Genome-Wide Association of Platelet Phenotypes

描述（由申请人提供）： 活化血小板在动脉粥样硬化斑块上的聚集引发动脉系统血栓形成，导致缺血综合征。血小板在体内聚集的倾向通过多种体外测定来表征。我们和其他人已经证明，许多这些血小板功能测定在动脉粥样硬化风险增加的人群中具有中度至高度遗传性，支持遗传变异是动脉血栓形成倾向个体差异的基础的假设。低剂量阿司匹林（阿萨）对血小板的抑制作用也是一种遗传性状，遗传变异可能是阿萨反应性的部分原因。我们对来自500个早发冠心病两代家族（60%白色，40%非裔美国人）的2000名参与阿司匹林反应性遗传研究（GeneSTAR）和约翰霍普金斯兄弟姐妹和家族心脏研究的个体进行了广泛的天然血小板功能和低剂量阿萨（81 mg/天，持续14天）后的血小板功能特征分析。所有研究参与者都进行了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在“正常天然”条件下和低剂量阿萨后修饰血小板功能的基因。我们建议对来自血小板功能表型分析的GeneSTAR参与者的DNA样本进行高密度单核苷酸多态性（SNP）基因分型（550，000个SNP，使用Illumina HumanHap 550 BeadChip），以平均6 kb密度覆盖整个基因组。我们建议，以确定是否有任何基因组位点与定量血小板表型优先高遗传力，生物学利益，和/或连锁STR标记，使用基于家庭的关联分析，与联合建模的连锁和关联。最高优先级的表型包括胶原蛋白、二磷酸腺苷（ADP）、花生四烯酸（AA）和富血小板血浆（PRP）中肾上腺素诱导的聚集、AA诱导的ATP释放和前列腺素代谢物11脱氢血栓烷B2的尿水平。我们将在心脏研究数据库中检查我们与三种基线天然血小板表型（PRP中胶原蛋白、肾上腺素和ADP诱导的聚集）相关的发现。这项研究代表了第一个全基因组SNP关联研究的综合血小板功能，并应导致新的定制抗血小板治疗，以预防血管血栓形成。(End摘要）

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)