142 results on '"Benoit, J."'
Search Results
2. A Comparative Analysis of the Lipoprotein(a) and Low-Density Lipoprotein Proteomic Profiles Combining Mass Spectrometry and Mendelian Randomization
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Arnaud Droit, Elvira Mass, Corey A. Scipione, Raphaëlle Bourgeois, Benoit J. Arsenault, Philippe Pibarot, Patrick Mathieu, Sylvie Bourassa, Audrey-Anne Després, Arnaud Girard, Marlys L. Koschinsky, Paolo Poggio, Jakie Guertin, Patricia L. Mitchell, Michael B. Boffa, Christian Couture, Patrick Couture, Romain Capoulade, Sébastien Thériault, Clarisse Gotti, and Nicolas Perrot
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medicine.medical_specialty ,lcsh:Diseases of the circulatory (Cardiovascular) system ,Apolipoprotein B ,030204 cardiovascular system & hematology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Mendelian randomization ,medicine ,030304 developmental biology ,0303 health sciences ,Proteomic Profile ,biology ,PCSK9 ,Lipoprotein(a) ,Blood proteins ,3. Good health ,Endocrinology ,chemistry ,lcsh:RC666-701 ,Low-density lipoprotein ,biology.protein ,Original Article ,lipids (amino acids, peptides, and proteins) ,Cardiology and Cardiovascular Medicine ,Lipoprotein - Abstract
Background: Lipoprotein(a) (Lp[a]), which consists of a low-density lipoprotein (LDL) bound to apolipoprotein(a), is one of the strongest genetic risk factors for atherosclerotic cardiovascular diseases. Few studies have performed hypothesis-free direct comparisons of the Lp(a) and the LDL proteomes. Our objectives were to compare the Lp(a) and the LDL proteomic profiles and to evaluate the effect of lifelong exposure to elevated Lp(a) or LDL cholesterol levels on the plasma proteomic profile. Methods: We performed a label-free analysis of the Lp(a) and LDL proteomic profiles of healthy volunteers in a discovery (n = 6) and a replication (n = 9) phase. We performed inverse variance weighted Mendelian randomization to document the effect of lifelong exposure to elevated Lp(a) or LDL cholesterol levels on the plasma proteomic profile of participants of the INTERVAL study. Results: We identified 15 proteins that were more abundant on Lp(a) compared with LDL (serping1, pi16, itih1, itih2, itih3, pon1, podxl, cd44, cp, ptprg, vtn, pcsk9, igfals, vcam1, and ttr). We found no proteins that were more abundant on LDL compared with Lp(a). After correction for multiple testing, lifelong exposure to elevated LDL cholesterol levels was associated with the variation of 18 plasma proteins whereas Lp(a) did not appear to influence the plasma proteome. Conclusions: Results of this study highlight marked differences in the proteome of Lp(a) and LDL as well as in the effect of lifelong exposure to elevated LDL cholesterol or Lp(a) on the plasma proteomic profile. Résumé: Contexte: La lipoprotéine(a) (Lp[a]), qui est constituée d’une lipoprotéine de basse densité (LDL) liée à une apolipoprotéine(a), est l’un des plus importants facteurs de risque génétiques de survenue d’une maladie cardiovasculaire athéroscléreuse. Peu d’études comparatives directes sans hypothèse ont porté sur le protéome de la Lp(a) et celui des LDL. Nos objectifs étaient de comparer les profils protéomiques de la Lp(a) et des LDL et d’évaluer l’effet d’une exposition à vie à un taux élevé de Lp(a) ou de cholestérol LDL sur le profil protéomique plasmatique. Méthodologie: Nous avons réalisé une analyse sans marquage des profils protéomiques de la Lp(a) et des LDL chez des volontaires en bonne santé dans le cadre d’une phase de découverte (n = 6) et d’une phase de réplication (n = 9). Pour rendre compte de l’effet d’une exposition à vie à un taux élevé de Lp(a) ou de cholestérol des LDL sur le profil protéomique plasmatique des participants de l’étude INTERVAL, nous avons utilisé une analyse de randomisation Mendélienne avec pondération par l’inverse de la variance. Résultats: Nous avons relevé 15 protéines associées en plus grande abondance à la Lp(a) qu’aux LDL (serping1, pi16, itih1, itih2, itih3, pon1, podxl, cd44, cp, ptprg, vtn, pcsk9, igfals, vcam1 et ttr). Nous n’avons noté aucune protéine associée en plus grande abondance aux LDL qu’à la Lp(a). Après correction pour tenir compte de la multiplicité des tests, l’exposition à vie à un taux élevé de cholestérol LDL a été associée à la variation de 18 protéines plasmatiques, tandis que le taux de Lp(a) ne semblait pas influencer le protéome plasmatique. Conclusions: Les résultats de notre étude font ressortir les différences marquées entre le protéome de la Lp(a) et celui des LDL, ainsi qu’entre l’effet sur le profil protéomique plasmatique de l’exposition à vie à un taux élevé de cholestérol LDL et celui de l’exposition à vie à un taux élevé de Lp(a).
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- 2021
3. Lipoprotein(a) has no major impact on calcification activity in patients with mild to moderate aortic valve stenosis
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Jeffrey Kroon, Kang H. Zheng, Aernout G Somsen, Hein J. Verberne, Nick S. Nurmohamed, Evangelos Tzolos, Erik S.G. Stroes, Benoit J. Arsenault, Yannick Kaiser, S. Matthijs Boekholdt, Marc R. Dweck, Cardiology, Radiology and nuclear medicine, ACS - Atherosclerosis & ischemic syndromes, Graduate School, Vascular Medicine, Experimental Vascular Medicine, ACS - Microcirculation, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Radiology and Nuclear Medicine, ACS - Amsterdam Cardiovascular Sciences, and ACS - Heart failure & arrhythmias
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Aortic valve ,medicine.medical_specialty ,aortic valve stenosis ,chemistry.chemical_compound ,Internal medicine ,medicine ,Humans ,In patient ,biology ,business.industry ,Cholesterol ,Calcinosis ,Lipoprotein(a) ,medicine.disease ,Blood pressure ,medicine.anatomical_structure ,positron emission tomography computed tomography ,chemistry ,Aortic valve stenosis ,Valvular Heart Disease ,biology.protein ,Cardiology ,Cardiology and Cardiovascular Medicine ,business ,Calcification ,Lipoprotein - Abstract
ObjectiveTo assess whether patients with aortic valve stenosis (AS) with elevated lipoprotein(a) (Lp(a)) are characterised by increased valvular calcification activity compared with those with low Lp(a).MethodsWe performed 18F-sodium fluoride (18F-NaF) positron emission tomography/CT in patients with mild to moderate AS (peak aortic jet velocity between 2 and 4 m/s) and high versus low Lp(a) (>50 mg/dL vs 18F-NaF uptake.Results52 individuals (26 matched pairs) were included in the analysis. The mean age was 66.4±5.5 years, 44 (84.6%) were men, and the mean aortic valve velocity was 2.80±0.49 m/s. The median Lp(a) was 79 (64–117) mg/dL and 7 (5–11) mg/dL in the high and low Lp(a) groups, respectively. Systolic blood pressure and low-density-lipoprotein cholesterol (corrected for Lp(a)) were significantly higher in the low Lp(a) group (141±12 mm Hg vs 128±12 mm Hg, 2.5±1.1 mmol/L vs 1.9±0.8 mmol/L). We found no difference in valvular 18F-NaF uptake between the high and low Lp(a) groups (3.02±1.26 vs 3.05±0.96, p=0.902). Linear regression analysis showed valvular calcium score to be the only significant determinant of valvular 18F-NaF uptake (β=0.63; 95% CI 0.38 to 0.88 per 1000 Agatston unit increase, p18F-NaF uptake (β=0.17; 95% CI −0.44 to 0.88, p=0.305 for the high Lp(a) group).ConclusionAmong patients with mild to moderate AS, calcification activity is predominantly determined by established calcium burden. The results do not support our hypothesis that Lp(a) is associated with valvular 18F-NaF uptake.
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- 2022
4. Interaction of Autotaxin With Lipoprotein(a) in Patients With Calcific Aortic Valve Stenosis
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Romain Devillers, Marlys L. Koschinsky, Marie-Chloé Boulanger, Patricia L. Mitchell, Jakie Guertin, Audrey-Anne Després, Benoit J. Arsenault, Raphaëlle Bourgeois, Nicolas Perrot, Michael B. Boffa, Patrick Couture, Philippe Pibarot, Patrick Mathieu, and Corey A. Scipione
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0301 basic medicine ,medicine.medical_specialty ,biology ,business.industry ,Calcific aortic valve stenosis ,Lipoprotein(a) ,030204 cardiovascular system & hematology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Human plasma ,Internal medicine ,cardiovascular system ,biology.protein ,Cardiology ,Medicine ,Biomarker (medicine) ,In patient ,Multivariable model ,Autotaxin ,Cardiology and Cardiovascular Medicine ,business ,Lipoprotein - Abstract
Summary Our objectives were to determine whether autotaxin (ATX) is transported by lipoprotein(a) [Lp(a)] in human plasma and if could be used as a biomarker of calcific aortic valve stenosis (CAVS). We first found that ATX activity was higher in Lp(a) compared to low-density lipoprotein fractions in isolated fractions of 10 healthy participants. We developed a specific assay to measure ATX-Lp(a) in 88 patients with CAVS and 144 controls without CAVS. In a multivariable model corrected for CAVS risk factors, ATX-Lp(a) was associated with CAVS (p = 0.003). We concluded that ATX is preferentially transported by Lp(a) and might represent a novel biomarker for CAVS.
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- 2020
5. Abstract P3-11-11: First-in-human CAR T for solid tumors targets the MUC1 transmembrane cleavage product
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Gregory L. Riley, Andrew K. Stewart, Erin K. Hanahoe, Cynthia Bamdad, Tyler E. Swanson, Benoit J. Smagghe, Nelson D. Glennie, and Pengyu Huang
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0301 basic medicine ,Cancer Research ,T cell ,digestive system ,Epitope ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,Growth factor receptor ,medicine ,skin and connective tissue diseases ,neoplasms ,MUC1 ,biology ,Chemistry ,biological factors ,digestive system diseases ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Immunohistochemistry ,Antibody ,Conformational epitope - Abstract
We developed a MUC1* targeting CAR T that is scheduled for a 1st-in-human clinical trial for metastatic breast cancers at the Fred Hutchinson Cancer Research Center in late 2019. huMNC2-CAR44 targets MUC1*, which is the transmembrane cleavage product of MUC1. MUC1* is a growth factor receptor that is activated when onco-embryonic growth factor NME7AB dimerizes its truncated extra cellular domain. The binding site for NME7AB is masked in full-length MUC1, as is the binding site for the huMNC2 antibody. Thus, huMNC2 does not bind to full-length MUC1, which is expressed on healthy epithelium. Previous attempts at a MUC1 targeting therapeutic all failed, presumably because they targeted the tandem repeat domain of full-length MUC1, which is shed after cleavage to MUC1*. huMNC2-CAR44 T cells are highly selective for cancerous tissues: first, because they target MUC1*, not the healthy full-length form. Secondly, the huMNC2 antibody recognizes a specific conformation of the MUC1* extra cellular domain that is created when MUC1 is cleaved by an enzyme that is overexpressed in many cancers, especially breast cancers. IHC studies of thousands of normal vs. cancerous human tissue specimens show that huMNC2-scFv almost exclusively binds to tumor tissues, hitting over 90% of breast, 83% ovarian, 78% pancreatic and 71% of lung cancers. Recognition of breast cancer specimens appears not to be limited by cancer sub-type. In vivo experiments of human tumors in NSG mice (n>300), show that huMNC2-CAR44 T cells robustly inhibited MUC1* positive solid tumors. A single injection of huMNC2-CAR44 T cells eliminated tumors in NSG mice which remained tumor free to Day 100, compared to control animals that had to be sacrificed at Day 20 due to excess tumor volume. Other animal experiments showed that huMNC2-CAR44 T cell efficacy increased with increasing antigen density. Dual tumor experiments of a high antigen density and low antigen density tumor in the same animal showed that adequate MUC1* density is required for a CAR T response, further supporting the idea that huMNC2-CAR44 T cells will selectively kill MUC1* positive tumors, while sparing normal tissues. Conclusion: MUC1* is the predominant form of MUC1 present on cancers. Antibodies that target conformational epitopes produced by specific subsets of cleavage enzymes make anti-MUC1* CAR T cells highly tumor selective. The generation of an anti-MUC1* CAR that recognizes a conformational epitope created when MUC1 is cleaved to MUC1* by a specific cleavage enzyme, argues that CARs could be made patient specific, based on which cleavage enzymes their tumors express. Citation Format: Cynthia C Bamdad, Andrew K Stewart, Pengyu Huang, Benoit J Smagghe, Scott T Moe, Tyler E Swanson, Thomas G Jeon, Danica M Page. First-in-human CAR T for solid tumors targets the MUC1 transmembrane cleavage product [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-11-11.
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- 2020
6. Mobilome-driven segregation of the resistome in biological wastewater treatment
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Susheel Bhanu Busi, Patrick May, Laura De Nies, Paul Wilmes, Benoit J. Kunath, Fonds National de la Recherche - FnR (CORE/BM/11333923) [sponsor], European Research Council (ERC-CoG 863664) [sponsor], Fonds National de la Recherche Luxembourg (PRIDE/11823097) [sponsor], Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (CRSII5_180241) [sponsor], Luxembourg Centre for Systems Biomedicine (LCSB): Eco-Systems Biology (Wilmes Group) [research center], and Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center]
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Environmental sciences & ecology [F08] [Life sciences] ,Microbiologie [F11] [Sciences du vivant] ,Public health, health care sciences & services [D22] [Human health sciences] ,Santé publique, services médicaux & soins de santé [D22] [Sciences de la santé humaine] ,Bacitracin ,Wastewater ,Biology ,Fosfomycin ,General Biochemistry, Genetics and Molecular Biology ,Water Purification ,Antibiotic resistance ,Plasmid ,medicine ,Humans ,Bacteriophages ,Microbiology [F11] [Life sciences] ,Genetics ,Sulfonamides ,General Immunology and Microbiology ,General Neuroscience ,Drug Resistance, Microbial ,General Medicine ,Anti-Bacterial Agents ,Resistome ,Sciences de l'environnement & écologie [F08] [Sciences du vivant] ,Aminoglycosides ,Genes, Bacterial ,Metagenomics ,Mobilome ,Mobile genetic elements ,medicine.drug - Abstract
Biological wastewater treatment plants (BWWTP) are considered to be hotspots of evolution and subsequent spread of antimicrobial resistance (AMR). Mobile genetic elements (MGEs) promote the mobilization and dissemination of antimicrobial resistance genes (ARGs) and are thereby critical mediators of AMR within the BWWTP microbial community. At present, it is unclear whether specific AMR categories are differentially disseminated via bacteriophages (phages) or plasmids. To understand the segregation of AMR in relation to MGEs, we analyzed meta-omic (metagenomic, metatranscriptomic and metaproteomic) data systematically collected over 1.5 years from a BWWTP. Our results showed a core group of fifteen AMR categories which were found across all timepoints. Some of these AMR categories were disseminated exclusively (bacitracin) or primarily (aminoglycoside, MLS, sulfonamide) via plasmids or phages (fosfomycin and peptide), whereas others were disseminated equally by both MGEs. Subsequent expression- and protein-level analyses further demonstrated that aminoglycoside, bacitracin and sulfonamide resistance genes were expressed more by plasmids, in contrast to fosfomycin and peptide AMR expression by phages, thereby validating our genomic findings. Longitudinal assessment further underlined these findings whereby the log2-fold changes of aminoglycoside, bacitracin and sulfonamide resistance genes were increased in plasmids, while fosfomycin and peptide resistance showed similar trends in phages. In the analyzed communities, the dominant taxon Candidatus Microthrix parvicella was a major contributor to several AMR categories whereby its plasmids primarily mediated aminoglycoside resistance. Importantly, we also found AMR associated with ESKAPEE pathogens within the BWWTP, for which MGEs also contributed differentially to the dissemination of ARGs. Collectively our findings pave the way towards understanding the segmentation of AMR within MGEs, thereby shedding new light on resistome populations and their mediators, essential elements that are of immediate relevance to human health.
