes Études (EPHE), Centre de Psychiatrie et Neurosciences (U894), ANR-16-CE14-0026,Fat4Brain,Le métabolisme des lipides dans le cerveau est un regulateur essentiel de l'homéostasie énergétique(2016), Bravo-San Pedro, J. M., Sica, V., Martins, I., Pol, J., Loos, F., Maiuri, M. C., Durand, S., Bossut, N., Aprahamian, F., Anagnostopoulos, G., Niso-Santano, M., Aranda, F., Ramirez-Pardo, I., Lallement, J., Denom, J., Boedec, E., Gorwood, P., Ramoz, N., Clement, K., Pelloux, V., Rohia, A., Pattou, F., Raverdy, V., Caiazzo, R., Denis, R. G. P., Boya, P., Galluzzi, L., Madeo, F., Migrenne-Li, S., Cruciani-Guglielmacci, C., Tavernarakis, N., Lopez-Otin, C., Magnan, C., Kroemer, G., Bravo-San-Pedro, José Manuel, Sica, Valentina, Martins, Isabelle, Pol, Jonathan G., Loos, Friedemann, Maiuri, Maria Chiara, Niso-Santano, Mireia, Aranda, Fernando, Gorwood, Philip, Ramoz, Nicolas, Cleḿent, Karine, Pelloux, Véronique, Raverdy, Violeta, Denis, Raphaël G.P., Boya, Patricia, Galluzzi, Lorenzo, Madeo, Frank, Cruciani-Guglielmacci, Céline, Tavernarakis, Nektarios, López-Otín, Carlos, Magnan, Christophe, and Kroemer, Guido

Subjects
Male, 0301 basic medicine, obesity, Anorexia Nervosa, Physiology, Mice, Obese, Weight Gain, Eating, Mice, 0302 clinical medicine, lipid metabolism, Acyl-CoA-binding protein, Beta oxidation, media_common, Diazepam Binding Inhibitor, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 2. Zero hunger, 0303 health sciences, Leptin Deficiency, Chemistry, Fatty Acids, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Anorexia, 3. Good health, anorexia, Lipogenesis, Female, medicine.symptom, Human, autophagy, medicine.medical_specialty, media_common.quotation_subject, Context (language use), Cell Line, 03 medical and health sciences, Internal medicine, Macroautophagy, Weight Loss, Autophagy, medicine, Animals, Humans, Obesity, Molecular Biology, 030304 developmental biology, Animal, Lipogenesi, Appetite, Cell Biology, Weight Lo, Mice, Inbred C57BL, Lipid metabolism, 030104 developmental biology, Endocrinology, Fatty Acid, 030217 neurology & neurosurgery
Abstract

24 p.-6 fig.-1 tab.-1 graph. abst., Autophagy facilitates the adaptation to nutritional stress. Here, we show that short-term starvation of cultured cells or mice caused the autophagy-dependent cellular release of acyl-CoA-binding protein (ACBP, also known as diazepam-binding inhibitor, DBI) and consequent ACBP-mediated feedback inhibition of autophagy. Importantly, ACBP levels were elevated in obese patients and reduced in anorexia nervosa. In mice, systemic injection of ACBP protein inhibited autophagy, induced lipogenesis, reduced glycemia, and stimulated appetite as well as weight gain. We designed three approaches to neutralize ACBP, namely, inducible whole-body knockout, systemic administration of neutralizing antibodies, and induction of antiACBP autoantibodies in mice. ACBP neutralization enhanced autophagy, stimulated fatty acid oxidation, inhibited appetite, reduced weight gain in the context of a high-fat diet or leptin deficiency, and accelerated weight loss in response to dietary changes. In conclusion, neutralization of ACBP might constitute a strategy for treating obesity and its co-morbidities., G.K. is supported by the Ligue Contre le Cancer (équipe labelisée); Agence National de la Recherche (ANR) – projets blancs; Cancéropôle Île-de-France; Chancelerie Des universités de Paris (Legs Poix); the European Research Council (ERC); Inserm Transfert, Fondation Carrefour; Institut National du Cancer (INCa); Inserm (HTE); Institut Universitaire de France; Leducq Foundation; the Labex immuno-Oncology; the RHU Torino Lumière; the Seattle Foundation; and the SIRICs SOCRATE and CARPEM. C.M. and C.C.-G. are supported by Agence National de la Recherche (ANR-16-CE14-0026, fat4brain proposal); C.L.-O. is supported by “Juan de Madariaga fellowship”; S.B. is supported by the Swedish Research Council Vetenskapsrådet (2015-05468) and the Austrian Science Fund FWF (P27183-B24); and F.M. is supported by the Austrian Science Fund FWF (grants P23490-B20, P29262, P24381, P29203, and P27893), DKplus Metabolic and Cardiovascular Diseases (W1226), Austrian Science Ministry, Karl Franzens University (“Unkonventionelle Forschung” and “flysleep”), NAWI Graz, and BioTechMed-Graz flagship project “EPIAge.” K.C. is supported by ANR MICRO-Obes and AP/HP (PHRC Microbaria). L.G. is supported by an intramural startup from the Department of Radiation Oncology of Weill Cornell Medical College (New York, US) and by Sotio a.c. (Prague, Czech Republic).

