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1. The genomics of heart failure: design and rationale of the HERMES consortium

Author

R. Thomas Lumbers, Sonia Shah, Honghuang Lin, Tomasz Czuba, Albert Henry, Daniel I. Swerdlow, Anders Mälarstig, Charlotte Andersson, Niek Verweij, Michael V. Holmes, Johan Ärnlöv, Per Svensson, Harry Hemingway, Neneh Sallah, Peter Almgren, Krishna G. Aragam, Geraldine Asselin, Joshua D. Backman, Mary L. Biggs, Heather L. Bloom, Eric Boersma, Jeffrey Brandimarto, Michael R. Brown, Hans‐Peter Brunner‐La Rocca, David J. Carey, Mark D. Chaffin, Daniel I. Chasman, Olympe Chazara, Xing Chen, Xu Chen, Jonathan H. Chung, William Chutkow, John G.F. Cleland, James P. Cook, Simon deDenus, Abbas Dehghan, Graciela E. Delgado, Spiros Denaxas, Alexander S. Doney, Marcus Dörr, Samuel C. Dudley, Gunnar Engström, Tõnu Esko, Ghazaleh Fatemifar, Stephan B. Felix, Chris Finan, Ian Ford, Francoise Fougerousse, René Fouodjio, Mohsen Ghanbari, Sahar Ghasemi, Vilmantas Giedraitis, Franco Giulianini, John S. Gottdiener, Stefan Gross, Daníel F. Guðbjartsson, Hongsheng Gui, Rebecca Gutmann, Christopher M. Haggerty, Pim van derHarst, Åsa K. Hedman, Anna Helgadottir, Hans Hillege, Craig L. Hyde, Jaison Jacob, J. Wouter Jukema, Frederick Kamanu, Isabella Kardys, Maryam Kavousi, Kay‐Tee Khaw, Marcus E. Kleber, Lars Køber, Andrea Koekemoer, Bill Kraus, Karoline Kuchenbaecker, Claudia Langenberg, Lars Lind, Cecilia M. Lindgren, Barry London, Luca A. Lotta, Ruth C. Lovering, Jian'an Luan, Patrik Magnusson, Anubha Mahajan, Douglas Mann, Kenneth B. Margulies, Nicholas A. Marston, Winfried März, John J.V. McMurray, Olle Melander, Giorgio Melloni, Ify R. Mordi, Michael P. Morley, Andrew D. Morris, Andrew P. Morris, Alanna C. Morrison, Michael W. Nagle, Christopher P. Nelson, Christopher Newton‐Cheh, Alexander Niessner, Teemu Niiranen, Christoph Nowak, Michelle L. O'Donoghue, Anjali T. Owens, Colin N.A. Palmer, Guillaume Paré, Markus Perola, Louis‐Philippe Lemieux Perreault, Eliana Portilla‐Fernandez, Bruce M. Psaty, Kenneth M. Rice, Paul M. Ridker, Simon P.R. Romaine, Carolina Roselli, Jerome I. Rotter, Christian T. Ruff, Marc S. Sabatine, Perttu Salo, Veikko Salomaa, Jessica vanSetten, Alaa A. Shalaby, Diane T. Smelser, Nicholas L. Smith, Kari Stefansson, Steen Stender, David J. Stott, Garðar Sveinbjörnsson, Mari‐Liis Tammesoo, Jean‐Claude Tardif, Kent D. Taylor, Maris Teder‐Laving, Alexander Teumer, Guðmundur Thorgeirsson, Unnur Thorsteinsdottir, Christian Torp‐Pedersen, Stella Trompet, Danny Tuckwell, Benoit Tyl, Andre G. Uitterlinden, Felix Vaura, Abirami Veluchamy, Peter M. Visscher, Uwe Völker, Adriaan A. Voors, Xiaosong Wang, Nicholas J. Wareham, Peter E. Weeke, Raul Weiss, Harvey D. White, Kerri L. Wiggins, Heming Xing, Jian Yang, Yifan Yang, Laura M. Yerges‐Armstrong, Bing Yu, Faiez Zannad, Faye Zhao, Regeneron Genetics Center, Jemma B. Wilk, Hilma Holm, Naveed Sattar, Steven A. Lubitz, David E. Lanfear, Svati Shah, Michael E. Dunn, Quinn S. Wells, Folkert W. Asselbergs, Aroon D. Hingorani, Marie‐Pierre Dubé, Nilesh J. Samani, Chim C. Lang, Thomas P. Cappola, Patrick T. Ellinor, Ramachandran S. Vasan, and J. Gustav Smith

