权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Pharmacogenomics of Anti-platlet Intervention-2 (PAPI-2) Study

抗血小板干预 2 (PAPI-2) 研究的药物基因组学

基本信息

批准号：
8319064
负责人：
ALAN R. SHULDINER
金额：
$ 80.21万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-23 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8319064
关键词：
Accounting Address Affect African American Aftercare Age Algorithms Alleles Amish Architecture Aspirin Biology Blood Platelets Blood group antibody D CCL18 gene CYP2C19 gene Cardiac Cardiovascular system Cessation of life Clinical Clinical Trials Collaborations Coronary heart disease DNA DNA Resequencing Data Databases Deposition Dose Double-Blind Method Educational workshop Ethnic Origin Event Exons Family member Founder Generation Funding General Population Genes Genetic Genetic Variation Genomics Genotype Goals Health Health Care Costs Hemorrhage Hospitals Hour Individual Intervention Measures Medicine Morbidity - disease rate Mutation Myocardial Infarction Patients Pharmaceutical Economics Pharmacogenomics Phenotype Platelet aggregation Plavix Population Principal Investigator Procedures Randomized Randomized Clinical Trials Recruitment Activity Research Research Personnel Rest Sampling Science Secondary Prevention Secure Signal Transduction Single Nucleotide Polymorphism Solutions Staging Tail Testing Translations Validation Variant Work arm caucasian American clinical practice clinical research site clopidogrel cohort cost effective design evidence base exome follow-up genetic variant genome wide association study genome-wide high risk human CYP2C19 protein improved insight loss of function member mortality multidisciplinary novel prevent primary outcome prospective response secondary outcome sex standard of care symposium trait trial comparing

项目摘要

DESCRIPTION (provided by applicant): Anti-platelet therapy with clopidogrel (Plavix) and aspirin is the standard of care for secondary prevention of myocardial Infarction. Despite its widespread use, 4 - 32% of Individuals are not responsive to clopidogrel. This renewal application will build upon significant progress made during the initial funding period in which we completed the Amish Pharmacogenomics of Anti-platelet lnterventlon-1 (PAPI-1) Study. Through the first genome-wide association study (GWAS) of its kind, we found that the loss of function cytochrome P450 2C19*2 (CYP2C19*2) variant is a major determinant of clopidogrel response, accounting for 12% of the variation in response. In an Independent cohort, we found that ~30% of the general population harboring CYP2C19*2 have poorer platelet response to clopidogrel and are at a 2.4-fold higher risk of having an ischemic cardiac event or death. The overall goal of this renewal application is to continue to advance the science of anti-platelet pharmacogenomics and its clinical translation. We hypothesize (a) CYP2C19 genotype-directed anti-platelet therapy will be superior to standard of care therapy; and (b) the genetic architecture of clopidogrel response Includes common and rare variants in yet-to-be identified genes. We have amassed a team of multidisciplinary investigators and collaborators and will capitalize on synergies created by active participation in the Pharmacogenomics Research Network to address the following Specific Alms: (1) To conduct the PAPI-2 Study, a prospective multicenter randomized double-blind clinical trial comparing cardiovascular events using CYP2C19 genotype-directed versus standard of care anti-platelet therapy in over 2000 patients with coronary heart disease; (2) To identify common variants in novel genes and loci for clopidogrel response by performing a large GWAS as part of a new Clopidogrel Pharmacogenomics GWAS Consortium; and (3) To identify rare variants in genes previously not known to influence platelet function or clopidogrel response by performing genome-wide exon (exome) sequencing from the extremes of the distribution of clopidogrel response. RELEVANCE: The proposed randomized clinical trial will provide the evidence base for translation of genotype-directed anti-platelet therapy into clinical practice. The Identification of common and rare variants in novel genes for clopidogrel response will provide new insights into platelet biology and variation in anti-platelet therapy response, and potentially, new targets for more effective agents to prevent and treat CHD.

Please try later.