ABCC3 Polymorphisms and mRNA Expression Influence the Concentration of a Carboxylic Acid Metabolite in Patients on Clopidogrel and Aspirin Therapy

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Luchessi, Andre Ducati ; Concheiro, Marta ; Germano, Juliana de Freitas ; Silbiger, Vivian Nogueira ; Bortolin, Raul Hernandes ; Cruz, Angelines ; Quintela, Oscar ; Brion, Maria ; Carracedo, Angel ; Iniguez, Andres ; Bravo, Marisol ; Lopez-Rivadulla, Manuel ; Crespo Hirata, Rosario Dominguez ; Moraes Rego Sousa, Amanda Guerra ; Hirata, Mario Hiroyuki

• Document type: Journal article
• Source: BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY; v. 120, n. 5, p. 466-474, MAY 2017.
• Web of Science Citations: 1

Abstract

Acetylsalicylic acid (ASA) and clopidogrel combined therapy has been reported to be beneficial in patients with acute coronary syndrome (ACS). Antiplatelet drug resistance, especially to clopidogrel, is a multifactorial phenomenon that affects a large number of ACS patients. The genetic contribution to this drug response is not fully elucidated. We investigated the relationship of ABC-type efflux subfamily C member 3 (ABCC3) polymorphisms and mRNA expression with plasma concentrations of clopidogrel, salicylic acid (SA) and a carboxylic acid metabolite (CAM). Clopidogrel, CAM and SA plasma concentrations were measured simultaneously by liquid chromatography-tandem mass spectrometry (LCMS/MS) from 83 ACS patients undergoing percutaneous coronary intervention. ABCC3 (rs757421, rs733392 and rs739923) and CYP2C19{*}2 (rs4244285) polymorphisms as well as mRNA expression were evaluated. A positive correlation was found between CAM concentrations and ABCC3 mRNA expression (r = 0.494, p < 0.0001). Patients carrying genotype AA (rs757421 variant) had higher CAM concentrations and ABCC3 mRNA expression as compared to those of GG + GA carriers (p = 0.017). A multiple linear regression analysis revealed that ABCC3 mRNA expression (p = 0.017), rs757421 AA genotype (p = 0.001), blood collection time (p = 0.018) and clopidogrel dose (p = 0.001) contributed to the concentration of CAM. No associations were observed for the CYP2C19{*}2 polymorphism. These results suggest that up-regulation of ABCC3 mRNA expression leads to increased plasma CAM levels through MRP3-mediated cell efflux. The ABCC3 rs757421 polymorphism may contribute to gene expression. Therefore, ABCC3 may be a potential biomarker for the response to clopidogrel. (AU)

• FAPESP's process: 09/10862-4 - Analysis pharmacogenomics: coronary syndromes in patients who underwent double antiplatelet aggregation, with an indication for implantation of stent
• Grantee: Amanda Guerra de Moraes Rego Souza
• Support Opportunities: Regular Research Grants