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- 2021
7. A trans‐omic Mendelian randomization study of parental lifespan uncovers novel aging biology and therapeutic candidates for chronic diseases
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Nooshin Ghodsian, Sébastien Thériault, Nicolas Perrot, Benoit J. Arsenault, Patricia L. Mitchell, Patrick Mathieu, Zhonglin Li, Jérôme Bourgault, Christian Couture, William Pelletier, and Yohan Bossé
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Male ,Parents ,Proteomics ,Aging ,Candidate gene ,Longevity ,Phenome ,Biology ,Polymorphism, Single Nucleotide ,Cohort Studies ,Transcriptome ,Metabolomics ,Mendelian Randomization ,Mendelian randomization ,Humans ,RNA-Seq ,Transcriptomics ,Gene ,Aged ,Parental Lifespan ,Genetics ,Original Paper ,Cell Biology ,Mendelian Randomization Analysis ,Middle Aged ,Original Papers ,Genetic architecture ,Phenotype ,Chronic Disease ,Female ,Proprotein Convertase 9 ,Genome-Wide Association Study - Abstract
The study of parental lifespan has emerged as an innovative tool to advance aging biology and our understanding of the genetic architecture of human longevity and aging‐associated diseases. Here, we leveraged summary statistics of a genome‐wide association study including over one million parental lifespans to identify genetically regulated genes from the Genotype‐Tissue Expression project. Through a combination of multi‐tissue transcriptome‐wide association analyses and genetic colocalization, we identified novel genes that may be associated with parental lifespan. Mendelian randomization (MR) analyses also identified circulating proteins and metabolites causally associated with parental lifespan and chronic diseases offering new drug repositioning opportunities such as those targeting apolipoprotein‐B‐containing lipoproteins. Liver expression of HP, the gene encoding haptoglobin, and plasma haptoglobin levels were causally linked with parental lifespan. Phenome‐wide MR analyses were used to map genetically regulated genes, proteins and metabolites with other human traits as well as the disease‐related phenome in the FinnGen cohorts (n = 135,638). Altogether, this study identified new candidate genes, circulating proteins and metabolites that may influence human aging as well as potential therapeutic targets for chronic diseases that warrant further investigation., Schematic overview of the analytical framework used to identify novel biological determinants of lifespan and potential drug targets for aging‐associated diseases using genome‐wide association study summary statistics of >1 million parental lifespans.
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- 2021
8. A multidimensional Mendelian randomization study on the impact of gut dysbiosis on chronic diseases and human longevity
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Hasanga D. Manikpurage, Benoit J. Arsenault, Nele Taba, Nooshin Ghodsian, Sébastien Thériault, Éloi Gagnon, Tõnu Esko, Patricia L. Mitchell, Patrick Mathieu, and Erik Abner
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biology ,business.industry ,media_common.quotation_subject ,Fatty liver ,Longevity ,Disease ,Type 2 diabetes ,Gut flora ,Bioinformatics ,medicine.disease ,biology.organism_classification ,Inflammatory bowel disease ,Mendelian randomization ,Medicine ,business ,media_common ,Kidney disease - Abstract
Alterations of the gut microbiota, often referred to as gut dysbiosis, have been associated with several chronic diseases and longevity in pre-clinical models as well as in observational studies. Whether these relationships underlie causal associations in humans remains to be established. We aimed to determine whether gut dysbiosis influences the risk of chronic diseases and longevity using a comprehensive 2-Sample Mendelian randomization (2SMR) approach. We included as exposures inflammatory bowel disease (IBD) as a human model of gut dysbiosis, 11 gut-associated metabolites and pathways and 48 microbial taxa. Study outcomes included eight chronic diseases previously linked with gut dysbiosis using observational studies (Alzheimer’s disease, depression, type 2 diabetes, non-alcoholic fatty liver disease, coronary artery disease (CAD), stroke, osteoporosis and chronic kidney disease) as well as parental longevity and life expectancy. Neither IBD, nor gut-associated metabolites were causally associated with chronic disease or lifespan. After multiple testing correction for 582 tests, no microbial taxa-chronic disease associations remained significant. After robustness analyses and multivariate MR to correct for body mass index and alcohol intake on all 42 nominally significant causal relationships, four associations remained. Altogether, results of this multidimensional Mendelian randomization study suggest that gut dysbiosis has little impact on chronic diseases and human longevity and that previous documented associations may not underly causal relationships. Studies with larger sample sizes and more optimal taxonomic discrimination may ultimately be required to determine whether the human gut microbiota plays a causal role in the etiology of chronic diseases and longevity.
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- 2021
9. The J domain of sacsin disrupts intermediate filament assembly
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Young Jc, Bernard B, Benoit J. Gentil, Dicaire M, Sandra Minotti, Dabbaghizadeh A, Dagher R, Cheng-Boivin Z, Heather D. Durham, and Paré A
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Neurofilament ,biology ,Chemistry ,biology.protein ,Regulator ,Vimentin ,Intermediate filament ,Homeostasis ,In vitro ,Loss function ,Hsp70 ,Cell biology - Abstract
Autosomal Recessive Spastic Ataxia of the Charlevoix Saguenay (ARSACS), is caused by loss of function mutations in the SACS gene, which encodes sacsin, a giant protein of 520 kDa. A key feature of the absence of sacsin in cells is the formation of abnormal bundles of intermediate filaments (IF) including neurofilaments (NF) in neurons and vimentin IF in fibroblasts, suggesting a role of sacsin in IF homeostasis. Sacsin contains a J domain (SacsJ) homologous to Hsp40, that can interact with Hsp70 chaperones. The SacsJ domain resolved NF bundles in cultured Sacs-/- neurons, however, its mechanism is still unclear. Here, we focused on the role of SacsJ in NF assembly. We report that the SacsJ domain directly interacts with NF proteins in vitro to disassemble NFL filaments, and to inhibit their initial assembly, in the absence of Hsp70. We generated a cell-penetrating peptide derived from this domain, SacsJ-myc-TAT, which was efficient in disassembling both vimentin IF and NF in cultured fibroblasts and Sacs+/+ motor neurons as well as NF bundles in cultured Sacs-/- motor neurons. Whereas a normal NF network was restored in Sacs-/- neurons treated with the SacsJ peptide, there was some loss of IF networks in Sacs+/+ fibroblasts or neurons. These results suggest that SacsJ is a key regulator of NF and IF networks in cells, with implications for its therapeutic use.
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- 2021
10. Lipoprotein Proteomics and Aortic Valve Transcriptomics Identify Biological Pathways Linking Lipoprotein(a) Levels to Aortic Stenosis
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Nicolas Perrot, Sylvie Bourassa, Nathalie Gaudreault, Marlys L. Koschinsky, Audrey-Anne Després, Jakie Guertin, Benoit J. Arsenault, Raphaëlle Bourgeois, Arnaud Droit, Arnaud Girard, Corey A Scipione, Jérôme Bourgault, Patrick Mathieu, Philippe Pibarot, Patricia L. Mitchell, Sébastien Thériault, Clarisse Gotti, Yohan Bossé, and Michael B. Boffa
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0301 basic medicine ,Aortic valve ,Leukocyte migration ,Pathology ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,030204 cardiovascular system & hematology ,Protein activation cascade ,Biochemistry ,Microbiology ,Article ,03 medical and health sciences ,transcriptomics ,0302 clinical medicine ,proteomics ,Aortic valve replacement ,Platelet degranulation ,lipoprotein(a) ,Medicine ,Molecular Biology ,biology ,business.industry ,Calcific aortic valve stenosis ,Lipoprotein(a) ,calcific aortic valve stenosis ,medicine.disease ,aortic valve ,QR1-502 ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,biology.protein ,cardiovascular system ,business ,Lipoprotein - Abstract
Lipoprotein(a) (Lp(a)) is one of the most important risk factors for the development of calcific aortic valve stenosis (CAVS). However, the mechanisms through which Lp(a) causes CAVS are currently unknown. Our objectives were to characterize the Lp(a) proteome and to identify proteins that may be differentially associated with Lp(a) in patients with versus without CAVS. Our second objective was to identify genes that may be differentially regulated by exposure to high versus low Lp(a) levels in explanted aortic valves from patients with CAVS. We isolated Lp(a) from the blood of 21 patients with CAVS and 22 volunteers and performed untargeted label-free analysis of the Lp(a) proteome. We also investigated the transcriptomic signature of calcified aortic valves from patients who underwent aortic valve replacement with high versus low Lp(a) levels (n = 118). Proteins involved in the protein activation cascade, platelet degranulation, leukocyte migration, and response to wounding may be associated with Lp(a) depending on CAVS status. The transcriptomic analysis identified genes involved in cardiac aging, chondrocyte development, and inflammation as potentially influenced by Lp(a). Our multi-omic analyses identified biological pathways through which Lp(a) may cause CAVS, as well as key molecular events that could be triggered by Lp(a) in CAVS development.
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- 2021
11. The Food Additive Xanthan Gum Drives Adaptation of the Human Gut Microbiota
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Matthew K. Schnizlein, S.P. McDonald, Harry Brumer, Nicholas A. Pudlo, Qiu L, La Rosa Sl, Flint G, Ashootosh Tripathi, J. Li, Bernard Henrissat, Phillip B. Pope, Nicolas Terrapon, Emiley A. Eloe-Fadrosh, Neha Varghese, Robertson A, Buttner D, Live Heldal Hagen, Eric C. Martens, Lombard, Matthew Ostrowski, Tianming Yao, Gabriel V. Pereira, Bruce R. Hamaker, Benoit J. Kunath, Thomas M. Schmidt, and Vincent B. Young
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chemistry.chemical_classification ,food.ingredient ,biology ,Food additive ,Glycoside hydrolase family 5 ,Gut flora ,biology.organism_classification ,Polysaccharide ,food ,chemistry ,medicine ,Food science ,Bacteroides ,Digestion ,Xanthan gum ,Ruminococcaceae ,medicine.drug - Abstract
The diets of industrialized countries reflect the increasing use of processed foods, often with the introduction of novel food additives. Xanthan gum is a complex polysaccharide with unique rheological properties that have established its use as a widespread stabilizer and thickening agent1. However, little is known about its direct interaction with the gut microbiota, which plays a central role in digestion of other, chemically-distinct dietary fiber polysaccharides. Here, we show that the ability to digest xanthan gum is surprisingly common in industrialized human gut microbiomes and appears to be contingent on the activity of a single bacterium that is a member of an uncultured bacterial genus in the family Ruminococcaceae. We used a combination of enrichment culture, multi-omics, and recombinant enzyme studies to identify and characterize a complete pathway in this uncultured bacterium for the degradation of xanthan gum. Our data reveal that this keystone degrader cleaves the xanthan gum backbone with a novel glycoside hydrolase family 5 (GH5) enzyme before processing the released oligosaccharides using additional enzymes. Surprisingly, some individuals harbor a Bacteroides species that is capable of consuming oligosaccharide products generated by the keystone Ruminococcaceae or a purified form of the GH5 enzyme. This Bacteroides symbiont is equipped with its own distinct enzymatic pathway to cross-feed on xanthan gum breakdown products, which still harbor the native linkage complexity in xanthan gum, but it cannot directly degrade the high molecular weight polymer. Thus, the introduction of a common food additive into the human diet in the past 50 years has promoted the establishment of a food chain involving at least two members of different phyla of gut bacteria.
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- 2021
12. HDL-enriched miR-30a-5p is associated with HDL-cholesterol levels and glucose metabolism in healthy men and women
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Benoit J. Arsenault, Simon-Pierre Guay, Elizabeth Hutchins, Cécilia Légaré, Renée Guérin, Kendall Van Keuren-Jensen, Luigi Bouchard, Véronique Desgagné, François Corbin, Marjorie Boyer, and Andrée-Anne Clément
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0301 basic medicine ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,030204 cardiovascular system & hematology ,Biology ,Carbohydrate metabolism ,Mir 30a 5p ,Fasting insulin ,03 medical and health sciences ,chemistry.chemical_compound ,Young Adult ,0302 clinical medicine ,Insulin resistance ,Internal medicine ,microRNA ,Genetics ,medicine ,Humans ,Cholesterol ,Gene Expression Profiling ,Cholesterol, HDL ,Cardiometabolic Risk Factors ,Computational Biology ,High-Throughput Nucleotide Sequencing ,Middle Aged ,medicine.disease ,Lipid Metabolism ,Healthy Volunteers ,MicroRNAs ,030104 developmental biology ,Endocrinology ,Glucose ,chemistry ,Gene Expression Regulation ,lipids (amino acids, peptides, and proteins) ,Female ,Energy Metabolism ,Lipoproteins, HDL ,Homeostasis ,Biomarkers ,Lipoprotein - Abstract
Aim: To investigate the associations between high-density lipoprotein (HDL)-enriched miRNAs and the cardiometabolic profile of healthy men and women. Patients & methods: miRNAs were quantified using next-generation sequencing of miRNAs extracted from purified HDL and plasma from 17 healthy men and women couples. Results: Among the HDL-enriched miRNAs, miR-30a-5p correlated positively with HDL-cholesterol levels, whereas miR-144-5p and miR-30a-5p were negatively associated with fasting insulin levels and Homeostasis model assessment of insulin resistance index. Overall, miR-30a-5p, miR-150-5p and sex contributed to 45% of HDL-cholesterol variance. A model containing only miR-30a-5p, age and sex explained 41% of fasting glucose variance. Conclusion: HDL-enriched miRNAs, notably miR-30a-5p, are associated with cardiometabolic markers. These miRNAs could play a role in HDL’s protective functions, particularly regarding glucose-insulin homeostasis.
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- 2021
13. Synergistic effect of short- and long-read sequencing on functional meta-omics
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Cedric Christian Laczny, Benoit J. Kunath, Patrick May, de Nies L, Galata, Rashi Halder, Paul Wilmes, Magdalena Calusinska, and Susheel Bhanu Busi
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Human gut ,Metagenomics ,Sequencing data ,Protein inference ,Computational biology ,Microbiome ,Biology ,computer.software_genre ,computer ,In situ study ,Data integration - Abstract
Real-world evaluations of metagenomic reconstructions are challenged by distinguishing reconstruction artefacts from genes and proteins present in situ. Here, we evaluate short-read-only, long-read-only, and hybrid assembly approaches on four different metagenomic samples of varying complexity and demonstrate how they affect gene and protein inference which is particularly relevant for downstream functional analyses. For a human gut microbiome sample, we use complementary metatranscriptomic, and metaproteomic data to evaluate the metagenomic data-based protein predictions. Our findings pave the way for critical assessments of metagenomic reconstructions and we propose a reference-independent solution based on the synergistic effects of multi-omic data integration for the in situ study of microbiomes using long-read sequencing data.
