Exome sequencing of extreme clopidogrel response phenotypes identifies B4GALT2 as a determinant of on-treatment platelet reactivity

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.

FIGURE 1. Illustration of the extreme phenotype exome sequencing study design

CAD: coronary artery disease; DAPT: dual antiplatelet therapy; HTPR: high on-treatment platelet reactivity; LTA: light transmission aggregometry; LTPR: low on-treatment platelet reactivity; PCI: percutaneous coronary intervention; PRU: P2Y12 reaction units; RPA: residual platelet aggregation; VN-P2Y₁₂: VerifyNow™ P2Y₁₂.

FIGURE 2. On-treatment platelet reactivity based on B4GALT2 c.909C>T (rs1061781) carrier status [non-carriers versus carriers (hetero- or homozygous)]

Platelet reactivity was measured in the discovery cohort by both the (A) VN-P2Y₁₂ and (B) LTA assays. The VN-P2Y₁₂ and LTA results are reported as P2Y12 reaction units (PRU) values and residual platelet aggregation (RPA), respectively.