title: 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.
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Scott
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Faculty of Medicine, UMRS_1166 ICAN, Institute of Cardiometabolism and Nutrition, AP-HP, Pitié-Salpêtrière Hospital, Institute of Cardiology, Paris, France.
authors.forename: J-P
authors.initials: JP
authors.lastname: Collet
authors.affiliation: Zena and Michael A. Wiener Cardiovascular Institute and Marie-Josée and Henry R. Kravis Center for Cardiovascular Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: U
authors.initials: U
authors.lastname: Baber
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: I
authors.initials: I
authors.lastname: Peter
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Linderman
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Sload
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: W
authors.initials: W
authors.lastname: Qiao
authors.affiliation: Zena and Michael A. Wiener Cardiovascular Institute and Marie-Josée and Henry R. Kravis Center for Cardiovascular Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Kini
authors.affiliation: Zena and Michael A. Wiener Cardiovascular Institute and Marie-Josée and Henry R. Kravis Center for Cardiovascular Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Sharma
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Desnick
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: V
authors.initials: V
authors.lastname: Fuster
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Hajjar
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Faculty of Medicine, UMRS_1166 ICAN, Institute of Cardiometabolism and Nutrition, AP-HP, Pitié-Salpêtrière Hospital, Institute of Cardiology, Paris, France.
authors.forename: G
authors.initials: G
authors.lastname: Montalescot
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Faculty of Medicine, UMRS_1166 ICAN, Institute of Cardiometabolism and Nutrition, AP-HP, Pitié-Salpêtrière Hospital, Institute of Cardiology, Paris, France.|Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: J-S
authors.initials: JS
authors.lastname: Hulot
mesh_terms: D000328:Adult; D000368:Aged; D001241:Aspirin / Q000008:administration & dosage; D001792:Blood Platelets / Q000187:drug effects*; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000188:drug therapy; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D004359:Drug Therapy, Combination; D059472:Exome; D005260:Female; D005700:Galactosyltransferases / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D010865:Pilot Projects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; C000613740:B4GALT2 protein, human; D005700:Galactosyltransferases; D013988:Ticlopidine; D001241:Aspirin