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- 2021
14. Exposure to Low Lipoprotein(a) Levels
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Benoit J. Arsenault
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biology ,business.industry ,Mendelian randomization ,Key (cryptography) ,biology.protein ,Medicine ,Physiology ,Lipoprotein(a) ,Healthy aging ,Cardiology and Cardiovascular Medicine ,business - Published
- 2019
15. Activated platelets promote an osteogenic programme and the progression of calcific aortic valve stenosis
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Ghada Mkannez, Lionel Tastet, Benoit J. Arsenault, Fayez Hadji, André Marette, Marie-Chloé Boulanger, Abdellaziz Dahou, Yohan Bossé, Patrick Mathieu, Younes Messadeq, Philippe Pibarot, Mohamed Jalloul Nsaibia, and Rihab Bouchareb
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Blood Platelets ,Platelet Membrane Glycoprotein IIb ,Pathology ,medicine.medical_specialty ,030204 cardiovascular system & hematology ,Fibrin ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Osteogenesis ,Lysophosphatidic acid ,medicine ,Animals ,Humans ,Platelet ,Platelet activation ,Receptor ,biology ,Phosphoric Diester Hydrolases ,business.industry ,Integrin beta3 ,Calcinosis ,Calcific aortic valve stenosis ,Aortic Valve Stenosis ,030229 sport sciences ,3. Good health ,Adenosine diphosphate ,chemistry ,Aortic Valve ,Apolipoprotein B-100 ,Disease Progression ,Microscopy, Electron, Scanning ,cardiovascular system ,biology.protein ,Lysophospholipids ,Autotaxin ,Cardiology and Cardiovascular Medicine ,business - Abstract
Aims Calcific aortic valve stenosis (CAVS) is characterized by a fibrocalcific process. Studies have shown an association between CAVS and the activation of platelets. It is believed that shear stress associated with CAVS promotes the activation of platelets. However, whether platelets actively participate to the mineralization of the aortic valve (AV) and the progression of CAVS is presently unknown. To identify the role of platelets into the pathobiology of CAVS. Methods and results Explanted control non-mineralized and mineralized AVs were examined by scanning electron microscope (SEM) for the presence of activated platelets. In-depth functional assays were carried out with isolated human valve interstitial cells (VICs) and platelets as well as in LDLR−/− apoB100/100 IGFII (IGFII) mice. Scanning electron microscope and immunogold markings for glycoprotein IIb/IIIa (GPIIb/IIIa) revealed the presence of platelet aggregates with fibrin in endothelium-denuded areas of CAVS. In isolated VICs, collagen-activated platelets induced an osteogenic programme. Platelet-derived adenosine diphosphate induced the release of autotaxin (ATX) by VICs. The binding of ATX to GPIIb/IIIa of platelets generated lysophosphatidic acid (LysoPA) with pro-osteogenic properties. In IGFII mice with CAVS, platelet aggregates were found at the surface of AVs. Administration of activated platelets to IGFII mice accelerated the development of CAVS by 2.1-fold, whereas a treatment with Ki16425, an antagonist of LysoPA receptors, prevented platelet-induced mineralization of the AV and the progression of CAVS. Conclusions These findings suggest a novel role for platelets in the progression of CAVS.
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- 2018
16. Sacsin, mutated in the ataxia ARSACS, regulates intermediate filament assembly and dynamics
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Marie Ménade, Kalle Gehring, Benoit J. Gentil, Roxanne Larivière, Sandra Minotti, Gia-Thanh Lai, Bernard Brais, J. Paul Chapple, and Heather D. Durham
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0301 basic medicine ,Ataxia ,Neurofilament ,Intermediate Filaments ,Biology ,Biochemistry ,Homology (biology) ,Protein filament ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Heat shock protein ,Genetics ,medicine ,Animals ,Humans ,Spinocerebellar Ataxias ,Intermediate filament ,Cytoskeleton ,Molecular Biology ,Cells, Cultured ,Heat-Shock Proteins ,Mice, Knockout ,Motor Neurons ,Fibroblasts ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,Muscle Spasticity ,Chaperone (protein) ,Mutation ,biology.protein ,medicine.symptom ,030217 neurology & neurosurgery ,Biotechnology - Abstract
Loss of sacsin, a large 520 kDa multidomain protein, causes autosomal recessive spastic ataxia of the Charlevoix-Saguenay, one of the most common childhood-onset recessive ataxias. A prominent feature is abnormal bundling of neurofilaments in many neuronal populations. This study shows the direct involvement of sacsin domains in regulating intermediate filament assembly and dynamics and identifies important domains for alleviating neurofilament bundles in neurons lacking sacsin. Peptides encoding sacsin internal repeat (SIRPT) 1, J-domains, and ubiquitin-like domain modified neurofilament assembly in vivo. The domains with chaperone homology, the SIRPT and the J-domain, had opposite effects, promoting and preventing filament assembly, respectively. In cultured Sacs-/- motor neurons, both the SIRPT1 and J-domain resolved preexisting neurofilament bundles. Increasing expression of heat shock proteins also resolved neurofilament bundles, indicating that this endogenous chaperone system can compensate to some extent for sacsin deficiency.-Gentil, B. J., Lai, G.-T., Menade, M., Lariviere, R., Minotti, S., Gehring, K., Chapple, J.-P., Brais, B., Durham, H. D. Sacsin, mutated in the ataxia ARSACS, regulates intermediate filament assembly and dynamics.
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- 2018
17. MTP deficiency caused by HADHB mutations: Pathophysiology and clinical manifestations
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Benoit J. Gentil, Rami Massie, and Robin Dagher
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0301 basic medicine ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Cardiomyopathy ,Schwann cell ,Mitochondrial trifunctional protein ,030105 genetics & heredity ,Biochemistry ,Lipid Metabolism, Inborn Errors ,Rhabdomyolysis ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Genetics ,medicine ,Humans ,Myopathy ,Molecular Biology ,biology ,business.industry ,Mitochondrial Trifunctional Protein ,Hypoketotic hypoglycemia ,Mitochondrial Myopathies ,medicine.disease ,medicine.anatomical_structure ,Peripheral neuropathy ,Phenotype ,Mitochondrial Trifunctional Protein, beta Subunit ,Mutation ,biology.protein ,medicine.symptom ,Nervous System Diseases ,business ,Cardiomyopathies ,030217 neurology & neurosurgery ,HADHB - Abstract
Mutations in the HADHB gene lead to Mitochondrial Trifunctional Protein (MTP) deficiency. MTP deficiency is a rare autosomal recessive disorder affecting long-chain fatty acid oxidation. Patients affected by MTP deficiency are unable to metabolize long-chain fatty-acids and suffer a variety of symptoms exacerbated during fasting. The three phenotypes associated with complete MTP deficiency are an early-onset cardiomyopathy and early death, an intermediate form with recurrent hypoketotic hypoglycemia and a sensorimotor neuropathy with episodic rhabdomyolysis with small amount of residual enzyme activities. This review aims to discuss the pathophysiological mechanisms and clinical manifestations of each phenotype, which appears different and linked to HADHB expression levels. Notably, the pathophysiology of the sensorimotor neuropathy is relatively unknown and we provide a hypothesis on the qualitative aspect of the role of acylcarnitine buildup in Schwann cells in MTP deficiency patients. We propose that acylcarnitine may exit the Schwann cell and alter membrane properties of nearby axons leading to axonal degeneration based on recent findings in different metabolic disorders.
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- 2021
18. Genetic Association and Mendelian Randomization for Hypothyroidism Highlight Immune Molecular Mechanisms
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Yohan Bossé, Patrick Mathieu, Samuel Mathieu, Benoit J. Arsenault, Christian Couture, Sébastien Thériault, and Zhonglin Li
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endocrine system ,History ,Candidate gene ,endocrine system diseases ,Polymers and Plastics ,Alternative splicing ,Biology ,Quantitative trait locus ,Bioinformatics ,Industrial and Manufacturing Engineering ,Immune checkpoint ,Mendelian randomization ,Business and International Management ,Interleukin-7 receptor ,Gene ,hormones, hormone substitutes, and hormone antagonists ,Genetic association - Abstract
We carried out a genome-wide association analysis including 51,194 cases of hypothyroidism and 443,383 controls. In total, 139 risk loci were associated to hypothyroidism with genes involved in lymphocyte function. Candidate genes associated with hypothyroidism were identified by using molecular quantitative trait loci, colocalization and enhancer-promoter chromatin looping. Mendelian randomization (MR) identified 42 blood expressed genes and circulating proteins as candidate causal molecules in hypothyroidism. Association data identified alternative splicing variant rs6897932 increasing secreted IL7R (sIL7R). MR with multiple instruments showed that circulating sIL7R was positively associated with the risk of hypothyroidism. Drug-gene interaction analysis provided evidence that immune checkpoint and tyrosine kinase inhibitors used in cancer therapy increase the risk of hypothyroidism. Hence, integrative mapping and MR support that expression of genes and proteins enriched in lymphocyte function are associated with the risk of hypothyroidism and provide genetic evidence for drug-induced hypothyroidism and identify actionable potential drug targets.
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- 2021
19. Tryptophan 2,3-Dioxygenase Expression Identified in Murine Decidual Stromal Cells Is Not Essential for Feto-Maternal Tolerance
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Delia Hoffmann, Tereza Dvorakova, Florence Schramme, Vincent Stroobant, Benoit J. Van den Eynde, and UCL - SSS/DDUV/GECE - Génétique cellulaire
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Male ,0301 basic medicine ,Kynurenine pathway ,Angiogenesis ,IDO1-indoleamine 2,3-dioxygenase 1 ,decidual stromal cell ,0302 clinical medicine ,Pregnancy ,TDO - tryptophan 2,3-dioxygenase ,Immunology and Allergy ,Maternal-Fetal Exchange ,Kynurenine ,Original Research ,Mice, Knockout ,INDUCTION ,CANCER ,Tryptophan Oxygenase ,3-dioxygenase ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,immunohistochemistry ,GROWTH ,Immunohistochemistry ,Female ,feto-maternal tolerance ,Life Sciences & Biomedicine ,lcsh:Immunologic diseases. Allergy ,Cell type ,Stromal cell ,placenta ,Immunology ,INHIBITION ,Gestational Age ,Biology ,Andrology ,KYNURENINE PATHWAY ,03 medical and health sciences ,Placenta ,Decidua ,Immune Tolerance ,medicine ,Animals ,Indoleamine-Pyrrole 2,3,-Dioxygenase ,SUPPRESSION ,TDO - tryptophan 2 ,Fetus ,Science & Technology ,IDO1—indoleamine 2 ,HUMAN PLACENTA ,TUMORAL IMMUNE RESISTANCE ,Decidualization ,IDO1—indoleamine 2,3-dioxygenase 1 ,DEGRADATION ,Mice, Inbred C57BL ,3-dioxygenase 1 ,Fertility ,030104 developmental biology ,Stromal Cells ,lcsh:RC581-607 ,INDOLEAMINE 2,3-DIOXYGENASE - Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) catalyze the rate-limiting step of tryptophan catabolism along the kynurenine pathway, which has important immuno suppressive properties, particularly in tumor cells and dendritic cells. The prominent expression of IDO1 in the placenta also suggested a role in preventing immune rejection of fetal tissues, and pharmacological inhibition of IDO1 induced abortion of allogeneic fetuses in mice. However, this was later challenged by the lack of rejection of allogeneic fetuses in IDO1-KO mice, suggesting that other mechanisms may compensate for IDO1 deficiency. Here we investigated whether TDO could contribute to feto-maternal tolerance and compensate for IDO1 deficiency in IDO1-KO mice. Expression of TDO mRNA was previously detected in placental tissues. We developed a new chimeric rabbit anti-TDO antibody to confirm TDO expression at the protein level and identify the positive cell type by immunohistochemistry in murine placenta. We observed massive TDO expression in decidual stromal cells, starting at day E3.5, peaking at day E6.5 then declining rapidly while remaining detectable until gestation end. IDO1 was also induced in decidual stromal cells, but only at a later stage of gestation when TDO expression declined. To determine whether TDO contributed to feto-maternal tolerance, we mated TDO-KO and double IDO1-TDO-KO females with allogeneic males. However, we did not observe reduced fertility. These results suggest that, despite its expression in decidual stromal cells, TDO is not a dominant mechanism of feto-maternal tolerance able to compensate for the absence of IDO1. Redundant additional mechanisms of immunosuppression likely take over in these KO mice. The massive expression of TDO during decidualization might suggest a role of TDO in angiogenesis or vessel tonicity, as previously described for IDO1. ispartof: FRONTIERS IN IMMUNOLOGY vol:11 ispartof: location:Switzerland status: published
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- 2020
20. Electronic Health Record-Based Genome-Wide Meta-Analysis and Mendelian Randomization Identify Metabolic and Phenotypic Consequences of Non-Alcoholic Fatty Liver Disease
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Alexis St-Amand, Patrick Mathieu, Nele Taba, Yohan Bossé, Erik Abner, Christian Couture, Sébastien Thériault, Patricia L. Mitchell, Marie-Claude Vohl, Émilie Gobeil, Nooshin Ghodsian, Benoit J. Arsenault, André Tchernof, Nicolas Perrot, and Tõnu Esko
- Subjects
Fatty liver ,nutritional and metabolic diseases ,Non alcoholic ,Disease ,Computational biology ,Biology ,medicine.disease ,Genome ,Phenotype ,digestive system diseases ,Electronic health record ,Meta-analysis ,Mendelian randomization ,medicine - Abstract
Non-alcoholic fatty liver disease (NAFLD) has been associated with several blood biomarkers and chronic diseases. Whether these associations underlie causal effects remains to be determined. We aimed at identifying blood metabolites, blood proteins and human diseases that are causally impacted by the presence of NAFLD using Mendelian randomization. We created a NAFLD genetic instrument from NAFLD loci (MTARC1, GCKR, LPL, TRIB1, LMO3, FTO, TM6SF2, APOE and PNPLA3) identified in a new electronic health record based-GWAS meta-analysis (6715 cases and 682,748 controls). We found a potentially causal effect of NAFLD on tyrosine metabolism as well as on blood levels of eight proteins that could potentially represent new early biomarkers of NAFLD. Using results from the UK Biobank, FinnGen and the COVID-19 Host Genetics Initiative, we found that NAFLD was not causally associated with diseases outside the spectrum of liver diseases, suggesting that the resolution of NAFLD might not prevent other diseases.
