Abstract 19040: Exome Sequencing of Extreme Phenotypes Identifies B4GALT2 as a Determinant of Clopidogrel Response Variability
There is wide interindividual variability in platelet aggregation in response to clopidogrel and high/low on-treatment platelet reactivity (HPR/LPR) is associated with more frequent adverse cardiovascular events. The CYP2C19*2 allele is the major genetic determinant of clopidogrel responsiveness but only accounts for ~12% of the variation thus urging for identification of additional variants. In a cohort of 636 coronary artery disease (CAD) patients, those with the most extreme pharmacodynamic response to clopidogrel were identified as LPR (P2Y12 reaction units (PRU)<50 and ADP-induced residual platelet aggregation (RPA)<5%) vs HPR (PRU>235 and RPA>60%). Four patients from each group with wild-type CYP2C19 (*1/*1) were subjected to exome sequencing (average 70X). Identified variants that clustered in the LPR or HPR groups (3 or 4 carriers vs. 0) were identified and the probabilities of observing the clustering of each variant according to reported European minor allele frequencies (MAF) were calculated. Forty-nine of the identified variants with the lowest probablilities (18 LPR, 31 HPR, p<0.001) were genotyped across the remaining 628 coronary patients, which identified a significant association between two B4GALT2 variants (c.909C>T; p.Ile303= and c.366G>C; p.Gln122His, D’=0.68, r2=0.30) and treatment response. Carriers of c.909C>T (MAF=0.102) had lower PRU (p=0.0077) and RPA (p=0.0008) compared to non-carriers, as did carriers of c.366G>C (MAF=0.070) with lower PRU (p=0.0211) and RPA (p=0.0046). Notably, these effects were independent of CYP2C19*2, suggesting an alternative biological pathway from clopidogrel metabolism. B4GALT2 is a platelet galactosyltransferase that catalyzes the biosynthesis of glycoconjugates and is involved in intercellular recognition and/or adhesion. Taken together, these data implicate B4GALT2 c.909C>T and c.366G>C as genetic determinants of clopidogrel sensitivity by directly influencing platelet aggregation. Their impact on clinical outcomes of CAD patients deserves further investigation.
Author Disclosures: S. Scott: None. J. Collet: None. I. Peter: None. Y. Yang: None. R. Hajjar: None. G. Montalescot: Employment; Modest; N/A. Research Grant; Modest; Abbott Vascular, Daiichi-Sankyo, Nanosperes, Stentys, INSERM, BMS, AstraZeneca, Biotronik, Eli Lilly, The Medicines Company, Medtronic, Menarini, Sanofi-Aventis, Pfizer, Accumetrics. Other Research Support; Modest; N/A. Speakers Bureau; Modest; N/A. Honoraria; Modest; N/A. Expert Witness; Modest; N/A. Ownership Interest; Modest; N/A. Consultant/Advisory Board; Modest; Bayer, Boehringer-Ingelheim, CFR, Europa, GLG, Iroko Cardio International, Lead-Up, LLC, Luminex, McKinsey, Remedica, Servier, TIMI Group, WebMD, Wolters, BMS, AstraZeneca, Biotronik, Eli Lilly. Other; Modest; N/A. Consultant/Advisory Board; Significant; The Medicines Company, Medtronic, Menarini, Sanofi-Aventis, Pfizer, Accumetrics. J. Hulot: Honoraria; Modest; Daiichi Sankyo.
- © 2014 by American Heart Association, Inc.