The polygenic implication of clopidogrel responsiveness: Insights from platelet reactivity analysis and next-generation sequencing
Clopidogrel is widely used worldwide as an antiplatelet therapy in patients with acute coronary disease. Genetic factors influence interindividual variability in response. Some studies have explored the polygenic contributions in the drug response, generating pharmacogenomic risk scores (PgxPRS). Im...
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Published in | PloS one Vol. 19; no. 7; p. e0306445 |
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Main Authors | , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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Public Library of Science
11.07.2024
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Abstract | Clopidogrel is widely used worldwide as an antiplatelet therapy in patients with acute coronary disease. Genetic factors influence interindividual variability in response. Some studies have explored the polygenic contributions in the drug response, generating pharmacogenomic risk scores (PgxPRS). Importantly, these factors are less explored in underrepresented populations, such as Latin-American countries. Identifying patients at risk of high-on-treatment platelet reactivity (HTPR) is highly valuable in translational medicine. In this study we used a custom next-generation sequencing (NGS) panel composed of 91 single nucleotide polymorphisms (SNPs) and 28 genes related to clopidogrel metabolism, to analyze 70 patients with platelet reactivity values, assessed through closure time (CT). Our results demonstrated the association of SNPs with HTPR and non-HTPR, revealing the strongest associations with rs2286823 (OR: 5,0; 95% CI: 1,02-24,48; p: 0,03), rs2032582 (OR: 4,41; 95% CI: 1,20-16,12; p: 0,019), and rs1045642 (OR: 3,38; 95% CI: 0,96-11,9; p: 0,05). Bivariate regression analysis demonstrated the significant association of several SNPs with the CT value, a "surrogate" biomarker of clopidogrel response. Exploratory results from the LASSO regression model showed a high discriminatory capacity between HTPR and non-HTPR patients (AUC: 0,955), and the generated PgxPRS demonstrated a significant negative association between the risk score, CT value, and the condition of HTPR and non-HTPR. To our knowledge, our study addresses for the first time the analysis of the polygenic contribution in platelet reactivity using NGS and establishes PgxPRS derived from the LASSO model. Our results demonstrate the polygenic implication of clopidogrel response and offer insights applicable to the translational medicine of antiplatelet therapy in an understudied population. |
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AbstractList | Clopidogrel is widely used worldwide as an antiplatelet therapy in patients with acute coronary disease. Genetic factors influence interindividual variability in response. Some studies have explored the polygenic contributions in the drug response, generating pharmacogenomic risk scores (PgxPRS). Importantly, these factors are less explored in underrepresented populations, such as Latin-American countries. Identifying patients at risk of high-on-treatment platelet reactivity (HTPR) is highly valuable in translational medicine. In this study we used a custom next-generation sequencing (NGS) panel composed of 91 single nucleotide polymorphisms (SNPs) and 28 genes related to clopidogrel metabolism, to analyze 70 patients with platelet reactivity values, assessed through closure time (CT). Our results demonstrated the association of SNPs with HTPR and non-HTPR, revealing the strongest associations with rs2286823 (OR: 5,0; 95% CI: 1,02-24,48; p: 0,03), rs2032582 (OR: 4,41; 95% CI: 1,20-16,12; p: 0,019), and rs1045642 (OR: 3,38; 95% CI: 0,96-11,9; p: 0,05). Bivariate regression analysis demonstrated the significant association of several SNPs with the CT value, a "surrogate" biomarker of clopidogrel response. Exploratory results from the LASSO regression model showed a high discriminatory capacity between HTPR and non-HTPR patients (AUC: 0,955), and the generated PgxPRS demonstrated a significant negative association between the risk score, CT value, and the condition of HTPR and non-HTPR. To our knowledge, our study addresses for the first time the analysis of the polygenic contribution in platelet reactivity using NGS and establishes PgxPRS derived from the LASSO model. Our results demonstrate the polygenic implication of clopidogrel response and offer insights applicable to the translational medicine of antiplatelet therapy in an understudied population. Clopidogrel is widely used worldwide as an antiplatelet therapy in patients with acute coronary disease. Genetic factors influence interindividual variability in response. Some studies have explored the polygenic contributions in the drug response, generating pharmacogenomic risk scores (PgxPRS). Importantly, these factors are less explored in underrepresented populations, such as Latin-American countries. Identifying patients at risk of high-on-treatment platelet reactivity (HTPR) is highly valuable in translational medicine. In this study we used a custom next-generation sequencing (NGS) panel composed of 91 single nucleotide polymorphisms (SNPs) and 28 genes related to clopidogrel metabolism, to