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- 2020
21. Roles of bacteriophages, plasmids and CRISPR immunity in microbial community dynamics revealed using time-series integrated meta-omics
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Emilie E. L. Muller, Nathan D. Hicks, Karoline Faust, Paul Keim, James M. Schupp, Susana Martinez Arbas, Shaman Narayanasamy, Haixu Tang, Cedric Christian Laczny, Malte Herold, Lance B. Price, Yuzhen Ye, Patrick May, Robert L. Moritz, John D. Gillece, Tony J. Lam, Sujun Li, Michael R. Hoopmann, Cindy M. Liu, Paul Wilmes, Laura Lebrun, Alexander Skupin, Benoit J. Kunath, Génétique moléculaire, génomique, microbiologie (GMGM), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)
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Microbiologie [F11] [Sciences du vivant] ,Ecosystem ecology ,phages ,Applied Microbiology and Biotechnology ,Genome ,FILAMENTOUS BACTERIUM ,Bacteriophage ,Plasmid ,TOOL ,CRISPR ,activated sludge ,Bacteriophages ,Clustered Regularly Interspaced Short Palindromic Repeats ,Microbiology [F11] [Life sciences] ,ComputingMilieux_MISCELLANEOUS ,Genetics ,0303 health sciences ,education.field_of_study ,Network topology ,metatranscriptomics ,Sewage ,Microbial consortium ,[SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] ,6. Clean water ,SINGLE CELLS ,Life Sciences & Biomedicine ,Plasmids ,Microbiology (medical) ,plasmids ,GENES ,Microbial Consortia ,Immunology ,Population ,Biology ,Microbiology ,Article ,Water Purification ,03 medical and health sciences ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,education ,Gene ,wastewater ,030304 developmental biology ,CANDIDATUS MICROTHRIX-PARVICELLA ,ENVIRONMENT ,metagenomics ,Science & Technology ,IDENTIFICATION ,SEQUENCES ,Bacteria ,030306 microbiology ,Bacteriology ,Cell Biology ,multi-omics ,biology.organism_classification ,REPEATS ,Metagenome ,Microbial Interactions ,Metagenomics ,Microbiome ,CRISPR-Cas Systems ,Mobile genetic elements ,[SDE.BE]Environmental Sciences/Biodiversity and Ecology ,time series ,RESISTANCE ,Genome, Bacterial ,[SDV.EE.IEO]Life Sciences [q-bio]/Ecology, environment/Symbiosis - Abstract
Viruses and plasmids (invasive mobile genetic elements (iMGEs)) have important roles in shaping microbial communities, but their dynamic interactions with CRISPR-based immunity remain unresolved. We analysed generation-resolved iMGE–host dynamics spanning one and a half years in a microbial consortium from a biological wastewater treatment plant using integrated meta-omics. We identified 31 bacterial metagenome-assembled genomes encoding complete CRISPR–Cas systems and their corresponding iMGEs. CRISPR-targeted plasmids outnumbered their bacteriophage counterparts by at least fivefold, highlighting the importance of CRISPR-mediated defence against plasmids. Linear modelling of our time-series data revealed that the variation in plasmid abundance over time explained more of the observed community dynamics than phages. Community-scale CRISPR-based plasmid–host and phage–host interaction networks revealed an increase in CRISPR-mediated interactions coinciding with a decrease in the dominant ‘Candidatus Microthrix parvicella’ population. Protospacers were enriched in sequences targeting genes involved in the transmission of iMGEs. Understanding the factors shaping the fitness of specific populations is necessary to devise control strategies for undesirable species and to predict or explain community-wide phenotypes., CRISPR-based immunity and microbial community dynamics in a wastewater treatment plant over one and a half years.
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- 2020
22. 89 First-in-human CAR T targets cleaved MUC1, the growth factor receptor form
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Mark G. Carter, Cynthia Bamdad, Trevor J. Grant, Tyler E. Swanson, Jennifer M. Specht, Benoit J. Smagghe, Andrew K. Stewart, Pengyu Huang, and Danica M. Page
- Subjects
biology ,medicine.diagnostic_test ,Chemistry ,Growth factor ,medicine.medical_treatment ,T cell ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,lcsh:RC254-282 ,In vitro ,medicine.anatomical_structure ,Growth factor receptor ,Cancer cell ,Biopsy ,Cancer research ,medicine ,biology.protein ,Antibody ,MUC1 - Abstract
Background Minerva Biotechnologies has opened a Phase I 1st-in-human CAR T clinical trial, NCT-04020575, for metastatic breast cancers at the Fred Hutchinson Cancer Research Center. huMNC2-CAR44 targets the truncated extra cellular domain of MUC1* (muk 1 star), which is the transmembrane cleavage product that remains after MUC1 is cleaved and the tandem repeat domain is shed from the cancer cells. No therapeutic that targets MUC1* has ever been tested in humans. All previous, failed attempts to therapeutically target MUC1 have targeted the tandem repeat domains, which are cleaved and shed from the surface of cancer cells. MUC1 cleavage increases as tumor stage increases. Cleavage and shedding of the tandem repeat domain unmasks an ectopic binding site for onco-embryonic growth factor NME7AB. The antibody fragment that targets the CAR to the tumor competes with NME7AB for binding to this same ectopic site. MUC1* growth factor receptor is activated when onco-embryonic growth factor NME7AB dimerizes its truncated extra cellular domain. Methods Autologous huMNC2-CAR44 T cells undergo a short 11-day manufacturing process, which includes an antigen stimulation step and preserves many of the cells in the naive and central memory state. Patients are pre-treated with standard Cy-Flu lymphodepletion. Dose escalation phase is standard 3 × 3 with a starting dose 3.3 × 10e5 CAR T cells and going up to 1.0 × 10e7 cells. Patients are eligible if biopsy is greater than or equal to 30% reactive with MNC2 in a CLIA validated diagnostic assay. Results In vitro, huMNC2-CAR44 T cells killed cancer cells, but not non-cancer cells even if they expressed MUC1 or a normal form of cleaved MUC1. In NSG mice (n>300), huMNC2-CAR44 T cells eliminated MUC1* positive tumors from implanted breast cancer cells. A single CAR T cell injection eliminated tumors for 100 days; control animals had to be sacrificed at Day 20. Further, huMNC2-CAR44 T cell mediated killing increased as MUC1* density increased. In tissue micro array studies, huMNC2-scFv recognized 95% of breast cancers, across all subtypes, 83% ovarian, 78% pancreatic and 71% of lung cancers. huMNC2-scFv showed almost no binding to normal tissues and no staining of critical organs. Although patient recruitment has been slowed by COVID-19, preliminary results indicate CAR T cell expansion and possible efficacy. Conclusions Preliminary results show that patients experienced robust CAR T cell expansion with CAR-positive T cells persisting at Day 60 post huMNC2-CAR44 T cell treatment. Possible signs of efficacy were measured. Trial Registration NCT04020575
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- 2020
23. Integration of time-series meta-omics data reveals how microbial ecosystems respond to disturbance
- Author
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James M. Schupp, Emilie E. L. Muller, Christian Jäger, Paul Keim, Laura Lebrun, Haixu Tang, Malte Herold, Paul Wilmes, Hugo Roume, Sujun Li, Michael R. Hoopmann, John D. Gillece, Patrick May, Abdul Sheik, Benoit J. Kunath, Luise A. K. Kleine-Borgmann, Irina Bessarab, Cedric Christian Laczny, Susana Martinez Arbas, Rohan Benjamin Hugh Williams, Yuzhen Ye, Anna Heintz-Buschart, Robert L. Moritz, Shaman Narayanasamy, MetaGenoPolis (MGP (US 1367)), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Génétique moléculaire, génomique, microbiologie (GMGM), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Water microbiology ,Proteomics ,0301 basic medicine ,meta-metabolomics ,Microbiologie [F11] [Sciences du vivant] ,Time Factors ,General Physics and Astronomy ,Wastewater ,Microbial ecology ,Bioreactors ,Dynamical systems ,activated sludge ,Microbiology [F11] [Life sciences] ,lcsh:Science ,ComputingMilieux_MISCELLANEOUS ,[SDV.EE]Life Sciences [q-bio]/Ecology, environment ,metatranscriptomics ,Multidisciplinary ,Microbiota ,Community structure ,[SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] ,6. Clean water ,metaproteomics ,Science ,030106 microbiology ,Niche ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Metabolomics ,ecological niche ,wastewater ,Ecosystem ,Ecological niche ,metagenomics ,Phenotypic plasticity ,Bacteria ,Resistance (ecology) ,General Chemistry ,15. Life on land ,030104 developmental biology ,13. Climate action ,Evolutionary biology ,Metagenomics ,Metaproteomics ,Metagenome ,lcsh:Q ,lipid accumulating organisms ,[SDE.BE]Environmental Sciences/Biodiversity and Ecology ,time series ,Adaptation - Abstract
The development of reliable, mixed-culture biotechnological processes hinges on understanding how microbial ecosystems respond to disturbances. Here we reveal extensive phenotypic plasticity and niche complementarity in oleaginous microbial populations from a biological wastewater treatment plant. We perform meta-omics analyses (metagenomics, metatranscriptomics, metaproteomics and metabolomics) on in situ samples over 14 months at weekly intervals. Based on 1,364 de novo metagenome-assembled genomes, we uncover four distinct fundamental niche types. Throughout the time-series, we observe a major, transient shift in community structure, coinciding with substrate availability changes. Functional omics data reveals extensive variation in gene expression and substrate usage amongst community members. Ex situ bioreactor experiments confirm that responses occur within five hours of a pulse disturbance, demonstrating rapid adaptation by specific populations. Our results show that community resistance and resilience are a function of phenotypic plasticity and niche complementarity, and set the foundation for future ecological engineering efforts., Herold et al. present an integrated meta-omics framework to investigate how mixed microbial communities, such as oleaginous bacterial populations in biological wastewater treatment plants, respond with distinct adaptation strategies to disturbances. They show that community resistance and resilience are a function of phenotypic plasticity and niche complementarity.
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- 2020
24. Obesity, Body Fat Distribution, and Circulating Glutamate Concentrations, A BI-Directional Mendelian Randomization Study
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Ina Maltais-Payette, Benoit J. Arsenault, Jérôme Bourgault, and André Tchernof
- Subjects
medicine.medical_specialty ,Adipose Tissue, Appetite, and Obesity ,Endocrinology, Diabetes and Metabolism ,Glutamate receptor ,Integrated Physiology of Obesity and Metabolic Disease ,Biology ,medicine.disease ,Obesity ,Endocrinology ,Internal medicine ,Mendelian randomization ,medicine ,AcademicSubjects/MED00250 ,Body fat distribution - Abstract
Background: Various observational studies have reported that circulating levels of the amino acid glutamate was significantly associated with central fat accumulation in men and women. This is the case in the Framingham Heart Study Generation 3 for waist circumference, in the TwinsUK cohort for trunk fat and in a cohort of 1449 Japanese for visceral adipose tissue area measured by computed tomography. However, whether the association between abdominal adiposity and circulating glutamate is causal, as well as the direction of this association, is unknown. Here, we aimed to determine whether obesity and abdominal obesity were causally associated with circulating glutamate levels. Methods: We used a two-sample bi-directional inverse-variance weighted Mendelian randomization study design (IVW-MR). We derived summary statistics for our exposures and outcomes from published genome-wide association studies from the GIANT consortium (n = 681 275) and blood metabolites (n = 7 804). We identified independent genetic variants (r2 < 0.1) associated with body mass index (BMI) and waist-to-hip ratio adjusted for BMI (WHRadjBMI, p < 5x10-8) as well as circulating glutamate (p < 5x10-5). Results: We found no causal association between circulating glutamate levels and BMI (beta = 0.082, SE = 0.0413, p = 0.0471) or WHRadjBMI (beta = -0.00106, SE = 0.0401, p = 0.979). However, there was a positive effect of BMI (beta = 0.0608, SE = 0.0150, p = 5.19x10-5) and WHRadjBMI (beta = 0.0701, SE = 0.0198, p = 3.98x10-4) on circulating glutamate level. Conclusion: This Mendelian randomization analysis suggests that obesity and abdominal obesity are causally related to elevated circulating glutamate levels. Glutamate levels are not causally related to adiposity. Whether the downregulation of branched-chain amino acid catabolism in adipose tissue reported in obesity underlies this association should be explored.
- Published
- 2021
25. A Trans-Omic Mendelian Randomization Study of Parental Lifespan Uncovers Novel Aging Biology and Drug Candidates for Human Healthspan Extension
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Patrick Mathieu, J. Bourgeault, Yohan Bossé, Christian Couture, Benoit J. Arsenault, William Pelletier, Sébastien Thériault, Nooshin Ghodsian, Nicolas Perrot, Patricia L. Mitchell, and Zhonglin Li
- Subjects
Drug ,Drug repositioning ,media_common.quotation_subject ,Mendelian randomization ,Computational biology ,Biology ,Phenome ,Omics ,Biobank ,Gene ,Genetic architecture ,media_common - Abstract
The study of parental lifespan has emerged as an innovative tool to advance aging biology and our understanding of the genetic architecture of human longevity and healthspan. Here, we leveraged summary statistics of a genome-wide association study including over one million parental lifespans to identify genetically regulated genes from the Genotype-Tissue Expression project through a combination of multi-tissue transcriptome-wide association analyses and genetic colocalization. Mendelian randomization (MR) analyses also identified circulating proteins and metabolites causally associated with parental lifespan that may offer new drug repositioning opportunities for healthspan such as drugs targeting apolipoprotein-B-containing lipoproteins. Liver expression of HP, the gene encoding haptoglobin, and plasma haptoglobin levels were causally linked with parental lifespan. Phenome-wide MR analyses were used to map genetically regulated genes, proteins and metabolites with the disease-related phenome in the UK Biobank and FinnGen. Altogether, this study identified novel biological determinants of aging and potential therapeutic targets for human healthspan extension.
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- 2020
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26. Genetic and In Vitro Inhibition of PCSK9 and Calcific Aortic Valve Stenosis
- Author
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George Thanassoulis, Tõnu Esko, Gianluca Polvani, Paolo Poggio, Sébastien Thériault, J. Gustav Smith, Patrick Mathieu, Hasanga D. Manikpurage, Christian Dina, Jean-Jacques Schott, Andreas Martinsson, Erik Abner, Thierry Le Tourneau, Benoit J. Arsenault, Nicolas Perrot, Elvira Mass, Nicholas J. Wareham, Donato Moschetta, Sidwell Rigade, Marina Camera, James C. Engert, Marie-Annick Clavel, David Messika-Zeitoun, Philippe Pibarot, Romain Capoulade, Yohan Bossé, Vincenza Valerio, Hao Yu Chen, S. Matthijs Boekholdt, Cardiology, ACS - Atherosclerosis & ischemic syndromes, and ACS - Heart failure & arrhythmias
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Apolipoprotein B ,CLINICAL RESEARCH ,CAD, coronary artery disease ,PBS, phosphate-buffered saline ,VLDL-C, very-low-density lipoprotein cholesterol ,030204 cardiovascular system & hematology ,HDL-C, high-density lipoprotein cholesterol ,Ad DMEM, advanced Dulbecco’s modified Eagle’s medium ,03 medical and health sciences ,aortic valve interstitial cell ,0302 clinical medicine ,proprotein convertase subtilisin/kexin type 9 ,CAVS, calcific aortic valve stenosis ,wGRS, weighted genetic risk score ,lipoprotein(a) ,Internal medicine ,PBST, 1× phosphate-buffered saline with 0.1% Triton ,medicine ,apolipoprotein B ,Neutralizing antibody ,IQR, interquartile range ,apoB, apolipoprotein B ,biology ,business.industry ,PCSK9 ,Calcific aortic valve stenosis ,Lipoprotein(a) ,Odds ratio ,calcific aortic valve stenosis ,Lp(a), lipoprotein(a) ,SNP, single nucleotide polymorphism ,VIC, valve interstitial cell ,Confidence interval ,In vitro ,TC, total cholesterol ,030104 developmental biology ,LDL cholesterol ,biology.protein ,Cardiology ,cardiovascular system ,LDL-C, low-density lipoprotein cholesterol ,Cardiology and Cardiovascular Medicine ,business ,PCSK9, proprotein convertase subtilisin/kexin type 9 - Abstract
Visual Abstract, Highlights • Aortic stenosis was less prevalent in carriers of the PCSK9 R46L variant. • Variation at the PCSK9 locus influences LDL-C levels, but not Lp(a). • PCSK9 is produced and secreted by aortic valves. • In vitro, PCSK9 inhibition might lower calcification in aortic valve cells. • PCSK9 inhibition could represent a therapeutic strategy for aortic stenosis., Summary The authors investigated whether PCSK9 inhibition could represent a therapeutic strategy in calcific aortic valve stenosis (CAVS). A meta-analysis of 10 studies was performed to determine the impact of the PCSK9 R46L variant on CAVS, and the authors found that CAVS was less prevalent in carriers of this variant (odds ratio: 0.80 [95% confidence interval: 0.70 to 0.91]; p = 0.0011) compared with noncarriers. PCSK9 expression was higher in the aortic valves of patients CAVS compared with control patients. In human valve interstitials cells submitted to a pro-osteogenic medium, PCSK9 levels increased and a PCSK9 neutralizing antibody significantly reduced calcium accumulation.
