Genetic Variation in PEAR1 Is Associated With Platelet Aggregation and Cardiovascular Outcomes

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 therapyplatelet 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. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00799396 and NCT00370045

[1]  A. Jaffe,et al.  A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines , 2015 .

[2]  A. Kauskot,et al.  A novel mechanism of sustained platelet αIIbβ3 activation via PEAR1. , 2012, Blood.

[3]  Andrew D. Johnson,et al.  Identification of a specific intronic PEAR1 gene variant associated with greater platelet aggregability and protein expression. , 2011, Blood.

[4]  E. Antman,et al.  Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. , 2010, JAMA.

[5]  Deepak L. Bhatt,et al.  Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. , 2010, Journal of the American College of Cardiology.

[6]  A. Feher,et al.  Clinical importance of aspirin and clopidogrel resistance. , 2010, World journal of cardiology.

[7]  G. Montalescot,et al.  Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele or proton pump inhibitor coadministration: a systematic meta-analysis. , 2010, Journal of the American College of Cardiology.

[8]  Andrew D. Johnson,et al.  Genome-wide meta-analyses identifies 7 loci associated with platelet aggregation in response to agonists , 2010, Nature genetics.

[9]  M. Gawaz,et al.  Platelet pharmacogenomics , 2010, Journal of thrombosis and haemostasis : JTH.

[10]  J. Ornato,et al.  2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST‐Elevation Myocardial Infarction (Updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (Updating the 2005 Guideline and 2007 Focused Update) , 2009, Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions.

[11]  M. Torres,et al.  Pharmacogenomics in aspirin intolerance. , 2009, Current drug metabolism.

[12]  J. O’Connell,et al.  Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. , 2009, JAMA.

[13]  E. Antman,et al.  Cytochrome p-450 polymorphisms and response to clopidogrel. , 2009, The New England journal of medicine.

[14]  A. Feher,et al.  The genetics of antiplatelet drug resistance , 2009, Clinical genetics.

[15]  W. Little,et al.  Incidence of coronary stent thrombosis based on academic research consortium definitions. , 2008, The American journal of cardiology.

[16]  A. F. Wilson,et al.  A Novel Variant in the Platelet Endothelial Aggregation Receptor-1 Gene Is Associated With Increased Platelet Aggregability , 2008, Arteriosclerosis, thrombosis, and vascular biology.

[17]  P. Morange,et al.  Effect of cytochrome p450 polymorphisms on platelet reactivity after treatment with clopidogrel in acute coronary syndrome. , 2008, The American journal of cardiology.

[18]  Jeffrey L. Anderson,et al.  2007 focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice guidelines. , 2008, Journal of the American College of Cardiology.

[19]  N. Schork,et al.  KCNMB1 genotype influences response to verapamil SR and adverse outcomes in the INternational VErapamil SR/Trandolapril STudy (INVEST) , 2007, Pharmacogenetics and genomics.

[20]  A. Bura,et al.  Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. , 2006, Blood.

[21]  Joseph P Ornato,et al.  ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention--summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to update the 2001 Guidelines for Percutaneous Coronary Intervention , 2006, Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions.

[22]  T. Quertermous,et al.  Platelet Endothelial Aggregation Receptor 1 (PEAR1), a Novel Epidermal Growth Factor Repeat-containing Transmembrane Receptor, Participates in Platelet Contact-induced Activation* , 2005, Journal of Biological Chemistry.

[23]  A. Sanabria,et al.  Randomized controlled trial. , 2005, World journal of surgery.

[24]  J. Eikelboom,et al.  Aspirin resistance: position paper of the Working Group on Aspirin Resistance , 2005, Journal of thrombosis and haemostasis : JTH.

[25]  M. Cattaneo.  Aspirin and Clopidogrel: Efficacy, Safety, and the Issue of Drug Resistance , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[26]  杨靓,et al.  Aspirin resistance , 2004 .

[27]  Carl J Pepine,et al.  A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial. , 2003, JAMA.

[28]  Kevin P. Bliden,et al.  Clopidogrel for Coronary Stenting Response Variability, Drug Resistance, and the Effect of Pretreatment Platelet Reactivity , 2003, Circulation.

[29]  A A Schäffer,et al.  Towards a complete North American Anabaptist genealogy: A systematic approach to merging partially overlapping genealogy resources. , 1999, American journal of medical genetics.

[30]  R. Agarwala,et al.  Software for constructing and verifying pedigrees within large genealogies and an application to the Old Order Amish of Lancaster County. , 1998, Genome research.

[31]  K. Bairy,et al.  Aspirin resistance. , 2007, Indian journal of physiology and pharmacology.

[32]  G. Lamas,et al.  ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction--executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1999 guidelines for the management of patients wi , 2004, Journal of the American College of Cardiology.