analyze 70 patients with platelet reactivity values, assessed through closure time (CT). Our results demonstrated the association of SNPs with HTPR and non-HTPR, revealing the strongest associations with rs2286823 (OR: 5,0; 95% CI: 1,02-24,48; p: 0,03), rs2032582 (OR: 4,41; 95% CI: 1,20-16,12; p: 0,019), and rs1045642 (OR: 3,38; 95% CI: 0,96-11,9; p: 0,05). Bivariate regression analysis demonstrated the significant association of several SNPs with the CT value, a "surrogate" biomarker of clopidogrel response. Exploratory results from the LASSO regression model showed a high discriminatory capacity between HTPR and non-HTPR patients (AUC: 0,955), and the generated PgxPRS demonstrated a significant negative association between the risk score, CT value, and the condition of HTPR and non-HTPR. To our knowledge, our study addresses for the first time the analysis of the polygenic contribution in platelet reactivity using NGS and establishes PgxPRS derived from the LASSO model. Our results demonstrate the polygenic implication of clopidogrel response and offer insights applicable to the translational medicine of antiplatelet therapy in an understudied population.Clopidogrel is widely used worldwide as an antiplatelet therapy in patients with acute coronary disease. Genetic factors influence interindividual variability in response. Some studies have explored the polygenic contributions in the drug response, generating pharmacogenomic risk scores (PgxPRS). Importantly, these factors are less explored in underrepresented populations, such as Latin-American countries. Identifying patients at risk of high-on-treatment platelet reactivity (HTPR) is highly valuable in translational medicine. In this study we used a custom next-generation sequencing (NGS) panel composed of 91 single nucleotide polymorphisms (SNPs) and 28 genes related to clopidogrel metabolism, to analyze 70 patients with platelet reactivity values, assessed through closure time (CT). Our results demonstrated the association of SNPs with HTPR and non-HTPR, revealing the strongest associations with rs2286823 (OR: 5,0; 95% CI: 1,02-24,48; p: 0,03), rs2032582 (OR: 4,41; 95% CI: 1,20-16,12; p: 0,019), and rs1045642 (OR: 3,38; 95% CI: 0,96-11,9; p: 0,05). Bivariate regression analysis demonstrated the significant association of several SNPs with the CT value, a "surrogate" biomarker of clopidogrel response. Exploratory results from the LASSO regression model showed a high discriminatory capacity between HTPR and non-HTPR patients (AUC: 0,955), and the generated PgxPRS demonstrated a significant negative association between the risk score, CT value, and the condition of HTPR and non-HTPR. To our knowledge, our study addresses for the first time the analysis of the polygenic contribution in platelet reactivity using NGS and establishes PgxPRS derived from the LASSO model. Our results demonstrate the polygenic implication of clopidogrel response and offer insights applicable to the translational medicine of antiplatelet therapy in an understudied population. |
Audience | Academic |
Author | Gaviria-Sabogal, Cristian Camilo Murcia, Luisa Ortega-Recalde, Oscar Parra, Katherine Contreras, Nora Vela, Ricardo Echeverría, Omar Angulo-Aguado, Mariana Ramírez-Santana, Carolina Calderón-Ospina, Carlos Morel, Adrien Cabrera, Rodrigo Rojas-Quintana, Manuel Eduardo Restrepo, Carlos Valero, Nattaly Fonseca-Mendoza, Dora Janeth |
AuthorAffiliation | Universiti Sains Malaysia, MALAYSIA 3 Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogotá D.C., Colombia 1 School of Medicine and Health Sciences, Center for Research in Genetics and Genomics (CIGGUR), Institute of Translational Medicine (IMT), Universidad Del Rosario, Bogotá D.C., Colombia 2 Hospital Universitario Mayor—Méderi—Universidad del Rosario, Bogotá D.C., Colombia 5 Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, United States of America 4 Departamento de Morfología, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá D.C., Colombia |
AuthorAffiliation_xml | – name: 3 Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogotá D.C., Colombia – name: 4 Departamento de Morfología, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá D.C., Colombia – name: 5 Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, United States of America – name: 1 School of Medicine and Health Sciences, Center for Research in Genetics and Genomics (CIGGUR), Institute of Translational Medicine (IMT), Universidad Del Rosario, Bogotá D.C., Colombia – name: Universiti Sains Malaysia, MALAYSIA – name: 2 Hospital Universitario Mayor—Méderi—Universidad del Rosario, Bogotá D.C., Colombia |