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- 2020
27. The S100B Protein and Partners in Adipocyte Response to Cold Stress and Adaptive Thermogenesis: Facts, Hypotheses, and Perspectives
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Jacques Baudier, Benoit J. Gentil, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), and McGill University = Université McGill [Montréal, Canada]
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0301 basic medicine ,p53 ,[SDV]Life Sciences [q-bio] ,lcsh:QR1-502 ,Adipose tissue ,Review ,S100 Calcium Binding Protein beta Subunit ,enlargosome ,Biochemistry ,ATAD3A ,lcsh:Microbiology ,RAGE (receptor) ,annexin2 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Adipocyte ,Adipocytes ,Animals ,Humans ,Secretion ,CYP2E1 ,Molecular Biology ,biology ,Endoplasmic reticulum ,Cold-Shock Response ,S100A10 ,Thermogenesis ,AHNAK ,Cell biology ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,biology.protein ,RPTPσ ,exocytosis ,S100 proteins ,Intracellular - Abstract
International audience; In mammals, adipose tissue is an active secretory tissue that responds to mild hypothermia and as such is a genuine model to study molecular and cellular adaptive responses to cold-stress. A recent study identified a mammal-specific protein of the endoplasmic reticulum that is strongly induced in the inguinal subcutaneous white adipocyte upon exposure to cold, calsyntenin 3β (CLSTN3β). CLSTN3β regulates sympathetic innervation of thermogenic adipocytes and contributes to adaptive non-shivering thermogenesis. The calcium-and zinc-binding S100B is a downstream effector in the CLSTN3β pathways. We review, here, the literature on the transcriptional regulation of the S100b gene in adipocyte cells. We also rationalize the interactions of the S100B protein with its recognized or hypothesized intracellular (p53, ATAD3A, CYP2E1, AHNAK) and extracellular (Receptor for Advanced Glycation End products (RAGE), RPTPσ) target proteins in the context of adipocyte differentiation and adaptive thermogenesis. We highlight a chaperon-associated function for the intracellular S100B and point to functional synergies between the different intracellular S100B target proteins. A model of non-classical S100B secretion involving AHNAK/S100A10/annexin2-dependent exocytosis by the mean of exosomes is also proposed. Implications for related areas of research are noted and suggestions for future research are offered.
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- 2020
28. Functional Characterization of Neurofilament Light Splicing and Misbalance in Zebrafish
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Benoit J. Gentil, María Letizia Campanari, Edor Kabashi, Raphael Munoz-Ruiz, Doris Lou Demy, Heather D. Durham, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], Gestionnaire, Hal Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
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0301 basic medicine ,Gene isoform ,Embryo, Nonmammalian ,Neurofilament ,amyotrophic lateral sclerosis (ALS) ,TDP-43 ,RNA Splicing ,[SDV]Life Sciences [q-bio] ,Motor Activity ,Primary transcript ,TARDBP ,Article ,Cell Line ,Polymerization ,03 medical and health sciences ,0302 clinical medicine ,neurofilament light (NEFL) ,neurofilaments (NFs) ,Neurofilament Proteins ,Animals ,Humans ,Cytoskeleton ,Intermediate filament ,Postural Balance ,lcsh:QH301-705.5 ,Zebrafish ,Motor Neurons ,Sequence Homology, Amino Acid ,biology ,Chemistry ,Gene Expression Regulation, Developmental ,General Medicine ,Zebrafish Proteins ,biology.organism_classification ,zebrafish ,Axons ,Cell biology ,DNA-Binding Proteins ,[SDV] Life Sciences [q-bio] ,Phenotype ,030104 developmental biology ,lcsh:Biology (General) ,RNA splicing ,Atrophy ,amyotrophic lateral sclerosis (ALS), neurofilament light (NEFL), TDP-43 ,030217 neurology & neurosurgery - Abstract
Neurofilaments (NFs), a major cytoskeletal component of motor neurons, play a key role in the differentiation, establishment and maintenance of their morphology and mechanical strength. The de novo assembly of these neuronal intermediate filaments requires the presence of the neurofilament light subunit (NEFL), whose expression is reduced in motor neurons in amyotrophic lateral sclerosis (ALS). This study used zebrafish as a model to characterize the NEFL homologue neflb, which encodes two different isoforms via a splicing of the primary transcript (neflbE4 and neflbE3). In vivo imaging showed that neflb is crucial for proper neuronal development, and that disrupting the balance between its two isoforms specifically affects the NF assembly and motor axon growth, with resultant motor deficits. This equilibrium is also disrupted upon the partial depletion of TDP-43 (TAR DNA-binding protein 43), an RNA-binding protein encoded by the gene TARDBP that is mislocalized into cytoplasmic inclusions in ALS. The study supports the interaction of the NEFL expression and splicing with TDP-43 in a common pathway, both biologically and pathogenetically.
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- 2020
29. Functional characterization of Neurofilament Light b splicing andmisbalance in zebrafish
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Heather D. Durham, Raphael Munoz-Ruiz, Doris Lou Demy, Edor Kabashi, María Letizia Campanari, and Benoit J. Gentil
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0303 health sciences ,Neurofilament ,biology ,Chemistry ,Protein subunit ,RNA-binding protein ,Primary transcript ,biology.organism_classification ,Cell biology ,03 medical and health sciences ,0302 clinical medicine ,RNA splicing ,Cytoskeleton ,Intermediate filament ,Zebrafish ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
Neurofilaments (NFs), a major cytoskeletal component of motor neurons, play a key role in their differentiation, establishment and maintenance of their morphology and mechanical strength. Thede novoassembly of these neuronal intermediate filaments requires the presence of the neurofilament light subunit, NEFL, which expression is reduced in motor neurons in Amyotrophic Lateral Sclerosis (ALS). This study used zebrafish as a model to characterize the NEFL homologueneflb, which encodes two different isoforms via splicing of the primary transcript (neflbE4andneflbE3).In vivoimaging showed thatneflbis crucial for proper neuronal development, and that disrupting the balance between its two isoforms specifically affects NF assembly and motor axon growth, with resulting motor deficits. This equilibrium is also disrupted upon partial depletion of TDP-43, a RNA binding protein that is mislocalized into cytoplasmic inclusions in ALS. The study supports interaction of NEFL expression and splicing with TDP-43 in a common pathway, both biologically and pathogenetically.
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- 2020
30. Rumen metaproteomics: Closer to linking rumen microbial function to animal productivity traits
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Phillip B. Pope, Live Heldal Hagen, Magnus Ø. Arntzen, Thea Os Andersen, and Benoit J. Kunath
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Proteomics ,animal structures ,Livestock ,Rumen ,Quantitative Trait Loci ,Computational biology ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Animals ,Microbiome ,Rumen microorganisms ,Animal Husbandry ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,biology ,Host Microbial Interactions ,030302 biochemistry & molecular biology ,food and beverages ,Ruminants ,biology.organism_classification ,Gastrointestinal Microbiome ,Productivity (ecology) ,Metaproteomics ,Metagenome ,Anaerobic bacteria ,Metagenomics ,Function (biology) ,Archaea - Abstract
The rumen microbiome constitutes a dense and complex mixture of anaerobic bacteria, archaea, protozoa, virus and fungi. Collectively, rumen microbial populations interact closely in order to degrade and ferment complex plant material into nutrients for host metabolism, a process which also produces other by-products, such as methane gas. Our understanding of the rumen microbiome and its functions are of both scientific and industrial interest, as the metabolic functions are connected to animal health and nutrition, but at the same time contribute significantly to global greenhouse gas emissions. While many of the major microbial members of the rumen microbiome are acknowledged, advances in modern culture-independent meta-omic techniques, such as metaproteomics, enable deep exploration into active microbial populations involved in essential rumen metabolic functions. Meaningful and accurate metaproteomic analyses are highly dependent on representative samples, precise protein extraction and fractionation, as well as a comprehensive and high-quality protein sequence database that enables precise protein identification and quantification. This review focuses on the application of rumen metaproteomics, and its potential towards understanding the complex rumen microbiome and its metabolic functions. We present and discuss current methods in sample handling, protein extraction and data analysis for rumen metaproteomics, and finally emphasize the potential of (meta)genome-integrated metaproteomics for accurate reconstruction of active microbial populations in the rumen.
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- 2020
31. Association of Long-term Exposure to Elevated Lipoprotein(a) Levels With Parental Life Span, Chronic Disease-Free Survival, and Mortality Risk: A Mendelian Randomization Analysis
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Christian Couture, Benoit J. Arsenault, Patrick Mathieu, Yannick Kaiser, Yohan Bossé, Sébastien Thériault, Erik S.G. Stroes, William Pelletier, Philippe Pibarot, S. Matthijs Boekholdt, Nicolas Perrot, Nicholas J. Wareham, Kay-Tee Khaw, Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Graduate School, Vascular Medicine, Experimental Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, Cardiology, and ACS - Heart failure & arrhythmias
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Male ,Parents ,Cross-sectional study ,Longevity ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Mendelian randomization ,Medicine ,Humans ,Prospective Studies ,Prospective cohort study ,030304 developmental biology ,Aged ,0303 health sciences ,biology ,business.industry ,Case-control study ,Mendelian Randomization Analysis ,General Medicine ,Odds ratio ,Lipoprotein(a) ,Middle Aged ,3. Good health ,European Prospective Investigation into Cancer and Nutrition ,Cross-Sectional Studies ,Phenotype ,Case-Control Studies ,biology.protein ,Female ,business ,Demography - Abstract
Importance: Elevated lipoprotein(a) (Lp[a]) levels are associated with atherosclerotic cardiovascular diseases. The association between high Lp(a) levels and human longevity phenotypes is, however, controversial. Objective: To examine whether genetically determined Lp(a) levels are associated with parental life span and chronic disease-free survival (health span) and the association between Lp(a) levels and long-term, all-cause mortality risk. Design, Setting, and Participants: In this genetic association study, cross-sectional mendelian randomization (UK Biobank [2006-2010] and LifeGen Consortium) and prospective analyses (European Prospective Investigation Into Cancer and Nutrition (EPIC)-Norfolk [1993-1997, with patients followed up to 2016]) were conducted using individual-level data on 139 362 participants. The association between a weighted genetic risk score of 26 independent single-nucleotide polymorphisms at the LPA locus on parental life span using individual participant data from the UK Biobank, as well as with summary statistics of a genome-wide association study of more than 1 million life spans (UK Biobank and LifeGen), were examined. The association between these single-nucleotide polymorphisms and the age at the end of the health span was tested using summary statistics of a previous genome-wide association study in the UK Biobank. The association between Lp(a) levels and all-cause mortality in the EPIC-Norfolk study was also investigated. Data were analyzed from December 2018 to December 2019. Exposures: Genetically determined and measured Lp(a) levels. Main Outcomes and Measures: Parental life span, health span, and all-cause mortality. Results: In 139 362 white British participants (mean [SD] age, 62.8 [3.9] years; 52% women) from the UK Biobank, increases in the genetic risk score (weighted for a 50-mg/dL increase in Lp[a] levels) were inversely associated with a high parental life span (odds ratio, 0.92; 95% CI, 0.89-0.94; P = 2.7 × 10-8). Using the Egger-mendelian randomization method, a negative association between LPA single-nucleotide polymorphisms and parental life span (mean [SD] Egger-mendelian randomization slope, -0.0019 [0.0002]; P = 2.22 × 10-18) and health span (-0.0019 [0.0003]; P = 3.00 × 10-13) was noted. In 18 720 participants from EPIC-Norfolk (5686 cases), the mortality risk for those with Lp(a) levels equal to or above the 95th percentile was equivalent to being 1.5 years older in chronologic age (β coefficient [SE], 0.194 [0.064]). Conclusions and Relevance: The results of this study suggest a potential causal effect of absolute Lp(a) levels on human longevity as defined by parental life span, health span, and all-cause mortality. The results also provide a rationale for trials of Lp(a)-lowering therapy in individuals with high Lp(a) levels.
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- 2020
32. Integration of absolute multi-omics reveals translational and metabolic interplay in mixed-kingdom microbiomes
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Phillip B. Pope, Torgeir R. Hvidsten, Magnus Ø. Arntzen, Francesco Delogu, and Benoit J. Kunath
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0303 health sciences ,biology ,030306 microbiology ,ved/biology ,ved/biology.organism_classification_rank.species ,RNA ,Computational biology ,Methanothermobacter ,biology.organism_classification ,Methanogen ,Transcriptome ,03 medical and health sciences ,Proteome ,Microbiome ,Model organism ,Function (biology) ,030304 developmental biology - Abstract
Microbiology is founded on well-known model organisms. For example, the majority of our fundamental knowledge regarding the quantitative levels of DNA, RNA, and protein backdates to keystone pure culture-based studies. Nowadays, meta-omic approaches allow us to directly access the molecules that constitute microbes and microbial communities, however due to a lack of absolute measurements, many original culture-derived “microbiology statutes” have not been updated or adapted to more complex microbiome settings. Within a cellulose-degrading and methanogenic consortium, we temporally measured genome-centric absolute RNA and protein levels per gene, and obtained a protein-to-RNA ratio of 102-104 for bacterial populations, whereas Archaeal RNA/protein dynamics (103-105: Methanothermobacter thermoautotrophicus) were more comparable to Eukaryotic representatives humans and yeast. The linearity between transcriptome and proteome had a population-specific change over time, highlighting a minimal subset of four functional carriers (cellulose degrader, fermenter, syntrophic acetate-oxidizer and methanogen) that coordinated their respective metabolisms, cumulating in the overarching community phenotype of converting polysaccharides to methane. Our findings show that upgrading multi-omic toolkits with traditional absolute measurements unlocks the scaling of core biological questions to dynamic and complex microbiomes, creating a deeper insight into inter-organismal relationships that drive the greater community function.