Subjects
Heart failure, Cardiomyopathy, Genetics, Biomarkers, Association studies, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Abstract Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome‐wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow‐up following heart failure diagnosis ranged from 2 to 116 months. Forty‐nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34–90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low‐frequency variants (allele frequency 0.01–0.05) at P

Published
2021
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2. The genomics of heart failure: design and rationale of the HERMES consortium

Author

Svati H. Shah, Olle Melander, Neneh Sallah, Quinn S. Wells, Jerome I. Rotter, Faye Zhao, Charlotte Andersson, Guðmundur Thorgeirsson, Ghazaleh Fatemifar, Alex S. F. Doney, Michael E. Dunn, David E. Lanfear, Ian Ford, Eric Boersma, Sonia Shah, Christopher Newton-Cheh, Douglas L. Mann, Niek Verweij, Carolina Roselli, Laura M. Yerges-Armstrong, Jian Yang, Christian Torp-Pedersen, Veikko Salomaa, Mary L. Biggs, Alaa Shalaby, Christoph Nowak, Stefan Gross, Patrick T. Ellinor, Mari Liis Tammesoo, Diane T. Smelser, Peter M. Visscher, Hans L. Hillege, Ruth C. Lovering, Honghuang Lin, Colin N. A. Palmer, Louis Philippe Lemieux Perreault, Jeffrey Brandimarto, Uwe Völker, Perttu Salo, Andrea Koekemoer, Rebecca Gutmann, Åsa K. Hedman, Nilesh J. Samani, Heming Xing, Faiez Zannad, Jaison Jacob, Harry Hemingway, Michael R. Brown, Franco Giulianini, Anubha Mahajan, Xing Chen, Alexander Niessner, Peter Almgren, Daniel I. Swerdlow, Gunnar Engström, Lars Lind, Tõnu Esko, Tomasz Czuba, Anna Helgadottir, Harvey D. White, David J. Stott, Johan Ärnlöv, Lars Køber, Chim C. Lang, Krishna G. Aragam, Kent D. Taylor, Anders Mälarstig, Frederick K. Kamanu, Kenneth B. Margulies, Michelle L. O'Donoghue, Andrew D. Morris, Sahar Ghasemi, J. Wouter Jukema, Jessica van Setten, Abbas Dehghan, Guillaume Paré, Luca A. Lotta, Giorgio E. M. Melloni, Albert Henry, Bruce M. Psaty, Paul M. Ridker, David J. Carey, Marie-Pierre Dubé, John S. Gottdiener, Xiaosong Wang, Per H. Svensson, Xu Chen, Patrik K. E. Magnusson, Claudia Langenberg, Alexander Teumer, Vilmantas Giedraitis, Simon de Denus, Michael W. Nagle, Marcus Dörr, Thomas P. Cappola, André G. Uitterlinden, Michael Morley, Eliana Portilla-Fernandez, J. Gustav Smith, Abirami Veluchamy, Peter Weeke, Ify R. Mordi, Unnur Thorsteinsdottir, Naveed Sattar, Folkert W. Asselbergs, Daniel I. Chasman, Daníel F. Guðbjartsson, Jonathan H. Chung, Marcus E. Kleber, Raul Weiss, Christopher P. Nelson, Spiros Denaxas, Bing Yu, Simon P. R. Romaine, Nicholas A Marston, Anjali T. Owens, Cecilia M. Lindgren, John J.V. McMurray, Joshua D. Backman, Michael V. Holmes, Stella Trompet, Hilma Holm, Kerri L. Wiggins, Jian'an Luan, Stephan B. Felix, Yifan Yang, Jemma B. Wilk, Maryam Kavousi, Markus Perola, Christian T. Ruff, Jean-Claude Tardif, G Sveinbjörnsson, Samuel C. Dudley, Nicholas J. Wareham, Teemu J. Niiranen, Andrew P. Morris, Danny Tuckwell, Maris Teder-Laving, R. Thomas Lumbers, James P. Cook, Géraldine Asselin, William A. Chutkow, Winfried März, Steven A. Lubitz, John G.F. Cleland, Bill Kraus, Ramachandran S. Vasan, Christopher M. Haggerty, Olympe Chazara, Chris Finan, Heather L. Bloom, Hans-Peter Brunner-La Rocca, Francoise Fougerousse, Kenneth Rice, Craig L. Hyde, Graciela E. Delgado, Mark Chaffin, Marc S. Sabatine, Alanna C. Morrison, Kay-Tee Khaw, Kari Stefansson, Felix Vaura, Barry London, Isabella Kardys, Aroon