Genome-Wide Association of Platelet Phenotypes

描述(由申请人提供)： 活化的血小板聚集在动脉粥样硬化斑块上，引发动脉系统血栓，导致缺血综合征。血小板在体内聚集的倾向是通过各种体外试验来表征的。我们和其他人已经证明，这些血小板功能分析中的许多在动脉粥样硬化风险增加的人群中具有中等到高度的遗传性，支持了这样的假设，即遗传变异是动脉血栓形成倾向的个体差异的基础。小剂量阿司匹林(ASA)对血小板的抑制也是一种可遗传的特征，基因变异可能是对ASA反应的部分原因。我们在参加阿司匹林反应性遗传研究(GeneSTAR)和约翰霍普金斯兄弟和家庭心脏研究的500名两代早期冠状动脉疾病家庭(60%白人，40%非裔美国人)的2000人中广泛地表征了天然血小板功能和服用低剂量阿司匹林(每天81毫克，连续14天)后的血小板功能。所有研究参与者都接受了500个短串联重复序列(STR)基因组扫描。这项建议的总体目标是确定改变血小板功能的基因，无论是在正常的天然条件下，还是在低剂量阿司匹林之后。我们建议对GeneSTAR参与者的DNA样本进行平均6kb密度的高密度单核苷酸多态(SNP)基因分型(550,000个SNP，使用Illumina Human Hap550珠芯片)，覆盖整个基因组。我们建议使用基于家族的关联分析，结合关联和关联的联合建模，确定是否有任何基因组座位与数量的血小板表型相关，这些表型优先考虑的是高遗传性、生物学兴趣和/或与STR标记的连锁。最优先的表型包括胶原、二磷酸腺苷(ADP)、花生四烯酸(AA)和肾上腺素在富血小板血浆(PRP)中诱导的聚集，AA诱导的ATP释放，以及尿中前列腺素代谢产物11去氢血栓烷B2的水平。我们将在弗雷明翰心脏研究数据库中检验我们的发现与三种基线天然血小板表型(胶原、肾上腺素和ADP诱导的PRP聚集)的关系。这项研究代表了第一个全基因组范围的SNP与全面的血小板功能相关的研究，应该会导致新的量身定做的抗血小板疗法来预防血管血栓。(摘要结束)

DESCRIPTION (provided by applicant): Aggregation of activated platelets on atherosclerotic plaques initiates thromboses of the arterial system, resulting in ischemic syndromes. The propensity of platelets to aggregate in vivo is characterized by a variety of in vitro assays. We and others have demonstrated that many of these platelet function assays are moderately to highly heritable in populations at increased risk for atherosclerosis, supporting the hypothesis that genetic variations underlie individual variability in the tendency for arterial thrombosis. Inhibition of platelets by low dose aspirin (ASA) is also a heritable trait and genetic variations may be in part responsible for responsiveness to ASA. We have extensively characterized native platelet function and platelet function after low dose ASA (81 mg/day for 14 days) in 2000 individuals from 500 2-generational families with premature coronary artery disease (60% white, 40% African American) participating in the Genetic Study of Aspirin Responsiveness (GeneSTAR) and the Johns Hopkins Sibling and Family Heart Study. All study participants have had a 500 short tandem repeat (STR) genome scan. The overall goal of this proposal is to identify genes that modify the function of platelets, both under "normal native" conditions, and following low dose ASA. We propose to perform high density single nucleotide polymorphism (SNP) genotyping (550,000 SNPs, using the Illumina HumanHap550 BeadChip) covering the entire genome at an average 6kb density, on the DNA samples from the GeneSTAR participants phenotyped for platelet function. We propose to determine whether any genomic loci are associated with quantitative platelet phenotypes prioritized for high heritability, biological interest, and/or linkage to STR markers, using family based association analysis, with joint modeling of linkage and association. Phenotypes of highest priority include aggregation induced by collagen, adenosine diphosphate (ADP), arachidonic acid (AA), and epinephrine in platelet rich plasma (PRP), ATP release induced by AA, and urinary levels of the prostaglandin metabolite, 11 dehydrothromboxane B2. We will examine our findings in relation to three baseline native platelet phenotypes (collagen-, epinephrine-, and ADP-induced aggregation in PRP) in the Framingham Heart Study database. This study represents the first genome -wide SNP association study of comprehensive platelet function and should lead to novel tailored anti-platelet therapy for the prevention of vascular thromboses. (End of Abstract)