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- 2019
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33. Genetic Association Analyses Highlight IL6 , ALPL , and NAV1 As 3 New Susceptibility Genes Underlying Calcific Aortic Valve Stenosis
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Sébastien Thériault, Christian Dina, David Messika-Zeitoun, Solena Le Scouarnec, Romain Capoulade, Nathalie Gaudreault, Sidwell Rigade, Zhonglin Li, Floriane Simonet, Maxime Lamontagne, Marie-Annick Clavel, Benoit J. Arsenault, Anne-Sophie Boureau, Simon Lecointe, Estelle Baron, Stéphanie Bonnaud, Matilde Karakachoff, Eric Charpentier, Imen Fellah, Jean-Christian Roussel, Jean Philippe Verhoye, Christophe Baufreton, Vincent Probst, Ronan Roussel, Richard Redon, François Dagenais, Philippe Pibarot, Patrick Mathieu, Thierry Le Tourneau, Yohan Bossé, Jean-Jacques Schott, B. Balkau, P. Ducimetière, E. Eschwège, F. Alhenc-Gelas, A. Girault, F. Fumeron, M. Marre, F. Bonnet, A. Bonnefond, P. Froguel, F. Rancière, J. Cogneau, C. Born, E. Caces, M. Cailleau, O Lantieri, J.G. Moreau, F. Rakotozafy, J. Tichet, S. Vol, Université Laval, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hémostase, bio-ingénierie et remodelage cardiovasculaires (LBPC), Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Galilée, CHU Pontchaillou [Rennes], Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de chirurgie cardio-vasculaire et thoracique, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE)-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), Université Laval [Québec] (ULaval), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut Galilée-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), and École pratique des hautes études (EPHE)
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0301 basic medicine ,aortic valve stenosis ,Genome-wide association study ,Disease ,030204 cardiovascular system & hematology ,Bioinformatics ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Interleukin 6 ,ComputingMilieux_MISCELLANEOUS ,Genetic association ,biology ,business.industry ,interleukin-6 ,ALPL ,Calcific aortic valve stenosis ,General Medicine ,medicine.disease ,3. Good health ,030104 developmental biology ,Aortic valve stenosis ,biology.protein ,[SDV.IB]Life Sciences [q-bio]/Bioengineering ,business ,transcriptome ,Genome-Wide Association Study - Abstract
Background: Calcific aortic valve stenosis (CAVS) is a frequent and life-threatening cardiovascular disease for which there is currently no medical treatment available. To date, only 2 genes, LPA and PALMD , have been identified as causal for CAVS. We aimed to identify additional susceptibility genes for CAVS. Methods: A GWAS (genome-wide association study) meta-analysis of 4 cohorts, totaling 5115 cases and 354 072 controls of European descent, was performed. A TWAS (transcriptome-wide association study) was completed to integrate transcriptomic data from 233 human aortic valves. A series of post-GWAS analyses were performed, including fine-mapping, colocalization, phenome-wide association studies, pathway, and tissue enrichment as well as genetic correlation with cardiovascular traits. Results: In the GWAS meta-analysis, 4 loci achieved genome-wide significance, including 2 new loci: IL6 (interleukin 6) on 7p15.3 and ALPL (alkaline phosphatase) on 1p36.12. A TWAS integrating gene expression from 233 human aortic valves identified NAV1 (neuron navigator 1) on 1q32.1 as a new candidate causal gene. The CAVS risk alleles were associated with higher mRNA expression of NAV1 in valve tissues. Fine-mapping identified rs1800795 as the most likely causal variant in the IL6 locus. The signal identified colocalizes with the expression of the IL6 RNA antisense in various tissues. Phenome-wide association analyses in the UK Biobank showed colocalized associations between the risk allele at the IL6 lead variant and higher eosinophil count, pulse pressure, systolic blood pressure, and carotid artery procedures, implicating modulation of the IL6 pathways. The risk allele at the NAV1 lead variant colocalized with higher pulse pressure and higher prevalence of carotid artery stenosis. Association results at the genome-wide scale indicated genetic correlation between CAVS, coronary artery disease, and cardiovascular risk factors. Conclusions: Our study implicates 3 new genetic loci in CAVS pathogenesis, which constitute novel targets for the development of therapeutic agents.
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- 2019
34. Saturated Fats from Butter but Not from Cheese Increase HDL-Mediated Cholesterol Efflux Capacity from J774 Macrophages in Men and Women with Abdominal Obesity
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Daniela Bernic, Emile Levy, Peter B. Jones, Patrick Couture, Denis Talbot, Benoît Lamarche, Bela F. Asztalos, Marjorie Boyer, Angelo Tremblay, Didier Brassard, Benoit J. Arsenault, and Maude Tessier-Grenier
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Male ,high-density lipoproteins ,Apolipoprotein B ,Nutrition and Disease ,Medicine (miscellaneous) ,Coronary Artery Disease ,030204 cardiovascular system & hematology ,chemistry.chemical_compound ,0302 clinical medicine ,Risk Factors ,030212 general & internal medicine ,Food science ,Abdominal obesity ,chemistry.chemical_classification ,Cross-Over Studies ,Nutrition and Dietetics ,biology ,Fatty Acids ,Reverse cholesterol transport ,monounsaturated fatty acids ,food and beverages ,Middle Aged ,Cholesterol ,Obesity, Abdominal ,Fatty Acids, Unsaturated ,Female ,lipids (amino acids, peptides, and proteins) ,Waist Circumference ,medicine.symptom ,Polyunsaturated fatty acid ,polyunsaturated fatty acids ,Adult ,cheese ,03 medical and health sciences ,medicine ,Humans ,saturated fatty acids ,Olive Oil ,Apolipoproteins B ,Macrophages ,Cholesterol, HDL ,Feeding Behavior ,medicine.disease ,Dietary Fats ,Crossover study ,Obesity ,J774 macrophages ,cholesterol efflux capacity ,butter ,chemistry ,biology.protein ,dairy ,Corn Oil ,diet ,Corn oil - Abstract
Background Recent evidence suggests that the association between dietary saturated fatty acids (SFAs) and coronary artery disease risk varies according to food sources. How SFAs from butter and cheese influence HDL-mediated cholesterol efflux capacity (CEC), a key process in reverse cholesterol transport, is currently unknown. Objective In a predefined secondary analysis of a previously published trial, we have examined how diets rich in SFAs from either cheese or butter influence HDL-mediated CEC, compared with diets rich in either monounsaturated fatty acids (MUFAs) or polyunsaturated fatty acids (PUFAs). Methods In a randomized crossover controlled consumption trial, 46 men and women with abdominal obesity consumed 5 isocaloric diets, each for 4 wk. Two diets were rich in SFAs either from cheese (CHEESE) or butter (BUTTER) [12.4-12.6% of energy (%E) as SFAs, 32%E as fat, 52%E as carbohydrates]. In 2 other diets, SFAs (5.8%E) were replaced with either MUFAs from refined olive oil (MUFA) or PUFAs from corn oil (PUFA). Finally, a lower fat and carbohydrate diet was used as a control (5.8%E as SFAs, 25.0%E as fat, 59%E as carbohydrates; CHO). Post-diet HDL-mediated CEC was determined ex vivo using radiolabelled J774 macrophages incubated with apolipoprotein B-depleted serum from the participants. Results Mean (±SD) age was 41.4 ± 14.2 y, and waist circumference was 107.6 ± 11.5 cm in men and 94.3 ± 12.4 cm in women. BUTTER and MUFA increased HDL-mediated CEC compared with CHEESE (+4.3%, P = 0.026 and +4.7%, P = 0.031, respectively). Exploring the significant diet × sex interaction (P = 0.044) revealed that the increase in HDL-mediated CEC after BUTTER compared with CHEESE was significant among men (+6.0%, P = 0.047) but not women (+2.9%, P = 0.19), whereas the increase after MUFA compared with CHEESE was significant among women (+9.1%, P = 0.008) but not men (-0.6%, P = 0.99). Conclusion These results provide evidence of a food matrix effect modulating the impact of dairy SFAs on HDL-mediated CEC with potential sex-related differences that deserve further investigation. This trial was registered at clinicaltrials.gov as NCT02106208.
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- 2018
35. PCSK9 Involvement in Aortic Valve Calcification
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Silvia S. Barbieri, Benoit J. Arsenault, Paolo Poggio, Paola Songia, Marina Camera, Vincenza Valerio, Nicola Ferri, Ilaria Zanotti, Romain Capoulade, and Laura Cavallotti
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0301 basic medicine ,medicine.medical_specialty ,Hemodynamics ,030204 cardiovascular system & hematology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Insulin resistance ,Phospholipase A2 ,Internal medicine ,medicine ,Animals ,Humans ,biology ,business.industry ,PCSK9 ,fungi ,Calcinosis ,Aortic Valve Stenosis ,Proprotein convertase ,medicine.disease ,Disease Models, Animal ,030104 developmental biology ,Aortic Valve ,biology.protein ,Cardiology ,Kexin ,Proprotein Convertase 9 ,Aortic valve calcification ,Cardiology and Cardiovascular Medicine ,business ,Calcification - Abstract
High levels of proprotein convertase subtilisin/kexin 9 (PCSK9) (>305 ng/ml) have been recently associated, along with insulin resistance and lipoprotein-associated phospholipase A2 activity, with aortic bioprosthesis calcification and able to predict hemodynamic valve deterioration [(1)][1].
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- 2018
36. Lipoprotein(a) is not associated with active calcification assessed with 18F-NaF PET/CT in patients with mild to moderate aortic valve stenosis
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A.G. Somsen, Kang H. Zheng, Hein J. Verberne, Nick S. Nurmohamed, Evangelos Tzolos, M R Dweck, S.M. Boekholdt, Benoit J. Arsenault, Yannick Kaiser, Erik S.G. Stroes, and Jeffrey Kroon
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medicine.medical_specialty ,PET-CT ,biology ,business.industry ,Lipoprotein(a) ,medicine.disease ,Internal medicine ,Aortic valve stenosis ,medicine ,biology.protein ,Cardiology ,In patient ,Cardiology and Cardiovascular Medicine ,business ,Calcification - Published
- 2021
37. Abstract 57: First-in-human CAR T targets MUC1 transmembrane cleavage product
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Danica M. Page, Thomas G. Jeon, Scott T. Moe, Tyler E. Swanson, Benoit J. Smagghe, Cynthia Bamdad, Trevor J. Grant, Andrew K. Stewart, Jennifer M. Specht, and Pengyu Huang
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Cancer Research ,Tumor microenvironment ,biology ,Chemistry ,Growth factor ,medicine.medical_treatment ,T cell ,Epitope ,medicine.anatomical_structure ,Oncology ,Growth factor receptor ,Cancer research ,medicine ,biology.protein ,Antibody ,MUC1 ,CD8 - Abstract
Purpose: To develop a MUC1-targeted CAR T that recognizes the growth factor receptor form, MUC1*, does not bind full-length MUC1, hits a wide range of solid tumor cancers, binds to little or no normal tissues, and effectively kills tumor cells. Methods: Because MUC1 is expressed on normal epithelial tissues, we needed to develop an antibody that would only bind to the aberrant, cancerous form - MUC1*. MUC1* (muk1 star) is the transmembrane portion that remains after MUC1 is enzymatically cleaved and the bulky tandem repeat domain is shed from the cell surface. MUC1* is a growth factor receptor that is activated by ligand-induced dimerization of its truncated extracellular domain. Via a novel screen we identified antibodies that bind to a specific conformation within the ectopic epitope that is created when MUC1 is cleaved to MUC1* by enzymes secreted by the tumor microenvironment. This set of antibodies competitively inhibit the binding of onco-embryonic growth factor NME7AB to the cancerous form of MUC1*. We incorporated one of these cancer-specific antibodies into a CAR T. Results: huMNC2-CAR44 is in a 1st-in-human clinical trial [NCT04020575] for metastatic breast cancers, currently being performed at the Fred Hutchinson Cancer Research Center. Our IND-enabling studies showed that huMNC2-scFv bound robustly to 95% of breast cancer tissues, 83% ovarian cancers, 78% pancreatic cancers and 71% of lung cancer tissues, but showed little to no binding to normal tissues. In co-culture experiments, huMNC2-CAR44 T cells did not kill MUC1* negative cells, even if they expressed full-length MUC1, and the presence of MUC1* negative cells did not elicit a cytokine response from the CAR T cells. In vivo, huMNC2-CAR44 T cells inhibited or completely obliterated a variety of MUC1* positive solid tumors in NSG mice (n≥400). The human CD8+ huMNC2-CAR44 T cells expanded in animals as tumors shrunk, whereas the untransduced T cells did not. Clinical trial was slowed by COVID-19, as Seattle was the first hotbed of the virus. Thus far, there have been no serious adverse events attributed to the CAR T therapy. Even at the lowest dosage, patients have had robust CAR T cell expansion and have also had measurable signs of efficacy. Conclusions: MUC1* is the predominant form of MUC1 on cancerous tissues. Antibodies that bind to a specific conformation within the ectopic growth factor binding site in the MUC1* extra cellular domain are tumor selective. CAR T cells incorporating these antibodies are highly effective against solid tumors in animals. Robust staining of cancerous tissues and minimal to no staining of normal tissues predicts a large therapeutic window for huMNC2-CAR44 T cell dosing. Early patient responses appear to fulfill the predictions of the IND-enabling studies. We have now developed a cryopreservation formulation which enables shipping frozen product to additional clinical sites for bedside thaw and infusion. The trial is currently enrolling patients. Citation Format: Cynthia Bamdad, Andrew K. Stewart, Pengyu Huang, Benoit J. Smagghe, Scott T. Moe, Tyler E. Swanson, Thomas G. Jeon, Danica M. Page, Trevor J. Grant, Jennifer M. Specht. First-in-human CAR T targets MUC1 transmembrane cleavage product [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 57.
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- 2021
38. Electronic Health Record-Based Genome-Wide Meta-Analysis Identifies New Susceptibility Loci for Non-Alcoholic Fatty Liver Disease
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Nele Taba, Christian Couture, Erik Abner, Nicolas Perrot, Émilie Gobeil, Patrick Mathieu, Tõnu Esko, Sébastien Thériault, Yohan Bossé, Alexis St Amand, Marie-Claude Vohl, Nooshin Ghodsian, Patricia L. Mitchell, Benoit J. Arsenault, and André Tchernof
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Endocrinology, Diabetes and Metabolism ,Fatty liver ,nutritional and metabolic diseases ,Non alcoholic ,Disease ,Computational biology ,From Bench to Bedside: Genetics, Development and Cell Signaling in Endocrinology ,Biology ,medicine.disease ,Genome ,digestive system ,digestive system diseases ,Genetics and Development (including Gene Regulation) ,Electronic health record ,Meta-analysis ,medicine ,Susceptibility locus ,AcademicSubjects/MED00250 - Abstract
Background: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of liver disease. Observational studies documented associations of NAFLD with several chronic and infectious diseases but whether these associations underlie causal effects is unknown. The molecular mechanisms and genetic architecture of NAFLD are poorly understood. Our objectives were to identify genetic loci associated with NAFLD and determine whether the presence of NAFLD was causally associated with human diseases. Methods: We created a NAFLD genetic instrument through the identification of independent single-nucleotide polymorphisms (SNPs) associated with NAFLD in a meta-analysis of genome-wide association study (GWAS) (6715 cases and 682,748 controls). Using inverse-variance weighted Mendelian Randomization (MR), we investigated the impact of NAFLD on human disease-related phenotypes in the UK Biobank and FinnGen cohorts as well as in the COVID-19 host genetics initiative. Results: We first performed a GWAS meta-analysis of four cohorts and found variants significantly associated with NAFLD (p800 diseases) using a genetic instrument for NAFLD. Results of these analyses suggest that NAFLD was not causally associated with diseases outside the spectrum of liver diseases. We also found no causal association between genetically predicted NAFLD and COVID-19-related outcomes. Conclusions: This study identified several new genetic loci associated with NAFLD. NAFLD was not causally associated with diseases outside those of the spectrum of liver diseases. This finding suggests that the resolution of NAFLD might not prevent other diseases previously associated with NAFLD.
