Equilibrative nucleoside transporter 1 gene polymorphisms and clinical outcomes following acute coronary syndromes: findings from the PLATelet inhibition and patient Outcomes (PLATO) study

Abstract

In the PLATelet inhibition and patient Outcomes (PLATO) study, the P2Y₁₂ inhibitors ticagrelor and clopidogrel were compared in the treatment of acute coronary syndromes (ACS). Ticagrelor was shown to reduce occurrence of the primary end point – a composite of death from vascular causes, myocardial infarction, or stroke – compared to clopidogrel. Ticagrelor’s pleiotropic effects on reuptake of adenosine via inhibition of equilibrative nucleoside transporter 1 (ENT1) have been hypothesized to contribute to this. Several polymorphisms of ENT1 are known to exist. We explored the interaction between ENT1 polymorphisms and clinical outcomes in ACS patients participating in the PLATO genetic substudy. Using genotyping data obtained in a genome-wide association study, the gene region encoding ENT1 was assessed and 94 polymorphisms were identified. After quality control filtering, data from 9943 participants were included. Subjects were divided into discovery (phase 1, n = 3970) and replication (phase 2, n = 5973) cohorts. Cox-regression analysis of the relationship between variants and seven efficacy and safety outcomes was performed in discovery, replication, and combined cohorts. Treatment–marker interactions were also determined. Although 35 variants were found with associations to the investigated outcomes reaching p < 0.05 in the discovery cohort, only one of these was replicated in phase 2 of the analysis and also reached the predetermined level of statistical significance in the combined data, taking into account the number of tests performed: the rare polymorphism rs141034817, with a frequency of 0.2%, was significantly associated with bleeding. Thirty-three treatment–marker interactions were found with a significance level of p < 0.05 in phase 1, but none was replicated in phase 2. We found no significant interaction between ENT1 genotype and clinical outcomes in ACS patients treated with ticagrelor or clopidogrel, apart from the association between a rare polymorphism and bleeding that requires further study. If ticagrelor’s pleiotropic effects on adenosine uptake are clinically relevant, these do not appear to be significantly affected by variation in the ENT1 gene.

Keywords:

• Acute coronary syndrome
• adenosine
• equilibrative nucleoside transporter 1
• thrombosis
• ticagrelor

Acknowledgment

The authors are grateful to Ebba Bergman, PhD, Uppsala Clinical Research Centre, for publication management support.

Disclosure statement

WAEP: no relevant disclosures. NE: institutional research grants from AstraZeneca. RCB: scientific advisory board member for Ionis Pharmaceuticals, AstraZeneca; safety review committee member for Portola, Akcea Therapeutics, all are considered modest. DV: grants from AstraZeneca. AH: reports being an employee of AstraZeneca. SKJ: institutional research grant, honoraria and consultant/advisory board fee from AstraZeneca; institutional research grant and consultant/advisory board fee from Medtronic; institutional research grants and honoraria from The Medicines Company; consultant/advisory board fees from Janssen, Bayer. LW: institutional research grant, consulting fee, lecture fee, travel support from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb and Pfizer; institutional research grant, consulting fee, lecture fee, travel support, honoraria from GlaxoSmithKline; institutional research grant from Roche Diagnostics, Merck & Co; consulting fees from Abbott; holds two patents involving GDF-15 licensed to Roche Diagnostics (EP2047275B1 and US8951742B2). RFS: institutional research grants, consultancy fees, and honoraria from AstraZeneca; Institutional research grants and consultancy fees from PlaqueTec; consultancy fees from Bayer, Actelion, Avacta, Bristol-Myers Squibb/Pfizer, Novartis, The Medicines Company and Idorsia.

Additional information

Funding

The PLATO study was funded by AstraZeneca. Support for the analysis and interpretation of results and preparation of the manuscript was provided through funds to the Uppsala Clinical Research Center and Duke Clinical Research Institute as part of the Clinical Study Agreement.