1. Exome sequencing of extreme clopidogrel response phenotypes identifies B4GALT2 as a determinant of on-treatment platelet reactivity.
- Author
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Scott, SA, Collet, J‐P, Baber, U, Yang, Y, Peter, I, Linderman, M, Sload, J, Qiao, W, Kini, AS, Sharma, SK, Desnick, RJ, Fuster, V, Hajjar, RJ, Montalescot, G, and Hulot, J‐S
- Subjects
CLOPIDOGREL ,EXOMES ,NUCLEOTIDE sequencing ,CORONARY disease ,MEMBRANE glycoproteins ,PATIENTS - Abstract
Interindividual variability in platelet aggregation is common among patients treated with clopidogrel and both high on-treatment platelet reactivity (HTPR) and low on-treatment platelet reactivity (LTPR) increase risks for adverse clinical outcomes. CYP2C19 influences clopidogrel response but only accounts for ∼12% of the variability in platelet reactivity. To identify novel variants implicated in on-treatment platelet reactivity, patients with coronary artery disease (CAD) with extreme pharmacodynamic responses to clopidogrel and wild-type CYP2C19 were subjected to exome sequencing. Candidate variants that clustered in the LTPR subgroup subsequently were genotyped across the discovery cohort ( n = 636). Importantly, carriers of B4GALT2 c.909C>T had lower on-treatment P2Y12 reaction units (PRUs; P = 0.0077) and residual platelet aggregation ( P = 0.0008) compared with noncarriers, which remained significant after adjusting for CYP2C19 and other clinical variables in both the discovery ( P = 0.0298) and replication ( n = 160; PRU: P = 0.0001) cohorts. B4GALT2 is a platelet-expressed galactosyltransferase, indicating that B4GALT2 c.909C>T may influence clopidogrel sensitivity through atypical cell-surface glycoprotein processing and platelet adhesion. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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