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- 2021
39. Pathobiology of Lp(a) in calcific aortic valve disease
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Marie-Chloé Boulanger, Yohan Bossé, Marlys L. Koschinsky, Patrick Mathieu, and Benoit J. Arsenault
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0301 basic medicine ,Aortic valve ,medicine.medical_specialty ,Apolipoprotein B ,Disease ,030204 cardiovascular system & hematology ,Bioinformatics ,Heart valve disorder ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,Prevalence ,Internal Medicine ,Humans ,Medicine ,biology ,Phosphoric Diester Hydrolases ,business.industry ,Calcinosis ,Aortic Valve Stenosis ,General Medicine ,Lipoprotein(a) ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Aortic Valve ,Aortic valve stenosis ,biology.protein ,Cardiology ,Autotaxin ,Cardiology and Cardiovascular Medicine ,business ,Lipoprotein - Abstract
Introduction: Calcific aortic valve disease (CAVD) is the most prevalent heart valve disorder. Gene variant in the LPA gene, which encodes for apolipoprotein(a), has been associated at the genome-wide level with CAVD. The process whereby Lp(a) promotes the development of CAVD is under intensive investigation and recent data have shed important insights into disease biology. In this regard, autotaxin (ATX), a lysophospholipase D, interacts with Lp(a) and promotes the mineralization of the aortic valve.Areas covered: In this paper, we are reviewing the biology of Lp(a) and the latest discoveries about the molecular processes that link this lipoprotein with the development of CAVD including the role of ATX.Expert commentary: Elevated Lp(a) levels are genetically determined and considered as an important risk factor for CAVD. Understanding how Lp(a) promotes the development/progression of CAVD is crucial as it may hold promise for the development of new therapies.
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- 2017
40. Lipoprotein(a) and coronary atheroma progression rates during long-term high-intensity statin therapy: Insights from SATURN
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Steven E. Nissen, M. John Chapman, Stephen J. Nicholls, Ron C. Hoogeveen, Peter Libby, Joel S. Raichlen, Benoit J. Arsenault, Christie M. Ballantyne, Rishi Puri, Raimund Erbel, Mingyuan Shao, and Philip J. Barter
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Male ,medicine.medical_specialty ,Atorvastatin ,Medizin ,Coronary Artery Disease ,030204 cardiovascular system & hematology ,Coronary artery disease ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Intravascular ultrasound ,Humans ,Medicine ,Rosuvastatin ,030212 general & internal medicine ,Rosuvastatin Calcium ,Aged ,Proportional Hazards Models ,Ultrasonography ,medicine.diagnostic_test ,biology ,business.industry ,Lipoprotein(a) ,Middle Aged ,medicine.disease ,Plaque, Atherosclerotic ,C-Reactive Protein ,Atheroma ,Disease Progression ,biology.protein ,Cardiology ,Female ,lipids (amino acids, peptides, and proteins) ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers ,Mace ,Lipoprotein ,medicine.drug - Abstract
Lipoprotein(a) [Lp(a)] is a low-density lipoprotein (LDL)-like particle that associates with major adverse cardiovascular events (MACE). We examined relationships between Lp(a) measurements and changes in coronary atheroma volume following long-term maximally-intensive statin therapy in coronary artery disease patients.Study of coronary atheroma by intravascular ultrasound: Effect of Rosuvastatin Versus Atorvastatin (SATURN) used serial intravascular ultrasound measures of coronary atheroma volume in patients treated with rosuvastatin 40 mg or atorvastatin 80 mg for 24 months. Baseline and follow-up Lp(a) levels were measured in 915 of the 1039 SATURN participants, and were correlated with changes in percent atheroma volume (ΔPAV).Mean age was 57.7 ± 8.6 years, 74% were men, 96% were Caucasian, with statin use prior to study enrolment occurring in 59.3% of participants. Baseline [median (IQR)] LDL-cholesterol (LDL-C) and measured Lp(a) levels (mg/dL) were 114 (99, 137) and 17.4 (7.6, 52.9) respectively; follow-up measures were 60 (47, 77), and 16.5 (6.7, 57.7) (change from baseline: p 0.001, p = 0.31 respectively). At baseline, there were 676 patients with Lp(a) levels50 mg/dL [median Lp(a) of 10.9 mg/dL], and 239 patients with Lp(a) levels ≥ 50 mg/dL [median Lp(a) of 83.2 mg/dL]. Quartiles of baseline and follow-up Lp(a) did not associate with ΔPAV. Irrespective of the achieved LDL-C (vs. ≥70 mg/dL), neither baseline nor on-treatment (vs. ≥median) Lp(a) levels significantly associated with ΔPAV. No significant differences were observed in ΔPAV in Lp(a) risers versus non-risers, nor in those patients with baseline or on-treatment Lp(a) levelsvs.50 mg/dL.In coronary artery disease patients prescribed long-term maximally intensive statin therapy with low on-treatment LDL-C levels, measured Lp(a) levels (predominantly below the 50 mg/dL threshold) do not associate with coronary atheroma progression. Alternative biomarkers may thus associate with residual cardiovascular risk in such patients.
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- 2017
41. OxLDL-derived lysophosphatidic acid promotes the progression of aortic valve stenosis through a LPAR1-RhoA–NF-κB pathway
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Ghada Mkannez, Benoit J. Arsenault, Patrick Mathieu, Mohamed Jalloul Nsaibia, Philippe Pibarot, Fayez Hadji, André Marette, Khai Le Quang, Marie-Chloé Boulanger, Abdellaziz Dahou, Marlys L. Koschinsky, Deborah Argaud, Rihab Bouchareb, and Yohan Bossé
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0301 basic medicine ,Aortic valve ,RHOA ,Physiology ,IκB kinase ,030204 cardiovascular system & hematology ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Physiology (medical) ,Lysophosphatidic acid ,medicine ,Animals ,Humans ,Phosphorylation ,Receptors, Lysophosphatidic Acid ,Receptor ,LPAR1 ,biology ,Chemistry ,NF-kappa B ,Calcinosis ,Calcific aortic valve stenosis ,Aortic Valve Stenosis ,Lipid signaling ,Lipoproteins, LDL ,Toll-Like Receptor 4 ,030104 developmental biology ,medicine.anatomical_structure ,Biochemistry ,Aortic Valve ,cardiovascular system ,Cancer research ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Lysophospholipids ,rhoA GTP-Binding Protein ,Cardiology and Cardiovascular Medicine ,Signal Transduction - Abstract
Aims Oxidatively modified lipoproteins may promote the development/progression of calcific aortic valve stenosis (CAVS). Oxidative transformation of low-density lipoprotein (OxLDL) generates lysophosphatidic acid (LPA), a lipid mediator that accumulates in mineralized aortic valves. LPA activates at least six different G protein-coupled receptors, which may play a role in the pathophysiology of CAVS. We hypothesized that LPA derived from OxLDL may promote a NF-κB signature that drives osteogenesis in the aortic valve. Methods and results The role of OxLDL-LPA was examined in isolated valve interstitial cells (VICs) and the molecular pathway was validated in human explanted aortic valves and in a mouse model of CAVS. We found that OxLDL-LPA promoted the mineralization and osteogenic transition of VICs through LPAR1 and the activation of a RhoA-NF-κB pathway. Specifically, we identified that RhoA/ROCK activated IκB kinase alpha, which promoted the phosphorylation of p65 on serine 536 (p65 pS536). p65 pS536 was recruited to the BMP2 promoter and directed an osteogenic program not responsive to the control exerted by the inhibitor of kappa B. In LDLR-/-/ApoB100/100/IGFII transgenic mice (IGFII), which develop CAVS under a high-fat and high-sucrose diet the administration of Ki16425, a Lpar1 blocker, reduced by three-fold the progression rate of CAVS and also decreased the osteogenic activity as measured with a near-infrared fluorescent probe that recognizes hydroxyapatite of calcium. Conclusions OxLDL-LPA promotes an osteogenic program in the aortic valve through a LPAR1-RhoA/ROCK-p65 pS536 pathway. LPAR1 may represent a suitable target to prevent the progression of CAVS.
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- 2017
42. 1st-in-human CAR T targets MUC1 transmembrane cleavage product
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P. Huang, Andrew K. Stewart, T. Jeon, S. Moe, K. Mathavan, Benoit J. Smagghe, T. Grant, D. Page, Cynthia Bamdad, and T. Swanson
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Cancer Research ,T cell ,medicine.medical_treatment ,Immunology ,digestive system ,Metastasis ,Growth factor receptor ,medicine ,Immunology and Allergy ,skin and connective tissue diseases ,neoplasms ,Genetics (clinical) ,MUC1 ,Transplantation ,biology ,Chemistry ,Growth factor ,Cell Biology ,medicine.disease ,biological factors ,digestive system diseases ,medicine.anatomical_structure ,Oncology ,biology.protein ,Cancer research ,Immunohistochemistry ,Antibody ,Conformational epitope - Abstract
Background & Aim We developed a CAR T that recognizes the growth factor receptor form, MUC1*, does not bind full-length MUC1, hits a wide range of cancers and shows to little or no binding to normal tissues. No therapeutic has ever been tested in humans that targets the MUC1 transmembrane cleavage product – MUC1*. A 1st-in-human clinical trial of huMNC2-CAR44, NCT04020575, for metastatic breast cancers is underway at the Fred Hutchinson Cancer Research Center. We expect to have patient data by conference time. Methods, Results & Conclusion MUC1* is a Class I growth factor receptor that is activated when onco-embryonic growth factor NME7AB dimerizes its truncated extra cellular domain. The binding site for NME7AB is ectopic and is only unmasked after the tandem repeat domain of MUC1 is cleaved and shed from the cell surface. Unlike full-length MUC1, MUC1* has no sites for O-linked glycosylation, so antibodies such as 5E5 that bind to aberrant, trapped glycans cannot bind to the MUC1*. Anti-MUC1* antibody huMNC2 binds to the conformational epitope that is unmasked when MUC1 is cleaved to MUC1* by MMP9. MMP9 has now been linked to poor prognosis and metastasis. huMNC2 competes with onco-embryonic growth factor NME7AB for this same conformational epitope on MUC1*. Neither huMNC2 nor NME7AB binds to full-length MUC1. IHC studies of thousands of human tissues – both normal and cancerous – show that the tumor associated antigen is MUC1* and not full-length MUC1. Patient-match primary and metastases show that as cancer stage progresses the amount of MUC1* increases. huMNC2-scFv bound robustly to 95% of the breast cancers, 83% ovarian, 78% pancreatic and 71% of lung cancer tissues (specimens n>2,800). There was little to no staining of normal tissues. In vivo, huMNC2-CAR44 T cells inhibited or completely obliterated a variety of MUC1* positive solid tumors in NSG mice (n>400). If safety is demonstrated, we will file for INDs for next-gen CARs, including logic-gated CARs with increased in vivo persistence. Conclusions MUC1* is the predominant form of MUC1 on cancerous tissues. Antibodies that target a conformational epitope in the membrane-proximal MUC1* extra cellular domain are tumor selective. CAR T cells targeting MUC1* extra cellular domain are highly effective against solid tumors in animals. Robust staining of cancerous tissues and minimal to no staining of normal tissues predicts large therapeutic window for huMNC2-CAR44 T cell dosing.
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- 2020
43. A trans‐omic Mendelian randomization study of parental lifespan uncovers novel aging biology and therapeutic candidates for chronic diseases.
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Perrot, Nicolas, Pelletier, William, Bourgault, Jérôme, Couture, Christian, Li, Zhonglin, Mitchell, Patricia L., Ghodsian, Nooshin, Bossé, Yohan, Thériault, Sébastien, Mathieu, Patrick, and Arsenault, Benoit J.
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LONGEVITY ,AGING ,GENOME-wide association studies ,HAPTOGLOBINS ,CHRONIC diseases ,DRUG target ,BIOLOGY - Abstract
The study of parental lifespan has emerged as an innovative tool to advance aging biology and our understanding of the genetic architecture of human longevity and aging‐associated diseases. Here, we leveraged summary statistics of a genome‐wide association study including over one million parental lifespans to identify genetically regulated genes from the Genotype‐Tissue Expression project. Through a combination of multi‐tissue transcriptome‐wide association analyses and genetic colocalization, we identified novel genes that may be associated with parental lifespan. Mendelian randomization (MR) analyses also identified circulating proteins and metabolites causally associated with parental lifespan and chronic diseases offering new drug repositioning opportunities such as those targeting apolipoprotein‐B‐containing lipoproteins. Liver expression of HP, the gene encoding haptoglobin, and plasma haptoglobin levels were causally linked with parental lifespan. Phenome‐wide MR analyses were used to map genetically regulated genes, proteins and metabolites with other human traits as well as the disease‐related phenome in the FinnGen cohorts (n = 135,638). Altogether, this study identified new candidate genes, circulating proteins and metabolites that may influence human aging as well as potential therapeutic targets for chronic diseases that warrant further investigation. [ABSTRACT FROM AUTHOR]
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- 2021
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44. ApoCIII-Lp(a) complexes in conjunction with Lp(a)-OxPL predict rapid progression of aortic stenosis
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Jens O Schmid, Benoit J. Arsenault, Ulrich F.W. Franke, James W. Tam, Jean-Pierre Després, Patrick Mathieu, Koon K. Teo, Yohan Bossé, Amber P. Sanchez, Nora Göbel, Joseph L. Witztum, Xiaohong Yang, Romain Capoulade, Calvin Yeang, Jean G. Dumesnil, Sotirios Tsimikas, Kwan-Leung Chan, Michael Torzewski, Manuel Mayr, Philippe Pibarot, and Sean A. Burnap
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Aortic valve ,Male ,medicine.medical_specialty ,Apolipoprotein B ,030204 cardiovascular system & hematology ,Apoprotein(a) ,Risk Assessment ,Lesion ,03 medical and health sciences ,0302 clinical medicine ,Aortic valve replacement ,Internal medicine ,medicine ,Humans ,Rosuvastatin ,030212 general & internal medicine ,Mortality ,Rosuvastatin Calcium ,Heart Valve Prosthesis Implantation ,Apolipoprotein C-III ,biology ,business.industry ,Anticholesteremic Agents ,Calcinosis ,Calcific aortic valve stenosis ,Aortic Valve Stenosis ,Middle Aged ,medicine.disease ,Immunohistochemistry ,Cardiac surgery ,Stenosis ,medicine.anatomical_structure ,Echocardiography ,Aortic Valve ,biology.protein ,Cardiology ,Disease Progression ,lipids (amino acids, peptides, and proteins) ,Female ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug - Abstract
ObjectiveThis study assessed whether apolipoprotein CIII-lipoprotein(a) complexes (ApoCIII-Lp(a)) associate with progression of calcific aortic valve stenosis (AS).MethodsImmunostaining for ApoC-III was performed in explanted aortic valve leaflets in 68 patients with leaflet pathological grades of 1–4. Assays measuring circulating levels of ApoCIII-Lp(a) complexes were measured in 218 patients with mild–moderate AS from the AS Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) trial. The progression rate of AS, measured as annualised changes in peak aortic jet velocity (Vpeak), and combined rates of aortic valve replacement (AVR) and cardiac death were determined. For further confirmation of the assay data, a proteomic analysis of purified Lp(a) was performed to confirm the presence of apoC-III on Lp(a).ResultsImmunohistochemically detected ApoC-III was prominent in all grades of leaflet lesion severity. Significant interactions were present between ApoCIII-Lp(a) and Lp(a), oxidised phospholipids on apolipoprotein B-100 (OxPL-apoB) or on apolipoprotein (a) (OxPL-apo(a)) with annualised Vpeak(all ppeak(pConclusionApoC-III is present on Lp(a) and in aortic valve leaflets. Elevated levels of ApoCIII-Lp(a) complexes in conjunction with Lp(a), OxPL-apoB or OxPL-apo(a) identify patients with pre-existing mild–moderate AS who display rapid progression of AS and higher rates of AVR/cardiac death.Trial registrationNCT00800800.
