Pharmacogenetic association study on clopidogrel response in Puerto Rican Hispanics with cardiovascular disease: a novel characterization of a Caribbean population

Hernández-Suárez, Dagmar F.; Botton, Mariana Rodrigues; Scott, Stuart A.; Tomey, Matthew I.; García, Mario J.; Wiley, Jose; Villablanca, Pedro; Melin, Kyle; López‐Candales, Angel; Renta, Jessicca Y.; Duconge, Jorge

doi:10.2147/pgpm.s165805

Cited by 9 publications

(20 citation statements)

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“…In this trial, determinants of decreased antiplatelet drug effects will be investigated and an ethno-specific treatment algorithm for risk stratification (see Risk score calculation) will be generated and implemented by clinicians to tailor antiplatelet therapy in Caribbean Hispanics with CAD/ACS undergoing PCI on DAPT. The risk score was developed by extracting key clinical, genetics (ie, CYP2C19 *2 allele) and lifestyle indicators from our previous studies 10 11 as well as from those by others (ie, the POPular Risk Score) 12 on how critical factors influence ultimate outcomes in patients from a similar study cohort ( table 3 ). The latter report describes how points are given in the risk score computation, which will be used the same way in the proposed protocol.…”

Section: Discussionmentioning

confidence: 99%

“… § PON1 is a second gene of choice for risk score predictions in this protocol because this single PON1 polymorphism (p.Q192R) was found to be statistically associated with clopidogrel resistance in our study cohort. 10 …”

Section: Discussionmentioning

confidence: 99%

“… 22–24 Likewise, we anticipate a prevalence of HTPR and CYP2C19 LOF alleles combined of approximately 30%. 10 11 …”

Section: Methods and Analysismentioning

confidence: 99%

“…All calculations assumed that 30% of the subjects within the genotype-guided subcohort (n=75) will present high-risk scores and will be escalated to ticagrelor. 10 As presented in table 2 , the detectable OR estimates for pairwise tests varied, starting from 1.9 for comparing patients with therapy based on current guidelines versus low-risk patients maintained/de-escalated to clopidogrel, 2.5 for low-risk patients maintained/de-escalated to clopidogrel versus high-risk patients switched/escalated to ticagrelor and 2.4 for patients with therapy based on current guidelines versus high-risk patients switched/escalated to ticagrelor.…”

Section: Methods and Analysismentioning

confidence: 99%

“…If no hits of GWAS significance (p value ≤5•10 −8 ) are detected, this factor will be excluded from the risk score calculation.†P value of the association test. ‡Adjusted ORs by performing a stepwise logistic regression analysis 10. §PON1 is a second gene of choice for risk score predictions in this protocol because this single PON1 polymorphism (p.Q192R) was found to be statistically associated with clopidogrel resistance in our study cohort.10 DM2, type 2 diabetes mellitus; GWAS, genome-wide association study; Hct, hematocrit; HTPR, high on-treatment platelet reactivity; LVEF, left ventricular ejection fraction; N/A, not available; ORs, odds ratios as indicators of clinical effects; PFT, platelet function testing.…”

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confidence: 99%

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Implementing a pharmacogenetic-driven algorithm to guide dual antiplatelet therapy (DAPT) in Caribbean Hispanics: protocol for a non-randomised clinical trial