D. Hingorani, Hongsheng Gui, Steen Stender, René Fouodjio, Mohsen Ghanbari, Pim van der Harst, Nicholas L. Smith, Karoline Kuchenbaecker, Adriaan A. Voors, Benoit Tyl, University College of London [London] (UCL), University College London Hospitals (UCLH), Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Lund University [Lund], Pfizer, Karolinska Institutet [Stockholm], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University of Groningen [Groningen], University of Oxford [Oxford], Dalarna University, Massachusetts General Hospital [Boston], Montreal Heart Institute - Institut de Cardiologie de Montréal, Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, University of Washington [Seattle], Emory University [Atlanta, GA], Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Pennsylvania [Philadelphia], The University of Texas Health Science Center at Houston (UTHealth), Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Department of Molecular and Functional Genomics, Geisinger, Danville, PA, Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), AstraZeneca, Novartis Institutes for BioMedical Research (NIBR), University of Glasgow, University of Liverpool, Université de Montréal (UdeM), Imperial College London, University of Heidelberg, Medical Faculty, University of Dundee, Universität Greifswald - University of Greifswald, University of Minnesota Medical School, University of Minnesota System, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Institut de Recherches Internationales Servier [Suresnes] (IRIS), Uppsala University, University of Maryland School of Medicine, University of Maryland System, University of Iceland [Reykjavik], deCODE genetics [Reykjavik], Henry Ford Hospital, Carver College of Medicine, University of Iowa, Geisinger Autism & Developmental Medicine Institute [Danville, PA, USA] (ADMI), ICIN - Netherlands Heart Institute, Leiden University Medical Center (LUMC), Netherlands Heart Institute, Partenaires INRAE, University of Cambridge [UK] (CAM), Rigshospitalet [Copenhagen], Copenhagen University Hospital, University of Leicester, Duke University [Durham], University of Iowa [Iowa City], Genentech, Inc., Genentech, Inc. [San Francisco], Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Skane University Hospital [Malmo], University of Edinburgh, Medizinische Universität Wien = Medical University of Vienna, University of Turku, National Institute for Health and Welfare [Helsinki], McMaster University [Hamilton, Ontario], Kaiser Permanente Washington Health Research Institute [Seattle] (KPWHRI), Harbor UCLA Medical Center [Torrance, Ca.], University Medical Center [Utrecht], University of Pittsburgh Medical Center [Pittsburgh, PA, États-Unis] (UPMC), University of Tartu, Aalborg University [Denmark] (AAU), Leiden University, University of Queensland [Brisbane], Ohio State University [Columbus] (OSU), Auckland City Hospital, GlaxoSmithKline, Glaxo Smith Kline, University of Texas Health Science Center, Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Duke University Medical Center, Regeneron Pharmaceuticals [Tarrytown], Vanderbilt University [Nashville], European Project, Langenberg, Claudia [0000-0002-5017-7344], Luan, Jian'an [0000-0003-3137-6337], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Groningen Kidney Center (GKC), Cardiology, University of Oxford, University of Pennsylvania, Universiteit Leiden, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), RS: Carim - H02 Cardiomyopathy, Epidemiology, and Internal Medicine