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- 2019
45. Human high-density lipoprotein microtranscriptome is unique and suggests an extended role in lipid metabolism
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Samuel Picard, Véronique Desgagné, Luigi Bouchard, Elizabeth Hutchins, Marjorie Boyer, Renée Guérin, Kendall Van Keuren-Jensen, Benoit J. Arsenault, François Corbin, Alexandre Maréchal, and Simon-Pierre Guay
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0301 basic medicine ,Adult ,Male ,Cancer Research ,Biology ,DNA sequencing ,03 medical and health sciences ,chemistry.chemical_compound ,Young Adult ,0302 clinical medicine ,High-density lipoprotein ,Sex Factors ,microRNA ,Genetics ,Humans ,RNA ,High-Throughput Nucleotide Sequencing ,Lipid metabolism ,Sequence Analysis, DNA ,Middle Aged ,Lipid Metabolism ,Fold change ,MicroRNAs ,030104 developmental biology ,chemistry ,Biochemistry ,030220 oncology & carcinogenesis ,Female ,Lipoproteins, HDL ,Transcriptome - Abstract
Aim: To comprehensively characterize the high-density lipoproteins (HDLs) microtranscriptome and to assess whether it is distinct from that of plasma and different between women and men. Methods: RNA was extracted from ultracentrifugation-purified HDLs and plasma from 17 healthy women and men couples, and libraries were sequenced on a HiSeq2500 platform. Results: On average, 310 ± 64 and 355 ± 31 miRNAs were detected (≥1 read per million) in HDLs and plasma, respectively. A total of 62 and 134 miRNAs were over-represented (e.g., miR-150-5p; fold change = 7.52; padj = 5.41 × 10-111) and under-represented (e.g., miR-22-3p; fold change = -5.28; padj = 2.11 × 10-154) in HDLs compared with plasma. These miRNAs were enriched in lipid metabolism and cellular processes-related pathways. Conclusion: HDLs exhibit a sex-independent miRNA profile distinct from that of plasma. These miRNAs may contribute to the HDLs' physiology.
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- 2019
46. Long-Term Exposure to Elevated Lipoprotein(a) Levels, Parental Lifespan and Risk of Mortality
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Yohan Bossé, Erik S.G. Stroes, Patrick Mathieu, Nicolas Perrot, Nicholas J. Wareham, Philippe Pibarot, S. Matthijs Boekholdt, Kay-Tee Khaw, Benoit J. Arsenault, Yannick Kaiser, William Pelletier, Sébastien Thériault, and Christian Couture
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0303 health sciences ,medicine.medical_specialty ,education.field_of_study ,Percentile ,biology ,business.industry ,Hazard ratio ,Population ,Single-nucleotide polymorphism ,Odds ratio ,Lipoprotein(a) ,030204 cardiovascular system & hematology ,Confidence interval ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Risk of mortality ,biology.protein ,education ,business ,030304 developmental biology - Abstract
BackgroundElevated Lipoprotein(a) (Lp[a]) levels are associated with a broad range of atherosclerotic cardiovascular diseases (CVD). The impact of high Lp(a) levels on human longevity is however controversial. Our objectives were to determine whether genetically-determined Lp(a) levels are associated with parental lifespan and to assess the association between measured and genetically-determined Lp(a) levels and long-term all-cause and cardiovascular mortality.MethodsWe determined the association between a genetic risk score of 26 single nucleotide polymorphisms weighted for their impact on Lp(a) levels (wGRS) and parental lifespan (at least one long-lived parent; father still alive and older than 90 or father’s age of death ≥90 or mother still alive and older than 93 or mother’s age of death ≥93) in 139,362 participants from the UK Biobank. A total of 17,686 participants were considered as having high parental lifespan. We also investigated the association between Lp(a) levels and all-cause and cardiovascular mortality in 18,720 participants from the EPIC-Norfolk study.ResultsIn the UK Biobank, increases in the wGRS (weighted for a 50 mg/dL increase in Lp(a) levels) were inversely associated with a high parental lifespan (odds ratio=0.92, 95% confidence interval [CI]=0.89-0.94, p=2.7×10−8). During the 20-year follow-up of the EPIC-Norfolk study, 5686 participants died (2412 from CVD-related causes). Compared to participants with Lp(a) levels th percentile of the Lp(a) distribution (in whom event rates were 29.8% and 11.3%, respectively for all-cause and cardiovascular mortality), those with Lp(a) levels equal or above the 95th percentile of the population distribution (≥70 mg/dL) had HRs of 1.22 (95% CI=1.09-1.37, event rate 37.5%) and 1.71 (95% CI=1.46-2.00, event rate 20.0%), for all-cause mortality and cardiovascular mortality, respectively.ConclusionsResults of this study suggest a potentially causal effect of Lp(a) on human longevity, support the use of parental lifespan as a tool to study the genetic determinants of human longevity, and provide a rationale for a trial of Lp(a)-lowering therapy in individuals with high Lp(a) levels.
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- 2019
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47. Lipoprotein(a), Oxidized Phospholipids, and Aortic Valve Microcalcification Assessed by 18F-Sodium Fluoride Positron Emission Tomography and Computed Tomography
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James C. Engert, Raphaëlle Bourgeois, Patrick Mathieu, Philippe Pibarot, Yohan Bossé, Maxime Nadeau, Sotirios Tsimikas, Michel Tessier, Mikaël Trottier, Mylène Shen, George Thanassoulis, Joseph L. Witztum, Marc R. Dweck, Audrey-Anne Després, Sébastien Thériault, Lionel Tastet, Marie-Annick Clavel, Jean Guimond, Patrick Couture, Benoit J. Arsenault, Anthony Poulin, Hao Yu Chen, and Nicolas Perrot
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Aortic valve ,lcsh:Diseases of the circulatory (Cardiovascular) system ,medicine.medical_specialty ,030204 cardiovascular system & hematology ,Cardiovascular ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Clinical Research ,Interquartile range ,Internal medicine ,Sodium fluoride ,medicine ,030304 developmental biology ,screening and diagnosis ,0303 health sciences ,biology ,medicine.diagnostic_test ,business.industry ,Calcific aortic valve stenosis ,Lipoprotein(a) ,3. Good health ,Detection ,medicine.anatomical_structure ,chemistry ,lcsh:RC666-701 ,Positron emission tomography ,biology.protein ,Cardiology ,cardiovascular system ,Original Article ,Microcalcification ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,4.2 Evaluation of markers and technologies ,Lipoprotein - Abstract
Background: Lipoprotein(a) (Lp[a]) is the preferential lipoprotein carrier of oxidized phospholipids (OxPLs) and a well-established genetic risk factor for calcific aortic valve stenosis (CAVS). Whether Lp(a) predicts aortic valve microcalcification in individuals without CAVS is unknown. Our objective was to estimate the prevalence of elevated Lp(a) and OxPL levels in patients with CAVS and to determine if individuals with elevated Lp(a) but without CAVS have higher aortic valve microcalcification. Methods: We recruited 214 patients with CAVS from Montreal and 174 patients with CAVS and 108 controls from Québec City, Canada. In a second group of individuals with high (≥75 nmol/L, n = 27) or low (
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- 2019
48. Genetic inhibition ofPCSK9, atherogenic lipoprotein concentrations, and calcific aortic valve stenosis
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Benoit J. Arsenault, Yohan Bossé, Andreas Martinsson, James C. Engert, Donato Moschetta, George Thanassoulis, Paolo Poggio, J. Gustav Smith, Elvira Mass, Marie-Annick Clavel, Romain Capoulade, Philippe Pibarot, Marina Camera, Patrick Mathieu, Christian Dina, Nicolas Perrot, Nicholas J. Wareham, S. Matthijs Boekholdt, Vincenza Valerio, Hao Yu Chen, and Sébastien Thériault
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Aortic valve ,medicine.medical_specialty ,Apolipoprotein B ,Population ,030204 cardiovascular system & hematology ,Gastroenterology ,Coronary artery disease ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Medicine ,030212 general & internal medicine ,education ,education.field_of_study ,biology ,business.industry ,PCSK9 ,Calcific aortic valve stenosis ,Odds ratio ,medicine.disease ,3. Good health ,medicine.anatomical_structure ,cardiovascular system ,biology.protein ,lipids (amino acids, peptides, and proteins) ,business ,Lipoprotein - Abstract
BackgroundProprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition reduces plasma concentrations of low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apoB) and lipoprotein(a) [Lp(a)]. Atherogenic lipoprotein levels have been linked with calcific aortic valve stenosis (CAVS). Our objectives were to determine the association between variants inPCSK9and lipoprotein-lipid levels, coronary artery disease (CAD) and CAVS, and to evaluate if PCSK9 could be implicated in aortic valve interstitial cells (VICs) calcification.MethodsWe built a genetic risk score weight for LDL-C levels (wGRS) using 10 independentPCSK9single nucleotide polymorphisms and determined its association with lipoprotein-lipid levels in 9692 participants of the EPIC-Norfolk study. We investigated the association between the wGRS and CAD and CAVS in the UK Biobank, as well as the association between thePCSK9R46L variant and CAVS in a meta-analysis of published prospective, population-based studies (Copenhagen studies, 1463 cases/101,620 controls) and unpublished studies (UK Biobank, 1350 cases/349,043 controls, Malmö Diet and Cancer study, 682 cases/5963 controls and EPIC-Norfolk study, 508 cases/20,421 controls). We evaluated PCSK9 expression and localization in explanted aortic valves by capillary Western blot and immunohistochemistry in patients with and without CAVS. Von Kossa staining was used to visualize aortic leaflet calcium deposits. PCSK9 expression under oxidative stress conditions in VICs was assessed.ResultsThe wGRS was significantly associated with lower LDL-C and apoB (pPCSK9variants with CAD were positively correlated with their effects on apoB levels. CAVS was less prevalent in carriers of thePCSK9R46L variant [odds ratio=0.71 (95% confidence interval, 0.57-0.88), pConclusionGenetic inhibition ofPCSK9is associated with lifelong reductions in the levels of non-Lp(a) apoB-containing lipoproteins as well as lower odds of CAD and CAVS. PCSK9 is abundant in fibrotic and calcified aortic leaflets. Oxidative stress increases PCSK9 expression in VICs. These results provide a rationale for performing randomized clinical trials of PCSK9 inhibition in CAVS.
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- 2019
49. Genetic association analyses highlight IL6, ALPL, and NAV1 as three new susceptibility genes underlying calcific aortic valve stenosis
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Nathalie Gaudreault, Richard Redon, Jean-Jacques Schott, Solena Le Scouarnec, Patrick Mathieu, Yohan Bossé, Christian Dina, Simon Lecointe, Thierry Le Tourneau, Stéphanie Bonnaud, Jean Philippe Verhoye, Philippe Pibarot, Zhonglin Li, Eric Charpentier, Anne-Sophie Boureau, Sidwell Rigade, Floriane Simonet, Sébastien Thériault, Christophe Baufreton, Romain Capoulade, Ronan Roussel, Estelle Baron, François Dagenais, Matilde Karakachoff, Maxime Lamontagne, Imen Fellah, Vincent Probst, Marie-Annick Clavel, David Messika-Zeitoun, Benoit J. Arsenault, and Jean-Christian Roussel
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Genetics ,0303 health sciences ,ALPL ,Calcific aortic valve stenosis ,Genome-wide association study ,030204 cardiovascular system & hematology ,Biology ,medicine.disease ,3. Good health ,Coronary artery disease ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Expression quantitative trait loci ,cardiovascular system ,medicine ,Gene ,030304 developmental biology ,Genetic association - Abstract
To date, only two replicated loci, LPA and PALMD, have been identified as causal genes for calcific aortic valve stenosis (CAVS) using genome-wide and transcriptome-wide association study (TWAS). To identify additional susceptibility genes for CAVS, we performed a GWAS meta-analysis totaling 5,115 cases and 354,072 controls of European descent. Four loci achieved genome-wide significance, including two new loci: IL6 (interleukin 6) on 7p15.3 and ALPL (alkaline phosphatase) on 1p36.12. A TWAS integrating an eQTL study of 233 human aortic valves identified NAV1 (neuron navigator 1) on 1q32.1 as a new candidate causal gene. The CAVS risk alleles were associated with higher mRNA expression of NAV1 in valve tissues. Association results at the genome-wide scale showed genetic correlation with coronary artery disease and cardiovascular risk factors. Our study highlights three new loci implicating inflammation, mineralization and blood vessel integrity in CAVS pathogenesis and supports shared genetic etiology with cardiovascular traits.
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- 2019
50. Metaproteomics: Sample Preparation and Methodological Considerations
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Benoit J. Kunath, Gustav Vaaje-Kolstad, Giusi Minniti, Magnus Ø. Arntzen, Phil B. Pope, Morten Skaugen, Vincent G. H. Eijsink, and Live Heldal Hagen
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03 medical and health sciences ,0302 clinical medicine ,Microbial ecology ,Metagenomics ,Metaproteomics ,Quantitative assessment ,030212 general & internal medicine ,Natural ecosystem ,Computational biology ,Biology - Abstract
Meta-omic techniques have progressed rapidly in the past decade and are frequently used in microbial ecology to study microorganisms in their natural ecosystems independent from culture restrictions. Metaproteomics, in combination with metagenomics, enables quantitative assessment of expressed proteins and pathways from individual members of the consortium. Together, metaproteomics and metagenomics can provide a detailed understanding of which organisms occupy specific metabolic niches, how they interact, and how they utilize nutrients, and these insights can be obtained directly from environmental samples. Here, we outline key aspects of sample preparation, database generation, and other methodological considerations that are required for successful quantitative metaproteomic analyses and we describe case studies on the integration with metagenomics for enhanced functional output.
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- 2019
Catalog
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