Pharmacogenomics of the Efficacy and Safety of Colchicine in COLCOT
| Autor: | 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 |
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| Přispěvatelé: | 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), Repositório da Universidade de Lisboa |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
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 |
| Zdroj: | Circulation: Genomic and Precision Medicine Circulation: Genomic and Precision Medicine, American Heart Association, In press, ⟨10.1161/CIRCGEN.120.003183⟩ Circulation. Genomic and precision medicine, vol 14, iss 2 Circulation. Genomic and Precision Medicine Repositório Científico de Acesso Aberto de Portugal Repositório Científico de Acesso Aberto de Portugal (RCAAP) instacron:RCAAP |
| ISSN: | 2574-8300 |
| DOI: | 10.1161/CIRCGEN.120.003183⟩ |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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