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

Dagmar F Hernandez-Suarez,¹ Mariana R Botton,² Stuart A Scott,² Matthew I Tomey,³ Mario J Garcia,⁴ Jose Wiley,⁴ Pedro A Villablanca,⁵ Kyle Melin,⁶ Angel Lopez-Candales,⁷ Jessicca Y Renta,⁸ Jorge Duconge<sup>9

1</sup>Cardiovascular Medicine Division, Department of Medicine, University of Puerto Rico School of Medicine, San Juan, PR, USA; ²Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; ³Cardiovascular Medicine Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; ⁴Division of Cardiovascular Diseases, Department of Medicine, Montefiore Medical Center/Albert Einstein College of Medicine New York, NY, USA; ⁵Division of Cardiology, Department of Medicine, New York University Langone Medical Center, New York, NY, USA; ⁶Department of Pharmacy Practice, University of Puerto Rico Medical Sciences Campus, San Juan, PR, USA; ⁷Cardiovascular Medicine Division, Department of Medicine, University of Puerto Rico School of Medicine, San Juan, PR, USA; ⁸Department of Biochemistry, University of Puerto Rico Medical Sciences Campus, San Juan, PR, USA; ⁹Pharmaceutical Sciences Department, University of Puerto Rico Medical Sciences Campus, San Juan, PR, USA

Introduction: High on-treatment platelet reactivity (HTPR) to clopidogrel imparts an increased risk for ischemic events in adults with coronary artery disease. Platelet reactivity varies with ethnicity and is influenced by both clinical and genetic variables; however, no clopidogrel pharmacogenetic studies with Puerto Rican patients have been reported. Therefore, we sought to identify clinical and genetic determinants of on-treatment platelet reactivity in a cohort of Puerto Rican patients with cardiovascular disease.
Methods: We performed a retrospective study of 111 patients on 75 mg/day maintenance dose of clopidogrel. Patients were allocated into 2 groups: Group I, without HTPR; and Group II, with HTPR. Platelet function was measured ex vivo using the VerifyNow® P2Y12 assay and HTPR was defined as P2Y12 reaction units (PRU) ≥230. Genotyping testing was performed using Taqman® Genotyping Assays.
Results: The mean PRU across the cohort was 203±61 PRU (range 8–324), and 42 (38%) patients had HTPR. Multiple logistic regression showed that 27% of the total variation in PRU was explained by a history of diabetes mellitus, hematocrit, CYP2C19*2, and PON1 p.Q192R. Body mass index (odds ratio [OR]=1.15; 95% CI: 1.03–1.27), diabetes mellitus (OR=3.46; 95% CI: 1.05–11.43), hematocrit (OR=0.75; 95% CI: 0.65–0.87), and CYP2C19*2 (OR=4.44; 95% CI: 1.21–16.20) were the only independent predictors of HTPR.
Conclusion: Moreover, we propose a predictive model to determine PRU values as measured by VerifyNow P2Y12 assay for the Puerto Rican Hispanic population. This model has the potential to identify Hispanic patients at higher risk for adverse events on clopidogrel.

Keywords: clopidogrel, platelet reactivity, genotyping, Hispanics, Puerto Rico