Genetic variation in PEAR1 is associated with platelet aggregation and cardiovascular outcomes

Joshua P. Lewis, Kathleen Ryan, Jeffrey R. O'Connell, Richard B. Horenstein, Coleen M. Damcott, Quince Gibson, Toni I. Pollin, Braxton D. Mitchell, Amber L. Beitelshees, Ruth Pakzy, Keith Tanner, Afshin Parsa, Udaya S. Tantry, Kevin P. Bliden, Wendy S Post, Nauder Faraday, William Raymond Herzog, Yan Gong, Carl J. Pepine, Julie A. JohnsonPaul A. Gurbel, Alan R. Shuldiner

Research output: Contribution to journalArticle

Abstract

Background-Aspirin or dual antiplatelet therapy with aspirin and clopidogrel is a standard therapy for patients who are at increased risk for cardiovascular events. However, the genetic determinants of variable response to aspirin (alone and in combination with clopidogrel) are not known. Methods and Results-We measured ex vivo platelet aggregation before and after dual antiplatelet therapy in individuals (n=565) from the Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and conducted a genome-wide association study of drug response. Significant findings were extended by examining genotype and cardiovascular outcomes in 2 independent aspirin-treated cohorts: 227 percutaneous coronary intervention patients and 1000 patients of the International Verapamil SR/Trandolapril Study (INVEST) Genetic Substudy (INVEST-GENES). Results from the genome-wide association study revealed a strong association between single-nucleotide polymorphisms on chromosome 1q23 and post-dual antiplatelet therapy platelet aggregation. Further genotyping revealed rs12041331 in the platelet endothelial aggregation receptor-1 (PEAR1) gene to be most strongly associated with dual antiplatelet therapy response (P=7.66×10-9). In white and black patients undergoing percutaneous coronary intervention, A-allele carriers of rs12041331 were more likely to experience a cardiovascular event or death compared with GG homozygotes (hazard ratio, 2.62; 95% confidence interval, 0.96-7.10; P=0.059; and hazard ratio, 3.97; 95% confidence interval, 1.10-14.31; P=0.035, respectively). In aspirin-treated INVEST-GENES patients, rs12041331 A-allele carriers had significantly increased risk of myocardial infarction compared with GG homozygotes (odds ratio, 2.03; 95% confidence interval, 1.01-4.09; P=0.048). Conclusion-Common genetic variation in PEAR1 may be a determinant of platelet response and cardiovascular events in patients on aspirin alone or in combination with clopidogrel.

Original languageEnglish (US)
Pages (from-to)184-192
Number of pages9
JournalCirculation: Cardiovascular Genetics
Volume6
Issue number2
DOIs
StatePublished - Apr 2013

Fingerprint

clopidogrel
Platelet Aggregation
Aspirin
trandolapril
Genome-Wide Association Study
Homozygote
Confidence Intervals
Percutaneous Coronary Intervention
Verapamil
Blood Platelets
Alleles
Therapeutics
Pharmacogenetics
Single Nucleotide Polymorphism
Chromosomes
Odds Ratio
Myocardial Infarction
Genotype
Pharmaceutical Preparations
Genes

Keywords

  • CYP2C19
  • PEAR1
  • Percutaneous coronary intervention
  • Pharmacogenomics
  • Platelets

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)
  • Genetics

Cite this

Lewis, J. P., Ryan, K., O'Connell, J. R., Horenstein, R. B., Damcott, C. M., Gibson, Q., ... Shuldiner, A. R. (2013). Genetic variation in PEAR1 is associated with platelet aggregation and cardiovascular outcomes. Circulation: Cardiovascular Genetics, 6(2), 184-192. https://doi.org/10.1161/CIRCGENETICS.111.964627

Genetic variation in PEAR1 is associated with platelet aggregation and cardiovascular outcomes. / Lewis, Joshua P.; Ryan, Kathleen; O'Connell, Jeffrey R.; Horenstein, Richard B.; Damcott, Coleen M.; Gibson, Quince; Pollin, Toni I.; Mitchell, Braxton D.; Beitelshees, Amber L.; Pakzy, Ruth; Tanner, Keith; Parsa, Afshin; Tantry, Udaya S.; Bliden, Kevin P.; Post, Wendy S; Faraday, Nauder; Herzog, William Raymond; Gong, Yan; Pepine, Carl J.; Johnson, Julie A.; Gurbel, Paul A.; Shuldiner, Alan R.

In: Circulation: Cardiovascular Genetics, Vol. 6, No. 2, 04.2013, p. 184-192.

