The polygenic implication of clopidogrel responsiveness: Insights from platelet reactivity analysis and next-generation sequencing

• Published in: PloS one Vol. 19; no. 7; p. e0306445
• Main Authors: Echeverría, Omar, Angulo-Aguado, Mariana, Vela, Ricardo, Calderón-Ospina, Carlos, Parra, Katherine, Contreras, Nora, Morel, Adrien, Cabrera, Rodrigo, Restrepo, Carlos, Ramírez-Santana, Carolina, Ortega-Recalde, Oscar, Rojas-Quintana, Manuel Eduardo, Murcia, Luisa, Gaviria-Sabogal, Cristian Camilo, Valero, Nattaly, Fonseca-Mendoza, Dora Janeth
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 11.07.2024; Public Library of Science (PLoS)
• Subjects: 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; Colombia; Latin America; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0306445

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.