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...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2021-11-01
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| Series: | Clinical and Translational Science |
| Online Access: | https://doi.org/10.1111/cts.13124 |
| _version_ | 1819097553001512960 |
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| 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 |
| collection | DOAJ |
| 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 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 (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. |
| first_indexed | 2024-12-22T00:16:55Z |
| format | Article |
| id | doaj.art-be462ad7effa4eb8aab47ac60bdf0e94 |
| institution | Directory Open Access Journal |
| issn | 1752-8054 1752-8062 |
| language | English |
| last_indexed | 2024-12-22T00:16:55Z |
| publishDate | 2021-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Science |
| spelling | doaj.art-be462ad7effa4eb8aab47ac60bdf0e942022-12-21T18:45:17ZengWileyClinical and Translational Science1752-80541752-80622021-11-011462254226610.1111/cts.13124Pharmacogenomic polygenic risk score for clopidogrel responsiveness among Caribbean Hispanics: A candidate gene approachJorge Duconge0Ednalise Santiago1Dagmar F. Hernandez‐Suarez2Mariangeli Moneró3Andrés López‐Reyes4Marines Rosario5Jessicca Y. Renta6Pablo González7Laura Ileana Fernández‐Morales8Luis Antonio Vélez‐Figueroa9Orlando Arce10Frances Marín‐Maldonado11Héctor Nuñez12Kyle Melin13Stuart A. Scott14Gualberto Ruaño15Department of Pharmaceutical Sciences School of Pharmacy University of Puerto Rico ‐ Medical Sciences Campus San Juan, Puerto Rico USAResearch Centers in Minority Institutions (RCMI) Program Center for Collaborative Research in Health Disparities (CCRHD) Academic Affairs Deanship University of Puerto Rico ‐ Medical Sciences Campus San Juan, Puerto Rico USADivision of Cardiovascular Medicine School of Medicine University of Puerto Rico ‐ Medical Sciences Campus San Juan, Puerto Rico USADepartment of Pharmacology School of Medicine University of Puerto Rico ‐ Medical Sciences Campus San Juan, Puerto Rico USADepartment of Biology College of Natural Sciences University of Puerto Rico ‐ Rio Piedras Campus San Juan, Puerto Rico USADepartment of Biology College of Natural Sciences University of Puerto Rico ‐ Rio Piedras Campus San Juan, Puerto Rico USAResearch Centers in Minority Institutions (RCMI) Program Center for Collaborative Research in Health Disparities (CCRHD) Academic Affairs Deanship University of Puerto Rico ‐ Medical Sciences Campus San Juan, Puerto Rico USADepartment of Pharmacology School of Medicine University of Puerto Rico ‐ Medical Sciences Campus San Juan, Puerto Rico USASchool of Medicine Universidad Central del Caribe Bayamon, Puerto Rico USASchool of Medicine Universidad Central del Caribe Bayamon, Puerto Rico USASchool of Medicine Universidad Central del Caribe Bayamon, Puerto Rico USAResearch Centers in Minority Institutions (RCMI) Program Center for Collaborative Research in Health Disparities (CCRHD) Academic Affairs Deanship University of Puerto Rico ‐ Medical Sciences Campus San Juan, Puerto Rico USADivision of Cardiovascular Medicine School of Medicine University of Puerto Rico ‐ Medical Sciences Campus San Juan, Puerto Rico USADepartment of Pharmacy Practice School of Pharmacy University of Puerto Rico ‐ Medical Sciences Campus San Juan, Puerto Rico USADepartment of Pathology Stanford University Palo Alto California USAInstitute of Living at Hartford Hospital Hartford Connecticut USAAbstract 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 (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.https://doi.org/10.1111/cts.13124 |
| spellingShingle | 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 Clinical and Translational Science |
| 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 |
| url | https://doi.org/10.1111/cts.13124 |
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