Research output: Contribution to journalArticle

Lewis, JP, Ryan, K, O'Connell, JR, Horenstein, RB, Damcott, CM, Gibson, Q, Pollin, TI, Mitchell, BD, Beitelshees, AL, Pakzy, R, Tanner, K, Parsa, A, Tantry, US, Bliden, KP, Post, WS, Faraday, N, Herzog, WR, Gong, Y, Pepine, CJ, Johnson, JA, Gurbel, PA & Shuldiner, AR 2013, 'Genetic variation in PEAR1 is associated with platelet aggregation and cardiovascular outcomes', Circulation: Cardiovascular Genetics, vol. 6, no. 2, pp. 184-192. https://doi.org/10.1161/CIRCGENETICS.111.964627
Lewis, Joshua P. ; Ryan, Kathleen ; O'Connell, Jeffrey R. ; Horenstein, Richard B. ; Damcott, Coleen M. ; Gibson, Quince ; Pollin, Toni I. ; Mitchell, Braxton D. ; Beitelshees, Amber L. ; Pakzy, Ruth ; Tanner, Keith ; Parsa, Afshin ; Tantry, Udaya S. ; Bliden, Kevin P. ; Post, Wendy S ; Faraday, Nauder ; Herzog, William Raymond ; Gong, Yan ; Pepine, Carl J. ; Johnson, Julie A. ; Gurbel, Paul A. ; Shuldiner, Alan R. / Genetic variation in PEAR1 is associated with platelet aggregation and cardiovascular outcomes. In: Circulation: Cardiovascular Genetics. 2013 ; Vol. 6, No. 2. pp. 184-192.
@article{57786995e34143ea8fcd0f098a8ac219,
title = "Genetic variation in PEAR1 is associated with platelet aggregation and cardiovascular outcomes",
abstract = "Background-Aspirin or dual antiplatelet therapy with aspirin and clopidogrel is a standard therapy for patients who are at increased risk for cardiovascular events. However, the genetic determinants of variable response to aspirin (alone and in combination with clopidogrel) are not known. Methods and Results-We measured ex vivo platelet aggregation before and after dual antiplatelet therapy in individuals (n=565) from the Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and conducted a genome-wide association study of drug response. Significant findings were extended by examining genotype and cardiovascular outcomes in 2 independent aspirin-treated cohorts: 227 percutaneous coronary intervention patients and 1000 patients of the International Verapamil SR/Trandolapril Study (INVEST) Genetic Substudy (INVEST-GENES). Results from the genome-wide association study revealed a strong association between single-nucleotide polymorphisms on chromosome 1q23 and post-dual antiplatelet therapy platelet aggregation. Further genotyping revealed rs12041331 in the platelet endothelial aggregation receptor-1 (PEAR1) gene to be most strongly associated with dual antiplatelet therapy response (P=7.66×10-9). In white and black patients undergoing percutaneous coronary intervention, A-allele carriers of rs12041331 were more likely to experience a cardiovascular event or death compared with GG homozygotes (hazard ratio, 2.62; 95{\%} confidence interval, 0.96-7.10; P=0.059; and hazard ratio, 3.97; 95{\%} confidence interval, 1.10-14.31; P=0.035, respectively). In aspirin-treated INVEST-GENES patients, rs12041331 A-allele carriers had significantly increased risk of myocardial infarction compared with GG homozygotes (odds ratio, 2.03; 95{\%} confidence interval, 1.01-4.09; P=0.048). Conclusion-Common genetic variation in PEAR1 may be a determinant of platelet response and cardiovascular events in patients on aspirin alone or in combination with clopidogrel.",
keywords = "CYP2C19, PEAR1, Percutaneous coronary intervention, Pharmacogenomics, Platelets",
author = "Lewis, {Joshua P.} and Kathleen Ryan and O'Connell, {Jeffrey R.} and Horenstein, {Richard B.} and Damcott, {Coleen M.} and Quince Gibson and Pollin, {Toni I.} and Mitchell, {Braxton D.} and Beitelshees, {Amber L.} and Ruth Pakzy and Keith Tanner and Afshin Parsa and Tantry, {Udaya S.} and Bliden, {Kevin P.} and Post, {Wendy S} and Nauder Faraday and Herzog, {William Raymond} and Yan Gong and Pepine, {Carl J.} and Johnson, {Julie A.} and Gurbel, {Paul A.} and Shuldiner, {Alan R.}",
year = "2013",
month = "4",
doi = "10.1161/CIRCGENETICS.111.964627",
language = "English (US)",
volume = "6",
pages = "184--192",
journal = "Circulation. Genomic and precision medicine",
issn = "1942-325X",
publisher = "Lippincott Williams and Wilkins Ltd.",
number = "2",

}

TY - JOUR

T1 - Genetic variation in PEAR1 is associated with platelet aggregation and cardiovascular outcomes

AU - Lewis, Joshua P.

AU - Ryan, Kathleen

AU - O'Connell, Jeffrey R.

AU - Horenstein, Richard B.

AU - Damcott, Coleen M.

AU - Gibson, Quince

AU - Pollin, Toni I.