Subjects
Male, Study Designs, Cardiomyopathy, Disease, 030204 cardiovascular system & hematology, 0302 clinical medicine, AFRICAN ANCESTRY, Epidemiology, 80 and over, WIDE ASSOCIATION, EPIDEMIOLOGY, Cardiac and Cardiovascular Systems, AGING RESEARCH, RISK, Aged, 80 and over, 0303 health sciences, Kardiologi, Genomics, Middle Aged, Prognosis, 3. Good health, Female, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, Heart failure, CLASSIFICATION, Heart Failure/genetics, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Genetic model, medicine, Genetics, Diseases of the circulatory (Cardiovascular) system, Humans, Allele frequency, Genotyping, METAANALYSIS, 030304 developmental biology, Aged, Association studies, Study Design, business.industry, Odds ratio, ADULTS, COHORTS, medicine.disease, RC666-701, REPLICATION, business, Biomarkers, Genome-Wide Association Study
Abstract

Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure.Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 x 10(-8) under an additive genetic model.Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.

Published
2021

3. Pharmacogenomics of the Efficacy and Safety of Colchicine in COLCOT

Author

François Roubille, Simon Kouz, Colin Berry, Habib Gamra, Rafael Diaz, Wolfgang Koenig, Ian Mongrain, Marc-André Legault, René Fouodjio, Amina Barhdadi, Marie-Pierre Dubé, Ghassan S. Kiwan, Lucie Blondeau, Aldo P. Maggioni, Marie-Claude Guertin, Fausto J. Pinto, Michelle Samuel, Anick Dubois, Maxine Sun, Philippe L. L’Allier, Jean-Claude Tardif, Nadia Bouabdallaoui, Audrey Lemaçon, David Rhainds, Géraldine Asselin, Louis-Philippe Lemieux Perreault, Sylvie Provost, Simon de Denus, David D. Waters, Jose Lopez-Sendon, Mariève Cossette, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), and Repositório da Universidade de Lisboa

Subjects
Male, Gastrointestinal Diseases, [SDV]Life Sciences [q-bio], Association Studies, Cardiovascular, chemistry.chemical_compound, 0302 clinical medicine, Clinical Studies, Colchicine, Myocardial infarction, Randomized Controlled Trials as Topic, pharmacogenetics, 0303 health sciences, Single Nucleotide, General Medicine, Middle Aged, 3. Good health, Treatment Outcome, myocardial infarction, Heart Disease, Gastrointestinal disorder, Cardiovascular Diseases, 6.1 Pharmaceuticals, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Cardiology, Female, Patient Safety, Acute coronary syndrome, Cardiovascular outcomes, Cardiovascular event, medicine.medical_specialty, Genotype, Clinical Trials and Supportive Activities, Polymorphism, Single Nucleotide, colchicine, acute coronary syndrome, 03 medical and health sciences, Genetic, Clinical Research, Internal medicine, Genetics, medicine, Humans, Polymorphism, Heart Disease - Coronary Heart Disease, Gastrointestinal diseases, Proportional Hazards Models, Aged, 030304 developmental biology, business.industry, Phosphotransferases, Human Genome, Evaluation of treatments and therapeutic interventions, Original Articles, Placebo Effect, medicine.disease, chemistry, Pharmacogenetics, Pharmacogenomics, Digestive Diseases, business, Acute Coronary Syndromes, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Supplemental Digital Content is available in the text., Background: The randomized, placebo-controlled COLCOT (Colchicine Cardiovascular Outcomes Trial) has shown the benefits of colchicine 0.5 mg daily to lower the rate of ischemic cardiovascular events in patients with a recent myocardial infarction. Here, we conducted a post hoc pharmacogenomic study of COLCOT with the aim to identify genetic predictors of the efficacy and safety of treatment with colchicine. Methods: There were 1522 participants of European ancestry from the COLCOT trial available for the pharmacogenomic study of COLCOT trial. The pharmacogenomic study’s primary cardiovascular end point was defined as for the main trial, as time to first occurrence of cardiovascular death, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina requiring coronary revascularization. The safety end point was time to the first report of gastrointestinal events. Patients’ DNA was genotyped using the Illumina Global Screening array followed by imputation. We performed a genome-wide association study in colchicine-treated patients. Results: None of the genetic variants passed the genome-wide association study significance threshold for the primary cardiovascular end point conducted in 702 patients in the colchicine arm who were compliant to medication. The genome-wide association study for gastrointestinal events was conducted in all 767 patients in the colchicine arm and found 2 significant association signals, one with lead variant rs6916345 (hazard ratio, 1.89 [95% CI, 1.52–2.35], P=7.41×10−9) in a locus which colocalizes with Crohn disease, and one with lead variant rs74795203 (hazard ratio, 2.51 [95% CI, 1.82–3.47]; P=2.70×10−8), an intronic variant in gene SEPHS1. The interaction terms between the genetic variants and treatment with colchicine versus placebo were significant. Conclusions: We found 2 genomic regions associated with gastrointestinal events in patients treated with colchicine. Those findings will benefit from replication to confirm that some patients may have genetic predispositions to lower tolerability of treatment with colchicine.