et al. 2020

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IntroductionMinority populations in the USA are disproportionately affected by cardiovascular conditions. Reduced responsiveness to clopidogrel among carriers of CYP2C19 variants has been reported in patients with either coronary artery disease (CAD) or acute coronary syndrome (ACS) after the percutaneous coronary intervention (PCI). Previous studies have evaluated CYP2C19 genotyping-guided antiplatelet therapy in selected populations; however, this has yet to be tested among Hispanics. Given the paucity of clinical research on CYP2C19 and antiplatelet clinical outcomes in Hispanics, our study will test the safety and efficacy of a genetic-driven treatment algorithm to guide dual antiplatelet therapy (DAPT) in Caribbean Hispanics.Methods and analysisThis is a multicentre, prospective, non-randomised clinical trial that proposes an assessment of pharmacogenomic-guided DAPT in post-PCI Caribbean Hispanic patients with ACS or CAD. We will recruit 250 patients to be compared with a matched non-concurrent cohort of 250 clopidogrel-treated patients (standard-of-care). Major adverse cardiovascular events (MACEs) such as all-cause death, myocardial infarction (MI), stroke, coronary revascularisation, stent thrombosis and bleedings over 6 months will be the study endpoints. Among the recruited, high-risk patients will be escalated to ticagrelor and low-risk patients will remain on clopidogrel. The primary objective is to determine whether genetic-guided therapy is superior to standard of care. The secondary objective will determine if clopidogrel treatment in low-risk patients is not associated with a higher rate of MACEs compared with escalated antiplatelet therapy in high-risk patients. Patients will be enrolled up to the group’s completion.Ethics and disseminationApproval was obtained from the Institutional Review Board of the University of Puerto Rico Medical Sciences Campus (protocol # A4070417). The study will be carried out in compliance with the Declaration of Helsinki and International Conference on Harmonization Good Clinical Practice Guidelines. Findings will be published in a peer-reviewed journal and controlled access to experimental data will be available.Trial registration numberNCT03419325; Pre-results.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“… 22–24 Likewise, we anticipate a prevalence of HTPR and CYP2C19 LOF alleles combined of approximately 30%. 10 11 …”

Section: Methods and Analysismentioning

confidence: 99%

Section: Methods and Analysismentioning

confidence: 99%

mentioning

confidence: 99%

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Implementing a pharmacogenetic-driven algorithm to guide dual antiplatelet therapy (DAPT) in Caribbean Hispanics: protocol for a non-randomised clinical trial

et al. 2020

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Pharmacogenomics in Latin American Populations

et al. 2019

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Discovery of Ancestry-specific Variants Associated with Clopidogrel Response among Caribbean Hispanics

Yang,

González,

Moneró

et al. 2023

Preprint

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BackgroundHigh on-treatment platelet reactivity (HTPR) with clopidogrel is predictive of ischemic events in adults with coronary artery disease. Despite strong data suggesting HTPR varies with ethnicity, including clinical and genetic variables, no genome-wide association study (GWAS) of clopidogrel response has been performed among Caribbean Hispanics. This study aimed to identify genetic predictors of HTPR in a cohort of Caribbean Hispanic cardiovascular patients from Puerto Rico.MethodsLocal Ancestry inference (LAI) and traditional GWASs were performed on a cohort of 511 clopidogrel-treated patients, stratified based on their P2Y12 reaction units (PRU) into responders and non-responders (HTPR).ResultsThe LAI GWAS identified variants within theCYP2C19region associated with HTPR, predominantly driven by individuals of European ancestry and absent in those with native ancestry. Incorporating local ancestry adjustment notably enhanced our ability to detect associations. While no loci reached traditional GWAS significance, three variants showed suggestive significance at chromosomes 3, 14 and 22 (OSBPL10rs1376606,DERL3rs5030613, andRGS6rs9323567). In addition, a variant in theUNC5Cgene on chromosome 4 was associated with an increased risk of HTPR. These findings were not identified in other cohorts, highlighting the unique genetic landscape of Caribbean Hispanics.ConclusionThis is the first GWAS of clopidogrel response in Hispanics, confirming the relevance of theCYP2C19cluster, particularly among those with European ancestry, and also identifying novel markers in a diverse patient population. Further studies are warranted to replicate our findings in other diverse cohorts and meta-analyses.

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Pharmacogenetic association study on clopidogrel response in Puerto Rican Hispanics with cardiovascular disease: a novel characterization of a Caribbean population

Cited by 9 publications

References 56 publications

Implementing a pharmacogenetic-driven algorithm to guide dual antiplatelet therapy (DAPT) in Caribbean Hispanics: protocol for a non-randomised clinical trial

Implementing a pharmacogenetic-driven algorithm to guide dual antiplatelet therapy (DAPT) in Caribbean Hispanics: protocol for a non-randomised clinical trial

Pharmacogenomics in Latin American Populations

Discovery of Ancestry-specific Variants Associated with Clopidogrel Response among Caribbean Hispanics

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