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 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.
authors: Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors: Joshua P
authors: JP
authors: Lewis
authors: Kathleen
authors: K
authors: Ryan
authors: Jeffrey R
authors: JR
authors: O'Connell
authors: Richard B
authors: RB
authors: Horenstein
authors: Coleen M
authors: CM
authors: Damcott
authors: Quince
authors: Q
authors: Gibson
authors: Toni I
authors: TI
authors: Pollin
authors: Braxton D
authors: BD
authors: Mitchell
authors: Amber L
authors: AL
authors: Beitelshees
authors: Ruth
authors: R
authors: Pakzy
authors: Keith
authors: K
authors: Tanner
authors: Afshin
authors: A
authors: Parsa
authors: Udaya S
authors: US
authors: Tantry
authors: Kevin P
authors: KP
authors: Bliden
authors: Wendy S
authors: WS
authors: Post
authors: Nauder
authors: N
authors: Faraday
authors: William
authors: W
authors: Herzog
authors: Yan
authors: Y
authors: Gong
authors: Carl J
authors: CJ
authors: Pepine
authors: Julie A
authors: JA
authors: Johnson
authors: Paul A
authors: PA
authors: Gurbel
authors: Alan R
authors: AR
authors: Shuldiner
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D002878:Chromosomes, Human, Pair 1; D000077144:Clopidogrel; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics*; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C502809:PEAR1 protein, human; D010975:Platelet Aggregation Inhibitors; D011956:Receptors, Cell Surface; D000077144:Clopidogrel; D013988:Ticlopidine
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