AU - Mitchell, Braxton D.

AU - Beitelshees, Amber L.

AU - Pakzy, Ruth

AU - Tanner, Keith

AU - Parsa, Afshin

AU - Tantry, Udaya S.

AU - Bliden, Kevin P.

AU - Post, Wendy S

AU - Faraday, Nauder

AU - Herzog, William Raymond

AU - Gong, Yan

AU - Pepine, Carl J.

AU - Johnson, Julie A.

AU - Gurbel, Paul A.

AU - Shuldiner, Alan R.

PY - 2013/4

Y1 - 2013/4

N2 - Background-Aspirin or dual antiplatelet therapy with aspirin and clopidogrel is a standard therapy for patients who are at increased risk for cardiovascular events. However, the genetic determinants of variable response to aspirin (alone and in combination with clopidogrel) are not known. Methods and Results-We measured ex vivo platelet aggregation before and after dual antiplatelet therapy in individuals (n=565) from the Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and conducted a genome-wide association study of drug response. Significant findings were extended by examining genotype and cardiovascular outcomes in 2 independent aspirin-treated cohorts: 227 percutaneous coronary intervention patients and 1000 patients of the International Verapamil SR/Trandolapril Study (INVEST) Genetic Substudy (INVEST-GENES). Results from the genome-wide association study revealed a strong association between single-nucleotide polymorphisms on chromosome 1q23 and post-dual antiplatelet therapy platelet aggregation. Further genotyping revealed rs12041331 in the platelet endothelial aggregation receptor-1 (PEAR1) gene to be most strongly associated with dual antiplatelet therapy response (P=7.66×10-9). In white and black patients undergoing percutaneous coronary intervention, A-allele carriers of rs12041331 were more likely to experience a cardiovascular event or death compared with GG homozygotes (hazard ratio, 2.62; 95% confidence interval, 0.96-7.10; P=0.059; and hazard ratio, 3.97; 95% confidence interval, 1.10-14.31; P=0.035, respectively). In aspirin-treated INVEST-GENES patients, rs12041331 A-allele carriers had significantly increased risk of myocardial infarction compared with GG homozygotes (odds ratio, 2.03; 95% confidence interval, 1.01-4.09; P=0.048). Conclusion-Common genetic variation in PEAR1 may be a determinant of platelet response and cardiovascular events in patients on aspirin alone or in combination with clopidogrel.

AB - Background-Aspirin or dual antiplatelet therapy with aspirin and clopidogrel is a standard therapy for patients who are at increased risk for cardiovascular events. However, the genetic determinants of variable response to aspirin (alone and in combination with clopidogrel) are not known. Methods and Results-We measured ex vivo platelet aggregation before and after dual antiplatelet therapy in individuals (n=565) from the Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and conducted a genome-wide association study of drug response. Significant findings were extended by examining genotype and cardiovascular outcomes in 2 independent aspirin-treated cohorts: 227 percutaneous coronary intervention patients and 1000 patients of the International Verapamil SR/Trandolapril Study (INVEST) Genetic Substudy (INVEST-GENES). Results from the genome-wide association study revealed a strong association between single-nucleotide polymorphisms on chromosome 1q23 and post-dual antiplatelet therapy platelet aggregation. Further genotyping revealed rs12041331 in the platelet endothelial aggregation receptor-1 (PEAR1) gene to be most strongly associated with dual antiplatelet therapy response (P=7.66×10-9). In white and black patients undergoing percutaneous coronary intervention, A-allele carriers of rs12041331 were more likely to experience a cardiovascular event or death compared with GG homozygotes (hazard ratio, 2.62; 95% confidence interval, 0.96-7.10; P=0.059; and hazard ratio, 3.97; 95% confidence interval, 1.10-14.31; P=0.035, respectively). In aspirin-treated INVEST-GENES patients, rs12041331 A-allele carriers had significantly increased risk of myocardial infarction compared with GG homozygotes (odds ratio, 2.03; 95% confidence interval, 1.01-4.09; P=0.048). Conclusion-Common genetic variation in PEAR1 may be a determinant of platelet response and cardiovascular events in patients on aspirin alone or in combination with clopidogrel.

KW - CYP2C19

KW - PEAR1

KW - Percutaneous coronary intervention

KW - Pharmacogenomics

KW - Platelets

UR - http://www.scopus.com/inward/record.url?scp=84878084293&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84878084293&partnerID=8YFLogxK

U2 - 10.1161/CIRCGENETICS.111.964627

DO - 10.1161/CIRCGENETICS.111.964627

M3 - Article

C2 - 23392654

AN - SCOPUS:84878084293

VL - 6

SP - 184

EP - 192

JO - Circulation. Genomic and precision medicine

JF - Circulation. Genomic and precision medicine

SN - 1942-325X

IS - 2

ER -