Published
2021

4. CYP3A4 genotype is associated with sildenafil concentrations in patients with heart failure with preserved ejection fraction

Author

Douglas L. Mann, Ian Mongrain, S. de Denus, René Fouodjio, Thomas P. Cappola, Naveen L. Pereira, Marie-Pierre Dubé, Svati H. Shah, Jean L. Rouleau, and Gordon S. Huggins

Subjects
0301 basic medicine, Male, Vasodilator Agents, 030226 pharmacology & pharmacy, law.invention, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, law, Medicine, Cytochrome P-450 CYP3A, pharmacogenetics, education.field_of_study, Ejection fraction, Exercise Tolerance, Middle Aged, Cardiology, cardiovascular system, Molecular Medicine, Female, Cardiology and Cardiovascular Medicine, pharmacokinetics, medicine.medical_specialty, Genotype, Sildenafil, Population, Article, Sildenafil Citrate, 03 medical and health sciences, Pharmacokinetics, Internal medicine, Genetics, Humans, education, Aged, Pharmacology, Heart Failure, business.industry, Repeated measures design, Stroke Volume, medicine.disease, respiratory tract diseases, 030104 developmental biology, Endocrinology, chemistry, Heart failure, business, Heart failure with preserved ejection fraction, Pharmacogenetics
Abstract

Despite its established inter-individual variability, sildenafil has been the subject of only a few pharmacogenetic investigations, with limited data regarding the genetic modulators of its pharmacokinetics. We conducted a pharmacogenetic substudy of patients randomized to sildenafil (n = 85) in the RELAX trial, which investigated the impact of high-dose sildenafil in patients with heart failure with preserved left ventricular ejection fraction (HFpEF). In the overall population, the CYP3A4 inferred phenotype appeared associated with the dose-adjusted peak concentrations of sildenafil at week 12 and week 24 (adjusted P=0.045 for repeated measures analysis), although this P value did not meet our corrected significance threshold of 0.0167. In the more homogeneous Caucasian subgroup, this association was significant (adjusted P=0.0165 for repeated measures). Hence, CYP3A4 inferred phenotype is associated with peak sildenafil dose-adjusted concentrations in patients with HFpEF receiving high doses of sildenafil. The clinical impact of this association requires further investigation.

Published
2017

5. Genotype-Dependent Effects of Dalcetrapib on Cholesterol Efflux and Inflammation

Author

Marie-Pierre Dubé, Sonia Alem, Yassamin Feroz Zada, Marie-Claude Guertin, Mathieu R. Brodeur, Reda Ibrahim, Gregory G. Schwartz, Sylvie Provost, Philippe L. L’Allier, Eric Rhéaume, Marie Boulé, Jean Grégoire, Jean-Claude Tardif, René Fouodjio, Anders G. Olsson, Ian Mongrain, and David Rhainds

Subjects
0301 basic medicine, Concordance, Dalcetrapib, Inflammation, 030204 cardiovascular system & hematology, Pharmacology, Biology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Genotype, Genetics, medicine, Cardiac and Cardiovascular Systems, Genetics (clinical), reactive protein, cholesterol efflux, dalcetrapib, HDL, pharmacogenetics, Kardiologi, Cholesterol, C-reactive protein, 030104 developmental biology, chemistry, biology.protein, Efflux, medicine.symptom, Cardiology and Cardiovascular Medicine, Pharmacogenetics
Abstract

Background— Dalcetrapib effects on cardiovascular outcomes are determined by adenylate cyclase 9 gene polymorphisms. Our aim was to determine whether these clinical end point results are also associated with changes in reverse cholesterol transport and inflammation. Methods and Results— Participants of the dal-OUTCOMES and dal-PLAQUE-2 trials were randomly assigned to receive dalcetrapib or placebo in addition to standard care. High-sensitivity C-reactive protein was measured at baseline and at end of study in 5243 patients from dal-OUTCOMES also genotyped for the rs1967309 polymorphism in adenylate cyclase 9. Cholesterol efflux capacity of high-density lipoproteins from J774 macrophages after cAMP stimulation was determined at baseline and 12 months in 171 genotyped patients from dal-PLAQUE-2. Treatment with dalcetrapib resulted in placebo-adjusted geometric mean percent increases in high-sensitivity C-reactive protein from baseline to end of trial of 18.1% ( P =0.0009) and 18.7% ( P =0.00001) in participants with the GG and AG genotypes, respectively, but the change was −1.0% ( P =0.89) in those with the protective AA genotype. There was an interaction between the treatment arm and the genotype groups ( P =0.02). Although the mean change in cholesterol efflux was similar among study arms in patients with GG genotype (mean: 7.8% and 7.4%), increases were 22.3% and 3.5% with dalcetrapib and placebo for those with AA genotype ( P =0.005). There was a significant genetic effect for change in efflux for dalcetrapib ( P =0.02), but not with placebo. Conclusions— Genotype-dependent effects on C-reactive protein and cholesterol efflux are supportive of dalcetrapib benefits on atherosclerotic cardiovascular outcomes in patients with the AA genotype at polymorphism rs1967309. Clinical Trials Registration— ClinicalTrials.gov; Unique Identifiers: NCT00658515 and NCT01059682.

