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

Abstract 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...

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Autores principales:	Jorge Duconge, Ednalise Santiago, Dagmar F. Hernandez‐Suarez, Mariangeli Moneró, Andrés López‐Reyes, Marines Rosario, Jessicca Y. Renta, Pablo González, Laura Ileana Fernández‐Morales, Luis Antonio Vélez‐Figueroa, Orlando Arce, Frances Marín‐Maldonado, Héctor Nuñez, Kyle Melin, Stuart A. Scott, Gualberto Ruaño
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270
Acceso en línea:	https://doaj.org/article/be462ad7effa4eb8aab47ac60bdf0e94
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spelling	oai:doaj.org-article:be462ad7effa4eb8aab47ac60bdf0e942021-11-19T17:51:34ZPharmacogenomic polygenic risk score for clopidogrel responsiveness among Caribbean Hispanics: A candidate gene approach1752-80621752-805410.1111/cts.13124https://doaj.org/article/be462ad7effa4eb8aab47ac60bdf0e942021-11-01T00:00:00Zhttps://doi.org/10.1111/cts.13124https://doaj.org/toc/1752-8054https://doaj.org/toc/1752-8062Abstract 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 CYP2C192 (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 CYP2C192 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 (rp = 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.Jorge DucongeEdnalise SantiagoDagmar F. Hernandez‐SuarezMariangeli MoneróAndrés López‐ReyesMarines RosarioJessicca Y. RentaPablo GonzálezLaura Ileana Fernández‐MoralesLuis Antonio Vélez‐FigueroaOrlando ArceFrances Marín‐MaldonadoHéctor NuñezKyle MelinStuart A. ScottGualberto RuañoWileyarticleTherapeutics. PharmacologyRM1-950Public aspects of medicineRA1-1270ENClinical and Translational Science, Vol 14, Iss 6, Pp 2254-2266 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270
spellingShingle	Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270 Jorge Duconge Ednalise Santiago Dagmar F. Hernandez‐Suarez Mariangeli Moneró Andrés López‐Reyes Marines Rosario Jessicca Y. Renta Pablo González Laura Ileana Fernández‐Morales Luis Antonio Vélez‐Figueroa Orlando Arce Frances Marín‐Maldonado Héctor Nuñez Kyle Melin Stuart A. Scott Gualberto Ruaño Pharmacogenomic polygenic risk score for clopidogrel responsiveness among Caribbean Hispanics: A candidate gene approach
description	Abstract 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 CYP2C192 (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 CYP2C192 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 (rp = 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.
format	article
author	Jorge Duconge Ednalise Santiago Dagmar F. Hernandez‐Suarez Mariangeli Moneró Andrés López‐Reyes Marines Rosario Jessicca Y. Renta Pablo González Laura Ileana Fernández‐Morales Luis Antonio Vélez‐Figueroa Orlando Arce Frances Marín‐Maldonado Héctor Nuñez Kyle Melin Stuart A. Scott Gualberto Ruaño
author_facet	Jorge Duconge Ednalise Santiago Dagmar F. Hernandez‐Suarez Mariangeli Moneró Andrés López‐Reyes Marines Rosario Jessicca Y. Renta Pablo González Laura Ileana Fernández‐Morales Luis Antonio Vélez‐Figueroa Orlando Arce Frances Marín‐Maldonado Héctor Nuñez Kyle Melin Stuart A. Scott Gualberto Ruaño
author_sort	Jorge Duconge
title	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_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_sort	pharmacogenomic polygenic risk score for clopidogrel responsiveness among caribbean hispanics: a candidate gene approach
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/be462ad7effa4eb8aab47ac60bdf0e94
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Pharmacogenomic polygenic risk score for clopidogrel responsiveness among Caribbean Hispanics: A candidate gene approach

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