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

被引：119

作者：

Lewis, Joshua P. ^{[1
]}

Ryan, Kathleen ^{[1
]}

O'Connell, Jeffrey R. ^{[1
]}

Horenstein, Richard B. ^{[1
]}

Damcott, Coleen M. ^{[1
]}

Gibson, Quince ^{[1
]}

Pollin, Toni I. ^{[1
]}

Mitchell, Braxton D. ^{[1
]}

Beitelshees, Amber L. ^{[1
]}

Pakzy, Ruth ^{[1
]}

Tanner, Keith ^{[1
]}

Parsa, Afshin ^{[2
]}

Tantry, Udaya S. ^{[3
]}

Bliden, Kevin P. ^{[3
]}

Post, Wendy S. ^{[4
]}

Faraday, Nauder ^{[5
]}

Herzog, William ^{[3
,4
]}

Gong, Yan ^{[6
,7
]}

Pepine, Carl J. ^{[8
]}

Johnson, Julie A. ^{[6
,7
]}

Gurbel, Paul A. ^{[3
]}

Shuldiner, Alan R. ^{[1
,9
]}

机构：

[1] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA

[2] Univ Maryland, Sch Med, Div Nephrol, Baltimore, MD 21201 USA

[3] Sinai Hosp, Sinai Ctr Thrombosis Res, Baltimore, MD 21215 USA

[4] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA

[5] Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA

[6] Univ Florida, Coll Pharm, Dept Pharmacotherapy & Translat Res, Gainesville, FL USA

[7] Univ Florida, Coll Pharm, Ctr Pharmacogen, Gainesville, FL USA

[8] Univ Florida, Coll Med, Div Cardiovasc Med, Gainesville, FL USA

[9] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21218 USA

来源：

CIRCULATION-CARDIOVASCULAR GENETICS | 2013年 / 6卷 / 02期

基金：

美国国家卫生研究院;

关键词：

CYP2C19; PEAR1; percutaneous coronary intervention; pharmacogenomics; platelets; 2007 FOCUSED UPDATE; DRUG-RESISTANCE; ASPIRIN RESISTANCE; CLOPIDOGREL; REACTIVITY; GENOTYPE; PHARMACOGENOMICS; POLYMORPHISMS; AGGREGABILITY; METAANALYSIS;

D O I：

10.1161/CIRCGENETICS.111.964627

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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=7.66x10(-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.

引用

页码：184 / +

页数：22

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