Published
2019

9. Maternal Glycemic Dysregulation During Pregnancy and Neonatal Blood DNA Methylation: Meta-analyses of Epigenome-Wide Association Studies

Author

Elmar W. Tobi, Diana L. Juvinao-Quintero, Justiina Ronkainen, Raffael Ott, Rossella Alfano, Mickaël Canouil, Madelon L. Geurtsen, Amna Khamis, Leanne K. Küpers, Ives Y. Lim, Patrice Perron, Giancarlo Pesce, Johanna Tuhkanen, Anne P. Starling, Toby Andrew, Elisabeth Binder, Robert Caiazzo, Jerry K.Y. Chan, Romy Gaillard, Peter D. Gluckman, Elina Keikkala, Neerja Karnani, Sanna Mustaniemi, Tim S. Nawrot, François Pattou, Michelle Plusquin, Violeta Raverdy, Kok Hian Tan, Evangelia Tzala, Katri Raikkonen, Christiane Winkler, Anette-G. Ziegler, Isabella Annesi-Maesano, Luigi Bouchard, Yap Seng Chong, Dana Dabelea, Janine F. Felix, Barbara Heude, Vincent W.V. Jaddoe, Jari Lahti, Brigitte Reimann, Marja Vääräsmäki, Amélie Bonnefond, Philippe Froguel, Sandra Hummel, Eero Kajantie, Marjo-Riita Jarvelin, Regine P.M. Steegers-Theunissen, Caitlin G. Howe, Marie-France Hivert, Sylvain Sebert, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Harvard Pilgrim Health Care Institute, University of Oulu, Helmholtz Zentrum München = German Research Center for Environmental Health, Klinikums rechts der Isar, Hasselt University (UHasselt), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), The Generation R Study Group, Imperial College London, Bioinformatics Institute (A*STAR), Singapore Institute for Clinical Sciences [Singapour] (SICS), Agency for science, technology and research [Singapore] (A*STAR), Université de Sherbrooke (UdeS), Centre Hospitalier Universitaire de Sherbrooke, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Epidemiology of Allergic and Respiratory Diseases Department [iPlesp] (EPAR), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), TKK Helsinki University of Technology (TKK), Colorado School of Public Health [Aurora, CO, USA] (CSPH), University of Colorado Anschutz [Aurora], Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Emory University School of Medicine, Emory University [Atlanta, GA], Recherche translationnelle sur le diabète - U 1190 (RTD), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), KK Women's and Children's Hospital [Singapore], Duke-NUS Medical School [Singapore], Liggins Institute, University of Auckland [Auckland], Finnish Institute for Health and Welfare [Helsinki, Finland] (FIHW), Oulu University Hospital [Oulu], Bioinformatics Institute [Singapore], Yong Loo Lin School of Medicine [Singapore], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institut Desbrest de santé publique (IDESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université du Québec à Chicoutimi (UQAC), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Norwegian University of Life Sciences (NMBU), Brunel University London [Uxbridge], Geisel School of Medicine at Dartmouth, Harvard Medical School [Boston] (HMS), Massachusetts General Hospital [Boston], Salvy-Córdoba, Nathalie, Obstetrics & Gynecology, Pediatrics, Binder, Elisabeth, Küpers, Leanne K., Geurtsen, Madelon L., Raikkonen, Katri, Tuhkanen, Johanna, Felix, Janine F., ALFANO, Rossella, Winkler, Christiane, Ott, Raffael, Dabelea, Dana, Khamis, Amna, Bouchard, Luigi, Bonnefond, Amélie, Canouil, Mickaël, Karnani, Neerja, Hummel, Sandra, Tobi, Elmar W, Sebert, Sylvain, Jarvelin, Marjo-Riita, Keikkala, Elina, Heude, Barbara, Pesce, Giancarlo, Steegers-Theunissen, Regine P.M., Lim, Ives Y., REIMANN, Brigitte, Caiazzo, Robert, Hian Tan, Kok, Chan, Jerry K.Y., Ronkainen, Justiina, Ziegler, Anette-G., NAWROT, Tim, Froguel, Philippe, Gluckman, Peter D., Raverdy, Violeta, Starling, Anne P., Howe, Caitlin G., Lahti, Jari, Mustaniemi, Sanna, Hivert, Marie-France, Seng Chong, Yap, Jaddoe, Vincent W.V., Perron, Patrice, Pattou, François, Annesi-Maesano, Isabella, Juvinao-Quintero, Diana L., Gaillard, Romy, Vääräsmäki, Marja, Plusquin, Michelle, Andrew, Toby, Kajantie, Eero, and Tzala, Evangelia

