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Pharmacogenomic polygenic risk score for clopidogrel responsiveness among Caribbean Hispanics: A candidate gene approach

This multicenter clinical study was aimed at conducting a targeted pharmacogenomic association analysis of residual on‐clopidogrel platelet reactivity in 474 Caribbean Hispanic patients. Platelet reactivity was measured using the VerifyNow P2Y12 assay and clopidogrel resistance was defined as P2Y12...

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Autores principales: Duconge, Jorge, Santiago, Ednalise, Hernandez‐Suarez, Dagmar F., Moneró, Mariangeli, López‐Reyes, Andrés, Rosario, Marines, Renta, Jessicca Y., González, Pablo, Ileana Fernández‐Morales, Laura, Antonio Vélez‐Figueroa, Luis, Arce, Orlando, Marín‐Maldonado, Frances, Nuñez, Héctor, Melin, Kyle, Scott, Stuart A., Ruaño, Gualberto
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8604227/
https://www.ncbi.nlm.nih.gov/pubmed/34415683
http://dx.doi.org/10.1111/cts.13124
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author Duconge, Jorge
Santiago, Ednalise
Hernandez‐Suarez, Dagmar F.
Moneró, Mariangeli
López‐Reyes, Andrés
Rosario, Marines
Renta, Jessicca Y.
González, Pablo
Ileana Fernández‐Morales, Laura
Antonio Vélez‐Figueroa, Luis
Arce, Orlando
Marín‐Maldonado, Frances
Nuñez, Héctor
Melin, Kyle
Scott, Stuart A.
Ruaño, Gualberto
author_facet Duconge, Jorge
Santiago, Ednalise
Hernandez‐Suarez, Dagmar F.
Moneró, Mariangeli
López‐Reyes, Andrés
Rosario, Marines
Renta, Jessicca Y.
González, Pablo
Ileana Fernández‐Morales, Laura
Antonio Vélez‐Figueroa, Luis
Arce, Orlando
Marín‐Maldonado, Frances
Nuñez, Héctor
Melin, Kyle
Scott, Stuart A.
Ruaño, Gualberto
author_sort Duconge, Jorge
collection PubMed
description This multicenter clinical study was aimed at conducting a targeted pharmacogenomic association analysis of residual on‐clopidogrel platelet reactivity in 474 Caribbean Hispanic patients. Platelet reactivity was measured using the VerifyNow P2Y12 assay and clopidogrel resistance was defined as P2Y12 reaction units (PRUs) greater than or equal to 208. Genotyping was performed using the whole‐genome Infinium MEGA BeadChip array. An ancestry‐adjusted, weighted polygenic risk score (wPGxRS) was developed to account for the effect of multiple variants on PRU and compared between clopidogrel responders and nonresponders. The mean PRU across the study cohort was 173.8 ± 68.5 and 33.5% of patients were defined as clopidogrel resistant. Multivariate linear regression showed that 19% of PRU variability was attributed to nine independent predictors, with CYP2C19*2 (rs4244285) accounting for ~ 7% of observed PRU variation (p < 0.001). PON1 rs662, ABCB1/MDR1 rs2032582, PEAR1 rs12041331 carrier status, and the interaction between African ancestry and rs12041331 carriers also predicted PRU among the participants (p ≤ 0.05). A clear gene‐dose effect was detected between PRU and CYP2C19*2 genotype, consistent with previous studies in European patient populations, as well as rs12777823. Importantly, a significant positive correlation was detected between our novel wPGxRS (4 variants) and PRU among the Hispanic patient population (r (p) = 0.35, p < 0.001). Moreover, the wPGxRS discriminated between nonresponders and responders (p = 0.003), indicating that this multigene‐based score is a useful predictor of clopidogrel resistance among Caribbean Hispanics. Taken together, these results help close the gap of knowledge on clopidogrel pharmacogenomics and its potential clinical implementation in this under‐represented population.