Published
2016

6. A prospective study of the impact of AGTR1 A1166C on the effects of candesartan in patients with heart failure

Author

René Fouodjio, Eileen O'Meara, Michael S. Phillips, Valérie Normand, Asmaa Mansour, Ian Mongrain, Nadia Giannetti, Thao Huynh, Candiid Ii investigators, Sylvie Provost, Michel White, Jacques Turgeon, Mathieu Langlois, Serge Lepage, Normand Racine, Richard Sheppard, Simon de Denus, Marie-Hélène Leblanc, Marie-Claude Guertin, Joel Lavoie, Jean-Lucien Rouleau, Marie-Pierre Dubé, Jean-Claude Tardif, and Anique Ducharme

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Tetrazoles, Blood Pressure, 030204 cardiovascular system & hematology, Kidney Function Tests, Plasma renin activity, Polymorphism, Single Nucleotide, Receptor, Angiotensin, Type 1, Renin-Angiotensin System, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Renin–angiotensin system, Natriuretic Peptide, Brain, Genetics, medicine, Humans, Prospective Studies, Prospective cohort study, Aged, Pharmacology, Heart Failure, Ejection fraction, Aldosterone, business.industry, Biphenyl Compounds, medicine.disease, Peptide Fragments, Candesartan, 030104 developmental biology, Blood pressure, Treatment Outcome, chemistry, Pharmacogenetics, Heart failure, Cardiology, Molecular Medicine, Benzimidazoles, Female, business, Angiotensin II Type 1 Receptor Blockers, Biomarkers, medicine.drug
Abstract

Aim: To evaluate the impact of AGTR1 A1166C (rs5186) on the response to candesartan in patients with heart failure. Materials & methods: Prospective, multicentre, open-label study. We studied 299 symptomatic patients with heart failure presenting a left ventricular ejection fraction ≤40%. Results: Reductions in the primary end points of natriuretic peptides were not significantly associated with AGTR1 A1166C. Nevertheless, carrying the 1166C allele was associated with a greater compensatory increase in renin activity (p = 0.037) after 16 weeks of treatment with candesartan and a more modest effect on aldosterone concentrations (p = 0.022). Conclusion: AGTR1 1166C carriers may experience a greater long-term compensatory renin–angiotensin–aldosterone system activation following treatment with candesartan. Whether these associations ultimately influence clinical outcomes requires investigation. Clinicaltrials.gov : NCT00400582

Published
2018

7. A PROSPECTIVE INVESTIGATION OF THE IMPACT OF AGTR1 A1166C ON THE NEUROHORMONAL AND HEMODYNAMIC EFFECTS OF CANDESARTAN IN HEART FAILURE PATIENTS

Author

René Fouodjio, Valérie Normand, Jacques Turgeon, J.C. Tardif, S. Lepage, S. de Denus, Ian Mongrain, Sylvie Provost, Eileen O'Meara, Asmaa Mansour, Anique Ducharme, Marie-Claude Guertin, Marie-Hélène Leblanc, Mathieu Dubé, Joel Lavoie, Jean-Lucien Rouleau, Normand Racine, Richard Sheppard, Nadia Giannetti, Mathieu Langlois, Thao Huynh, Michel White, and Michael S. Phillips

Subjects
medicine.medical_specialty, Candesartan, business.industry, Internal medicine, Heart failure, medicine, Cardiology, Cardiology and Cardiovascular Medicine, business, medicine.disease, Hemodynamic effects, medicine.drug
Published
2016

8. CYP3A4 Genotype is Associated with Sildenafil Concentrations in Patients with Heart Failure with Preserved Ejection Fraction

Author

Marie-Pierre Dubé, René Fouodjio, Jean L. Rouleau, Douglas L. Mann, Simon de Denus, Thomas P. Cappola, Svati H. Shah, Ian Mongrain, Naveen L. Pereira, and Gordon S. Huggins

Subjects
medicine.medical_specialty, CYP3A4, business.industry, Sildenafil, chemistry.chemical_compound, chemistry, Internal medicine, Genotype, medicine, Cardiology, In patient, Cardiology and Cardiovascular Medicine, business, Heart failure with preserved ejection fraction
Published
2016

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