Subjects
Endocrinology, Diabetes and Metabolism, MESH: Epigenome, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Epigenesis, Genetic, Endocrinology & Metabolism, Epigenome, MESH: DNA Methylation, MESH: Pregnancy, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, SDG 3 - Good Health and Well-being, HYPERGLYCEMIA, Pregnancy, Internal Medicine, Humans, MESH: Fetal Blood, MESH: Epigenesis, Genetic, Advanced and Specialized Nursing, MESH: Diabetes, Gestational, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Science & Technology, MESH: Humans, MESH: Infant, Newborn, Infant, Newborn, DNA Methylation, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Fetal Blood, Diabetes, Gestational, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Diabetes Mellitus, Type 2, Female, Life Sciences & Biomedicine, MESH: Female, MESH: Diabetes Mellitus, Type 2
Abstract

OBJECTIVE Maternal glycemic dysregulation during pregnancy increases the risk of adverse health outcomes in her offspring; a risk thought to be linearly related to maternal hyperglycemia. It is hypothesized that changes in offspring DNA methylation (DNAm) underline these associations. RESEARCH DESIGN AND METHODS To address this hypothesis, we conducted fixed-effect meta-analyses of epigenome-wide association study (EWAS) results from eight birth cohorts investigating relationships between cord blood DNAm and fetal exposure to maternal glucose (Nmax= 3,503), insulin (Nmax= 2,062), and the area under the curve of glucose (AUCgluc) following oral glucose tolerance tests (OGTT, Nmax= 1,505). We performed look-up analyses for identified CpG dinucleotides (CpGs) in independent observational cohorts to examine associations between DNAm and cardiometabolic traits as well as tissue-specific gene expression. RESULTS Greater maternal AUCgluc was associated with lower cord blood DNAm at neighboring CpGs cg26974062 (β= -0.013 [SE=2.1x10-3], PFDR= 5.1x10-3) and cg02988288 (β= -0.013 [SE=2.3x10-3], PFDR =0.031) in TXNIP. These associations were attenuated in women with GDM. Lower blood DNAm at these two CpGs near TXNIP was associated with multiple metabolic traits later in life, including type 2 diabetes. TXNIP DNAm in liver biopsies was associated with hepatic expression of TXNIP. We observed little evidence of associations between either maternal glucose or insulin and cord blood DNAm. CONCLUSION Maternal hyperglycemia, as reflected by AUCgluc, was associated with lower cord blood DNAm at TXNIP. Associations between DNAm at these CpGs and metabolic traits in subsequent look-up analyses suggest that these may be candidate loci to investigate in future causal and mediation analyses.