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spelling pubmed-86042272021-11-24 Pharmacogenomic polygenic risk score for clopidogrel responsiveness among Caribbean Hispanics: A candidate gene approach Duconge, Jorge Santiago, Ednalise Hernandez‐Suarez, Dagmar F. Moneró, Mariangeli López‐Reyes, Andrés Rosario, Marines Renta, Jessicca Y. González, Pablo Ileana Fernández‐Morales, Laura Antonio Vélez‐Figueroa, Luis Arce, Orlando Marín‐Maldonado, Frances Nuñez, Héctor Melin, Kyle Scott, Stuart A. Ruaño, Gualberto Clin Transl Sci Research This multicenter clinical study was aimed at conducting a targeted pharmacogenomic association analysis of residual on‐clopidogrel platelet reactivity in 474 Caribbean Hispanic patients. Platelet reactivity was measured using the VerifyNow P2Y12 assay and clopidogrel resistance was defined as P2Y12 reaction units (PRUs) greater than or equal to 208. Genotyping was performed using the whole‐genome Infinium MEGA BeadChip array. An ancestry‐adjusted, weighted polygenic risk score (wPGxRS) was developed to account for the effect of multiple variants on PRU and compared between clopidogrel responders and nonresponders. The mean PRU across the study cohort was 173.8 ± 68.5 and 33.5% of patients were defined as clopidogrel resistant. Multivariate linear regression showed that 19% of PRU variability was attributed to nine independent predictors, with CYP2C19*2 (rs4244285) accounting for ~ 7% of observed PRU variation (p < 0.001). PON1 rs662, ABCB1/MDR1 rs2032582, PEAR1 rs12041331 carrier status, and the interaction between African ancestry and rs12041331 carriers also predicted PRU among the participants (p ≤ 0.05). A clear gene‐dose effect was detected between PRU and CYP2C19*2 genotype, consistent with previous studies in European patient populations, as well as rs12777823. Importantly, a significant positive correlation was detected between our novel wPGxRS (4 variants) and PRU among the Hispanic patient population (r (p) = 0.35, p < 0.001). Moreover, the wPGxRS discriminated between nonresponders and responders (p = 0.003), indicating that this multigene‐based score is a useful predictor of clopidogrel resistance among Caribbean Hispanics. Taken together, these results help close the gap of knowledge on clopidogrel pharmacogenomics and its potential clinical implementation in this under‐represented population. John Wiley and Sons Inc. 2021-08-20 2021-11 /pmc/articles/PMC8604227/ /pubmed/34415683 http://dx.doi.org/10.1111/cts.13124 Text en © 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Research
Duconge, Jorge
Santiago, Ednalise
Hernandez‐Suarez, Dagmar F.
Moneró, Mariangeli
López‐Reyes, Andrés
Rosario, Marines
Renta, Jessicca Y.
González, Pablo
Ileana Fernández‐Morales, Laura
Antonio Vélez‐Figueroa, Luis
Arce, Orlando
Marín‐Maldonado, Frances
Nuñez, Héctor
Melin, Kyle
Scott, Stuart A.
Ruaño, Gualberto
Pharmacogenomic polygenic risk score for clopidogrel responsiveness among Caribbean Hispanics: A candidate gene approach
title Pharmacogenomic polygenic risk score for clopidogrel responsiveness among Caribbean Hispanics: A candidate gene approach
title_full Pharmacogenomic polygenic risk score for clopidogrel responsiveness among Caribbean Hispanics: A candidate gene approach
title_fullStr Pharmacogenomic polygenic risk score for clopidogrel responsiveness among Caribbean Hispanics: A candidate gene approach
title_full_unstemmed Pharmacogenomic polygenic risk score for clopidogrel responsiveness among Caribbean Hispanics: A candidate gene approach
title_short Pharmacogenomic polygenic risk score for clopidogrel responsiveness among Caribbean Hispanics: A candidate gene approach
title_sort pharmacogenomic polygenic risk score for clopidogrel responsiveness among caribbean hispanics: a candidate gene approach
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8604227/
https://www.ncbi.nlm.nih.gov/pubmed/34415683
http://dx.doi.org/10.1111/cts.13124
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