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 and low (LTPR) on-treatment platelet reactivity 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, coronary artery disease (CAD) patients 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 (PRU; p=0.0077) and residual platelet aggregation (p=0.0008) compared to non-carriers, 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.

Effect of cilostazol on platelet reactivity among patients with peripheral artery disease on clopidogrel therapy

“…Unfortunately, up to 83% of patients treated with DAPT have high on-treatment platelet reactivity (HTPR) to clopidogrel, which is a risk factor for MACE [2]. This inter-individual variation in platelet reactivity has been associated with several clinical and genetic variables including body mass index, diabetes mellitus (DM), concomitant use of some drugs, smoking status and variant alleles in the ABCB1, P2RY12, PON1, CES1 and B4GALT2 genes [3–9]. Importantly, even though the effects of HTPR on clinical adverse outcomes have been extensively described in patients with coronary artery disease (CAD) undergoing percutaneous coronary interventions [10], the utility of HTPR in predicting MACE and guiding APT in PAD has been poorly explored.…”

Investigating Real-World Clopidogrel Pharmacogenetics in Stroke Using a Bioresource Linked to Electronic Medical Records

“…Finally, due to the limited sample size and limitations of the EMR data, we could not include all environmental or genetic factors that could influence clopidogrel response. [31][32][33] However, it is unlikely that these factors would be differently distributed between the CYP2C19 genotype groups, as there is no evidence linking CYP2C19 with any diseases or conditions independent of drug metabolism and response, and, thus, they are not likely to introduce bias to our analysis. 5 In conclusion, we have shown that using purely observational routinely collected healthcare data and record linkage methodology, it is possible to demonstrate the real-world impact of CYP2C19 genotype on clopidogrel efficacy.…”

A Multiplex Pharmacogenetics Assay using the MinION Nanopore Sequencing Device

“…Pharmacogenomics Implementation Consortium (CPIC) guidelines [13], as well as covering new 26 variants reported in recent publications [3][4][5][6]15] (Table 1). Use of a polymerase chain reaction (PCR) 27…”

“…Both CYP2C19 and CYP2C9 are 5 polymorphic genes with more than 30 known alleles [1]. Moreover, recent publications suggest that 6 other genes are also associated with variable drug response, including B4GALT2 [3] and ABCB1 [4,5] 7…”