Author_xml | – sequence: 1 givenname: Omar orcidid: 0009-0000-6753-0178 surname: Echeverría fullname: Echeverría, Omar organization: School of Medicine and Health Sciences, Center for Research in Genetics and Genomics (CIGGUR), Institute of Translational Medicine (IMT), Universidad Del Rosario, Bogotá D.C., Colombia – sequence: 2 givenname: Mariana surname: Angulo-Aguado fullname: Angulo-Aguado, Mariana organization: School of Medicine and Health Sciences, Center for Research in Genetics and Genomics (CIGGUR), Institute of Translational Medicine (IMT), Universidad Del Rosario, Bogotá D.C., Colombia – sequence: 3 givenname: Ricardo surname: Vela fullname: Vela, Ricardo organization: School of Medicine and Health Sciences, Center for Research in Genetics and Genomics (CIGGUR), Institute of Translational Medicine (IMT), Universidad Del Rosario, Bogotá D.C., Colombia – sequence: 4 givenname: Carlos surname: Calderón-Ospina fullname: Calderón-Ospina, Carlos organization: School of Medicine and Health Sciences, Center for Research in Genetics and Genomics (CIGGUR), Institute of Translational Medicine (IMT), Universidad Del Rosario, Bogotá D.C., Colombia – sequence: 5 givenname: Katherine surname: Parra fullname: Parra, Katherine organization: Hospital Universitario Mayor-Méderi-Universidad del Rosario, Bogotá D.C., Colombia – sequence: 6 givenname: Nora surname: Contreras fullname: Contreras, Nora organization: School of Medicine and Health Sciences, Center for Research in Genetics and Genomics (CIGGUR), Institute of Translational Medicine (IMT), Universidad Del Rosario, Bogotá D.C., Colombia – sequence: 7 givenname: Adrien surname: Morel fullname: Morel, Adrien organization: School of Medicine and Health Sciences, Center for Research in Genetics and Genomics (CIGGUR), Institute of Translational Medicine (IMT), Universidad Del Rosario, Bogotá D.C., Colombia – sequence: 8 givenname: Rodrigo surname: Cabrera fullname: Cabrera, Rodrigo organization: School of Medicine and Health Sciences, Center for Research in Genetics and Genomics (CIGGUR), Institute of Translational Medicine (IMT), Universidad Del Rosario, Bogotá D.C., Colombia – sequence: 9 givenname: Carlos orcidid: 0000-0001-6410-0084 surname: Restrepo fullname: Restrepo, Carlos organization: School of Medicine and Health Sciences, Center for Research in Genetics and Genomics (CIGGUR), Institute of Translational Medicine (IMT), Universidad Del Rosario, Bogotá D.C., Colombia – sequence: 10 givenname: Carolina surname: Ramírez-Santana fullname: Ramírez-Santana, Carolina organization: Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogotá D.C., Colombia – sequence: 11 givenname: Oscar surname: Ortega-Recalde fullname: Ortega-Recalde, Oscar organization: Departamento de Morfología, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá D.C., Colombia – sequence: 12 givenname: Manuel Eduardo orcidid: 0000-0002-8604-4658 surname: Rojas-Quintana fullname: Rojas-Quintana, Manuel Eduardo organization: Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, United States of America – sequence: 13 givenname: Luisa orcidid: 0000-0003-2998-8561 surname: Murcia fullname: Murcia, Luisa organization: Hospital Universitario Mayor-Méderi-Universidad del Rosario, Bogotá D.C., Colombia – sequence: 14 givenname: Cristian Camilo orcidid: 0009-0004-9482-4373 surname: Gaviria-Sabogal fullname: Gaviria-Sabogal, Cristian Camilo organization: School of Medicine and Health Sciences, Center for Research in Genetics and Genomics (CIGGUR), Institute of Translational Medicine (IMT), Universidad Del Rosario, Bogotá D.C., Colombia – sequence: 15 givenname: Nattaly surname: Valero fullname: Valero, Nattaly organization: School of Medicine and Health Sciences, Center for Research in Genetics and Genomics (CIGGUR), Institute of Translational Medicine (IMT), Universidad Del Rosario, Bogotá D.C., Colombia – sequence: 16 givenname: Dora Janeth orcidid: 0000-0002-7323-6570 surname: Fonseca-Mendoza fullname: Fonseca-Mendoza, Dora Janeth organization: School of Medicine and Health Sciences, Center for Research in Genetics and Genomics (CIGGUR), Institute of Translational Medicine (IMT), Universidad Del Rosario, Bogotá D.C., Colombia |
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ContentType | Journal Article |
Copyright | Copyright: © 2024 Echeverría et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. COPYRIGHT 2024 Public Library of Science 2024 Echeverría et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. 2024 Echeverría et al 2024 Echeverría et al |
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SubjectTerms | Acute coronary syndromes Adenosine diphosphate Aged Analysis Biology and Life Sciences Biomarkers Bivariate analysis Blood Platelets - drug effects Blood Platelets - metabolism Cardiac patients Cardiovascular disease Care and treatment Chromosomes Clopidogrel Clopidogrel - pharmacology Clopidogrel - therapeutic use Coronary heart disease Drug dosages Female Gene sequencing Genetic analysis Genetic aspects Genetic factors Genetic testing Genetic variability Genomes Heart diseases High-Throughput Nucleotide Sequencing - methods Humans Male Medical research Medicine and Health Sciences Medicine, Experimental Middle Aged Multifactorial Inheritance - genetics Mutation Next-generation sequencing Nucleotides Pharmacodynamics Pharmacogenetics Pharmacogenomics Pharmacokinetics Physiological aspects Platelet Aggregation Inhibitors - pharmacology Platelet Aggregation Inhibitors - therapeutic use Platelets Polymorphism, Single Nucleotide Population studies Regression analysis Regression models Research and analysis methods Risk Single nucleotide polymorphisms Single-nucleotide polymorphism Software Ticlopidine - analogs & derivatives Ticlopidine - pharmacology Ticlopidine - therapeutic use Translation |
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Title | The polygenic implication of clopidogrel responsiveness: Insights from platelet reactivity analysis and next-generation sequencing |
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