Published
2022

10. PSD3 downregulation confers protection against fatty liver disease

Author

Rosellina M. Mancina, Kavitha Sasidharan, Anna Lindblom, Ying Wei, Ester Ciociola, Oveis Jamialahmadi, Piero Pingitore, Anne-Christine Andréasson, Giovanni Pellegrini, Guido Baselli, Ville Männistö, Jussi Pihlajamäki, Vesa Kärjä, Stefania Grimaudo, Ilaria Marini, Marco Maggioni, Barbara Becattini, Federica Tavaglione, Carly Dix, Marie Castaldo, Stephanie Klein, Mark Perelis, Francois Pattou, Dorothée Thuillier, Violeta Raverdy, Paola Dongiovanni, Anna Ludovica Fracanzani, Felix Stickel, Jochen Hampe, Stephan Buch, Panu K. Luukkonen, Daniele Prati, Hannele Yki-Järvinen, Salvatore Petta, Chao Xing, Clemens Schafmayer, Elmar Aigner, Christian Datz, Richard G. Lee, Luca Valenti, Daniel Lindén, Stefano Romeo, Mancina, Rosellina M, Sasidharan, Kavitha, Lindblom, Anna, Wei, Ying, Ciociola, Ester, Jamialahmadi, Ovei, Pingitore, Piero, Andréasson, Anne-Christine, Pellegrini, Giovanni, Baselli, Guido, Männistö, Ville, Pihlajamäki, Jussi, Kärjä, Vesa, Grimaudo, Stefania, Marini, Ilaria, Maggioni, Marco, Becattini, Barbara, Tavaglione, Federica, Dix, Carly, Castaldo, Marie, Klein, Stephanie, Perelis, Mark, Pattou, Francoi, Thuillier, Dorothée, Raverdy, Violeta, Dongiovanni, Paola, Fracanzani, Anna Ludovica, Stickel, Felix, Hampe, Jochen, Buch, Stephan, Luukkonen, Panu K, Prati, Daniele, Yki-Järvinen, Hannele, Petta, Salvatore, Xing, Chao, Schafmayer, Clemen, Aigner, Elmar, Datz, Christian, Lee, Richard G, Valenti, Luca, Lindén, Daniel, Romeo, Stefano, HUS Internal Medicine and Rehabilitation, Department of Medicine, and Department of Biochemistry and Developmental Biology

Subjects
Genotype, Endocrinology, Diabetes and Metabolism, VARIANT, SUSCEPTIBILITY, Polymorphism, Single Nucleotide, Article, Cell Line, Mice, Ribonucleases, Physiology (medical), Internal Medicine, Animals, Guanine Nucleotide Exchange Factors, Humans, RNA-Seq, Alleles, Non-alcoholic steatohepatitis, NONALCOHOLIC STEATOHEPATITIS, HERITABILITY, Gene Expression Profiling, fungi, NASH, Genetic Variation, Cell Biology, Metabolic syndrome, Fatty Liver, Metabolism, Gene Expression Regulation, Liver, EXOME-WIDE ASSOCIATION, 3121 General medicine, internal medicine and other clinical medicine, ACID, Hepatocytes, SECRETION, Disease Susceptibility, VLDL, Biomarkers, TRIGLYCERIDES, Non-alcoholic fatty liver disease
Abstract

Fatty liver disease (FLD) is a growing health issue with burdening unmet clinical needs. FLD has a genetic component but, despite the common variants already identified, there is still a missing heritability component. Using a candidate gene approach, we identify a locus (rs71519934) at the Pleckstrin and Sec7 domain-containing 3 (PSD3) gene resulting in a leucine to threonine substitution at position 186 of the protein (L186T) that reduces susceptibility to the entire spectrum of FLD in individuals at risk. PSD3 downregulation by short interfering RNA reduces intracellular lipid content in primary human hepatocytes cultured in two and three dimensions, and in human and rodent hepatoma cells. Consistent with this, Psd3 downregulation by antisense oligonucleotides in vivo protects against FLD in mice fed a non-alcoholic steatohepatitis-inducing diet. Thus, translating these results to humans, PSD3 downregulation might be a future therapeutic option for treating FLD., Employing a candidate gene approach, Mancina et al. identify a genetic variant of the Pleckstrin and Sec7 domain-containing 3 (PSD3) gene that reduces susceptibility to fatty liver disease. Functional studies in vitro and in vivo demonstrate that targeting PSD3 protects against fatty liver disease.

Published
2022

Catalog

Books, media, physical & digital resources
See catalog results